EA047335B1 - ANTIBODY MOLECULES TO CD73 AND THEIR APPLICATIONS - Google Patents

Abstract

The invention relates to antibody molecules that bind to human CD73. Also disclosed are a combination of said antibody molecules to CD73, a pharmaceutical composition comprising said antibody molecule, nucleic acids encoding the variable regions of said antibody molecules, a vector, a host cell, a method for producing an antibody molecule that binds to human CD73, the use of an antibody molecule or pharmaceutical composition for the production of a medicament for stimulating an immune response in a subject or for the production of a medicament for the treatment of cancer in a subject, as well as a method for detecting CD73 in a biological sample or in a subject.

Description

This application contains a sequence listing that was filed electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy in question, created on June 15, 2018, is named N2067-7123WO_SL.txt and is 497959 bytes in size.

State of the art

Cluster of differentiation 73 (CD73), also known as ecto-5'-nucleotidase (ecto-5'NT), is a glycosyl-phosphatidylinositol (GPI)-linked cell surface enzyme present in most tissues and particularly expressed in endothelial cells. cells and subsets of hematopoietic cells (Resta et al., Immunol Rev161:95-109 (1998) and Colgan et al., Prinergic Signal 2:351-60 (2006)). CD73 catalyzes the conversion of adenosine monophosphate (AMP) to adenosine. Adenosine is a signaling molecule that mediates its biological effects through several receptors, including adenosine A1, A2A, A2B, and A3 receptors. The A2A receptor has received particular attention due to its widespread expression on immune cells. Adenosine is characterized by pleiotropic effects in the tumor microenvironment, including expansion of regulatory T cells (Tregs), inhibition of interferon (ZFN)-y-mediated effector T cell (Teff) responses, and expansion of myeloid-derived suppressor cells (MDSCs). See, for example, Allard B, et al., Curr Opin Pharmacol 29:7-16 (2016) and Allard D, et al., Immunotherapy 8:145-163 (2016).

CD73 is also expressed on cancer cells, including colon, lung, pancreatic, ovarian, bladder, leukemia, glioma, glioblastoma, melanoma, thyroid, esophageal, prostate and breast cancers (Jin et al ., Cancer Res 70:224555 (2010) and Stagg et al., PNAS 107: 1547-52 (2010); Zhang et al., Cancer Res 70:6407-11 (2010)). High levels of CD73 expression have been reported to correlate with poor outcome in various cancers, such as lung cancer, melanoma, triple-negative breast cancer, head and neck squamous cell carcinoma, and colorectal cancer. See, for example, Allard B, et al., Expert Opin Ther Targets 18:863-881 (2014); Leclerc BG, et al., Clin Cancer Res 22:158–166 (2016); Ren ZH, et al., Oncotarget 7:61690–61702 (2016); Ren ZH, et al., Oncol Lett 12:556-562 (2016); and Turcotte M, et al., Cancer Res 75:44944503 (2015).

Given the ongoing need for improved strategies for targeting diseases such as cancer, new compositions and methods for regulating CD73 activity and related therapeutic agents are highly desirable.

Short description

Disclosed herein are antibody molecules that bind to CD73 (cluster of differentiation 73) with high affinity and specificity. Also provided are nucleic acid molecules encoding antibody molecules, expression vectors, host cells, and methods for producing antibody molecules. Also provided are immunoconjugates, multi- or bispecific antibody molecules, and pharmaceutical compositions containing antibody molecules. The anti-CD73 antibody molecules disclosed herein can be used (alone or in combination with other agents or therapeutic modalities) for the treatment, prevention and/or diagnosis of disorders, including immunological disorders and cancer. Thus, compositions and methods of treating and/or diagnosing various disorders, including cancer and immunological disorders, using anti-CD73 antibody molecules are disclosed herein.

Accordingly, in certain aspects, the present invention provides an antibody molecule (e.g., an isolated or recombinant antibody molecule) characterized by one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more, for example all) of the following properties:

(i) binds to CD73, e.g. human CD73, with high affinity, e.g., with a dissociation constant (KD) of less than about 100 nM, e.g., less than about 10 nM, 1 nM, 0.1 nM, or 0.01 nM , for example, when studying an antibody molecule in the form of a bivalent antibody molecule using the Octet system;

(ii) binds to soluble human CD73 or membrane-bound human CD73 or both;

(iii) binds substantially to CD73 of non-human primates, e.g., CD73 of the cynomolgus monkey, with a dissociation constant (KD) of less than about 100 nM, e.g., less than about 10 nM, 1 nM, 0.1 nM, or 0. 01 nM, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using the Octet system;

(iv) does not bind to mouse CD73, for example, when determined using the Octet system, for example, as described in example 1;

- 1 047335 (v) inhibits or reduces the enzymatic activity of CD73 (for example, soluble human CD73 or membrane-bound human CD73), for example inhibits human CD73-mediated conversion of adenosine monophosphate (AMP) to adenosine or reduces its level, which for example is measured using the method described herein, for example, by testing the antibody molecule as a bivalent antibody using phosphate quantitation using a malachite green (MG) reaction or using a modified Cell Titer Glo (CTG) assay, for example, as described in Example 1;

(vi) increases the level of proliferation of anti-CD3 antibody/anti-CD28 antibody-stimulated T cells, e.g., CD4+ T cells, in the presence of adenosine monophosphate (AMP), as measured, for example, by a method described herein, e.g., by examining an antibody molecule as a bivalent antibody in the CellTrace Violet (CTV) cell proliferation assay, for example, as described in Example 1;

(vii) increases the level of human CD73 internalization into the cell upon binding to human CD73 expressed on the cell surface, e.g. increases the level of human CD73 internalization into the cell by at least 1.2-fold, 1.3-fold, 1.4-fold, 1. 5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times , 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times or 100 times.

(viii) binds to an epitope on CD73, for example the same or similar epitope as the epitope recognized by an antibody molecule described herein, for example an anti-human CD73 antibody molecule described herein, for example an antibody molecule from table. 1;

(ix) binds to the same (or substantially the same) epitope or an epitope overlapping (or substantially overlapping) with an epitope of a second anti-CD73 antibody molecule, wherein the second antibody molecule is an antibody molecule described herein, e.g. , shown in table. 1;

(x) inhibits, for example, competitively inhibits, the binding of a second anti-CD73 antibody molecule, where the second antibody molecule is an antibody molecule described herein, for example, the antibody molecule shown in table. 1;

(xi) has the same or similar binding affinity or specificity, or both, as the antibody molecule described in Table 1, for example, an antibody molecule containing a heavy chain variable region and a light chain variable region shown in Table 1. 1;

(xii) binds to the N-terminal domain of human CD73;

(xiii) binds to the A-loop and/or B-loop of human CD73;

(xiv) reduces the level of hydrogen-deuterium exchange at one or more regions of a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), upon binding wherein one or more regions are selected from the group consisting of residues 158-172, residues 206215, residues 368-387, and residues 87-104 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using mass spectrometry of hydrogen-deuterium exchange;

(xv) upon binding to a protein containing the amino acid sequence of residues 27547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), causes a conformational change of residues 368-387 of SEQ ID NO: 105 ;

(xvi) interacts, for example directly or indirectly, with at least one, two, three or four residues within residues 158-172 of SEQ ID NO: 105;

(xvii) interacts, for example directly or indirectly, with at least one, two, three, four or five residues within residues 206-215 of SEQ ID NO: 105;

(xviii) interacts, for example directly or indirectly, with at least one, two, three, four or five residues within residues 368-387 of SEQ ID NO: 105 or 106;

(xix) interacts, for example directly or indirectly, with at least one, two, three, four or five residues within residues 87-104 of SEQ ID NO: 105;

(xx) binds to a human CD73 dimer, wherein the dimer consists of a first CD73 monomer and a second CD73 monomer, wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second antigen binding domain binds with a second CD73 monomer, for example, in a study using size exclusion chromatography;

(xxi) preferentially binds to CD73 in an open conformation, for example in a catalytically inactive conformation, rather than to CD73 in a closed conformation, for example in a catalytically active conformation, for example does not bind or binds to CD73 in a closed conformation, for example CD73 in a catalytically active conformation, with a lower affinity, for example with an affinity that is 50%, 60%, 70%, 80%, 90%, 95%, or 99% lower than when the antibody molecule binds to CD73 in an open conformation, for example a catalytically inactive conformation;

(xxii) blocks human CD73 in a catalytically inactive open conformation;

- 2 047335 (xxiii) prevents or reduces the level of conversion of human CD73 from a catalytically inactive open conformation to a catalytically active closed conformation, for example reduces the level of conversion by at least 1.5 times, 2 times, 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times or 100 times;

(xxiv) characterized by one or more biological properties of an antibody molecule described herein, such as the antibody molecule shown in Table 1;

(xxv) characterized by one or more pharmacokinetic properties of an antibody molecule described herein, for example the antibody molecule shown in Table 1;

(xxvi) modulates (eg, inhibits) one or more activities of CD73, eg, leads to one or more of the following: inhibition or reduction of CD73 enzymatic activity; inhibiting the conversion of adenosine monophosphate (AMP) to adenosine or reducing its level; increasing the level of proliferation of anti-CD3/anti-CD28-stimulated T cells, such as CD4+ T cells, in the presence of adenosine monophosphate (AMP); inhibition of proliferation of regulatory T cells; increased levels of effector T cell responses; and/or inhibition of migration, infiltration or proliferation of myeloid-derived suppressor cells.

In one aspect, this document discloses an antibody molecule that binds to a human CD73 dimer, wherein the dimer consists of a first CD73 monomer and a second CD73 monomer, wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second antigen binding domain binds to the second CD73 monomer, for example, in a size exclusion chromatography assay. In one embodiment, the first or second CD73 monomer comprises the amino acid sequence of residues 27-547 of SEQ ID NO: 105. In one embodiment, the first or second CD73 monomer consists of the amino acid sequence of SEQ ID NO: 171.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30%, 35% or 40% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, wherein each of the complexes consists of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of molecules antibodies in the complex relative to the total number of antibody molecules that bind to CD73 (excluding unbound antibody molecules), for example, as described in Example 2. In one embodiment, disclosed herein is a composition containing multiple antibody molecules that bind to a human CD73 dimer wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein where each of multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30%, 35% or 40% of the antibody molecules in the composition bind to the CD73 dimer to form a complex where each of these complexes consists of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography (SEC), involving the following steps:

(i) incubating a sample containing an equimolar amount of the bivalent antibody molecule and CD73 monomer overnight at 4°C;

(ii) passing the sample through a SEC column (eg Shodex Protein KW-803 column (ID 8x300 mm)) at room temperature in a buffer containing 90% 2x PBS and 10% isopropanol by volume; and (iii) analysis of SEC peaks to obtain relative percentages of distinguishable CD73 antibody species by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules).

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 70%, 75% or 80% of the antibody molecules in the specified composition bind

- 3 047335 with a CD73 dimer to form a complex, wherein each of said complexes consists of one antibody molecule and one CD73 dimer, for example when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number antibody molecules that bind to CD73 (excluding unbound antibody molecules), for example, as described in Example 2. In one embodiment, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first monomer CD73 and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consisting of the amino acid sequence of SEQ ID NO: 171), wherein each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 70%, 75% or 80% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, wherein each of the complexes consists of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography (SEC), involving the following steps:

(i) incubating a sample containing an equimolar amount of the bivalent antibody molecule and CD73 monomer overnight at 4°C;

(ii) passing the sample through a SEC column (eg Shodex Protein KW-803 column (ID 8x300 mm)) at room temperature in a buffer containing 90% 2x PBS and 10% isopropanol by volume; and (iii) analysis of SEC peaks to obtain relative percentages of distinguishable CD73 antibody species by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules).

In one aspect, this document discloses multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (eg , each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 60%, 65% or 70 % of the antibody molecules in the composition bind to a CD73 dimer to form a complex, wherein each of the complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in complex with respect to the total number of antibody molecules that bind to CD73 (excluding unbound antibody molecules), for example, as described in Example 2. In one embodiment, multiple antibody molecules are disclosed herein that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if each of several antibody molecules contains the same first antigen-binding domain and the same second antigen-binding domain, no more than 60%, 65% or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography (SEC), involving the following steps:

(i) incubating a sample containing an equimolar amount of the bivalent antibody molecule and CD73 monomer overnight at 4°C;

(ii) passing the sample through a SEC column (eg Shodex Protein KW-803 column (ID 8x300 mm)) at room temperature in a buffer containing 90% 2x PBS and 10% isopropanol by volume; and (iii) analysis of SEC peaks to obtain relative percentages of distinguishable CD73 antibody species by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules).

In one aspect, this document discloses multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (eg , each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25% or 30 % of the antibody molecules in the composition bind to a CD73 dimer to form a complex, wherein each of the complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage

- 4 047335 is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in Example 2. In one embodiment, multiple antibody molecules are disclosed herein that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 105). 171), wherein each of several antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, no more than 20%, 25% or 30% of the antibody molecules in the composition bind to the CD73 dimer to form complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography (SEC), comprising the following steps:

(i) incubating a sample containing an equimolar amount of the bivalent antibody molecule and CD73 monomer overnight at 4°C;

(ii) passing the sample through a SEC column (eg Shodex Protein KW-803 column (ID 8x300 mm)) at room temperature in a buffer containing 90% 2x PBS and 10% isopropanol by volume; and (iii) analysis of SEC peaks to obtain relative percentages of distinguishable CD73 antibody species by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules).

In one aspect, disclosed herein is an antibody molecule that binds human CD73, wherein the antibody molecule preferably binds CD73 in an open conformation, such as a catalytically inactive conformation, rather than CD73 in a closed conformation, such as a catalytically active conformation, such as does not bind at all. or binds to CD73 in a closed conformation, for example CD73 in a catalytically active conformation, with a lower affinity, for example with an affinity that is 50%, 60%, 70%, 80%, 90%, 95%, or 99% lower, than when the antibody molecule binds to CD73 in an open conformation, such as a catalytically inactive conformation.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule prevents or reduces the level of conversion of human CD73 from a catalytically inactive open conformation to a catalytically active closed conformation, e.g., reduces the level of conversion by at least 1.5-fold , 2 times, 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times or 100 times compared to the conversion rate in the absence of the antibody molecule.

In one aspect, this document discloses an antibody molecule that binds to human CD73, wherein the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), when linked, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87-104 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (eg pH 7.5) and room temperature.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange at the residue(s) XC selected from the core region C (residues 368-387 from SEQ ID NO: 105), to a greater extent than at the residue(s) X _A , selected from core region A (residues 158-172 of SEQ ID NO: 105), residue(s) X _B selected from core region B (residues 206-215 of SEQ ID NO: 105), or residue(s) ) XD selected from the core region D (residues 297-309 of SEQ ID NO: 105), for example, when studying the antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example mass spectrometry hydrogen-deuterium exchange, carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature, while

X _C equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20,

Xa equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14,

X _B equals 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and

XD equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13.

In one embodiment, the antibody molecule, upon binding to a protein containing amino

- 5 047335 acidic sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171) provides a decrease in the average level of hydrogen-deuterium exchange over 20 residues selected from the core region C , to a greater extent than by (i) 14 residues selected from core region A, (ii) 10 residues selected from core region B, or (iii) 13 residues selected from core region D, for example, in the study of an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7, 5) and room temperature. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region C to be reduced to a greater extent than in core region A. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange to be reduced in core region C to a greater extent than that of core region A. than in core region B. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region C to a greater extent than in core region D. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region region C to a greater extent than in core region A and core region B. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange in core region C to a greater extent than in core region A and core region D. In one In an embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region C to be reduced to a greater extent than in core region B and core region D. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region C to be reduced to a greater extent than in core region B and core region D. degree than in crustal region A, crustal region B and crustal region D.

In one embodiment, the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange 15 residues selected from core region C to a greater extent than (i) 10 residues selected from core region A, (ii) 8 residues selected from core region B, or (iii) 10 residues selected from core region region D, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region C to be reduced to a greater extent than in core region A. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange to be reduced in core region C to a greater extent than that of core region A. than in core region B. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region C to a greater extent than in core region D. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region region C to a greater extent than in core region A and core region B. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange in core region C to a greater extent than in core region A and core region D. In one In an embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange in core region C to a greater extent than in core region B and core region D. In one embodiment, binding of an antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region C to a greater extent than in core region B and core region D. degree than in crustal region A, crustal region B and crustal region D.

In one embodiment, the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange 10 residues selected from core region C to a greater extent than (i) 7 residues selected from core region A, (ii) 5 residues selected from core region B, or (iii) 7 residues selected from core region region D, for example, when studying an antibody molecule in the form of a bivalent antibody molecule with approx.

- 6 047335 without hydrogen-deuterium exchange mass spectrometry, for example as described in example 2, for example hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region C to be reduced to a greater extent than in core region A. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange to be reduced in core region C to a greater extent than that of core region A. than in core region B. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region C to a greater extent than in core region D. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region region C to a greater extent than in core region A and core region B. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange in core region C to a greater extent than in core region A and core region D. In one In an embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region C to be reduced to a greater extent than in core region B and core region D. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region C to be reduced to a greater extent than in core region B and core region D. degree than in crustal region A, crustal region B and crustal region D.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange at residues 368-387 from SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215 or residues 297-309 from SEQ ID NO: 105 , for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7- 8 (for example, pH 7.5) and room temperature. In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158172 of SEQ ID NO: 105 and at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than at residues 158-172 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105. NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange at residues 368- 387 of SEQ ID NO: 105 to a greater extent than residues 158-172 of SEQ ID NO: 105, residues 206-215 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange at the residue(s) X _A selected from the core region A (residues 158-172 from SEQ ID NO: 105), to a greater extent than at the residue(s) X _B selected from core region B (residues 206-215 of SEQ ID NO: 105), XC residue(s) selected from core region C (residues 368-387 of SEQ ID NO: 105), or residue(s) ) X _D selected from the core region D (residues 297-309 of SEQ ID NO: 105), for example, when studying the antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example hydrogen-deuterium exchange mass spectrometry, carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature, while:

Xa equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14,

X _B equals 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10,

X _C equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20, and

X _D equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13.

- 7 047335

In one embodiment, the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange 14 residues selected from core region A more than (i) 10 residues selected from core region B, (ii) 20 residues selected from core region C, or (iii) 13 residues selected from core region region D, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region A to decrease to a greater extent than in core region B. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange to decrease in core region A to a greater extent than that of core region A. than in core region C. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region A to a greater extent than in core region D. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region region A to a greater extent than in core region B and core region C. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange in core region A to a greater extent than in core region B and core region D. In one In an embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region A to be reduced to a greater extent than in core region C and core region D. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region A to be reduced to a greater extent than in core region A and core region D. degree than in crustal region B, crustal region C and crustal region D.

In one embodiment, the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange 10 residues selected from core region A more than (i) 8 residues selected from core region B, (ii) 15 residues selected from core region C, or (iii) 10 residues selected from core region region D, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region A to decrease to a greater extent than in core region B. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange to decrease in core region A to a greater extent than that of core region A. than in core region C. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region A to be reduced to a greater extent than in core region D. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region A to be reduced to a greater extent than in core region D. degree than in core region B and core region C. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region A to a greater extent than in core region B and core region D. In one embodiment, binding of the antibody provides a decrease in the average level of hydrogen-deuterium exchange in core region A to a greater extent than in core region C and core region D. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange in core region A to a greater extent than in core region A. cortical area B, cortical area C and cortical area D.

In one embodiment, the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange 7 residues selected from core region A more than (i) 5 residues selected from core region B, (ii) 10 residues selected from core region C, or (iii) 7 residues selected from core region region D, for example, when studying an antibody molecule in the form of a bivalent antibody molecule with approx.

- 8 047335 without hydrogen-deuterium exchange mass spectrometry, for example as described in example 2, for example hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region A to decrease to a greater extent than in core region B. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange to decrease in core region A to a greater extent than that of core region A. than in core region C. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region A to a greater extent than in core region D. In one embodiment, binding of the antibody causes a decrease in the average level of hydrogen-deuterium exchange in core region region A to a greater extent than in core region B and core region C. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange in core region A to a greater extent than in core region B and core region D. In one In an embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region A to be reduced to a greater extent than in core region C and core region D. In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange in core region A to be reduced to a greater extent than in core region A and core region D. degree than in crustal region B, crustal region C and crustal region D.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange for residues 158-172 from SEQ ID NO: 105 to a greater extent than for residues 206-215 from SEQ ID NO: 105, for residues 368-387 from SEQ ID NO : 105 or at residues 297-309 of SEQ ID NO: 105, for example, when studying the antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature. In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105. 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 368-387 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a decrease in the average level of hydrogen deuterium exchange for residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 206-215 of SEQ ID NO: 105, for residues 368-387 of SEQ ID NO: 105, and for residues 297-309 of SEQ ID NO: 105.

In one aspect, this document discloses an antibody molecule that binds to human CD73, wherein the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), when linked, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87-104 of SEQ ID NO: 105, wherein the region having the greatest decrease in the average hydrogen-deuterium exchange rate among one or more regions is not residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example as described in Example 2, for example hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), leads to a decrease in the average level of hydrogen-deuterium vol.

- 9,047,335 exchanges of more than, for example, 0.02, 0.03, 0.04, 0.05 or 0.06 Da per residue, for residues 368,387 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7, 5) and room temperature.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7 -8 (for example, pH 7.5) and room temperature.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule interacts, for example, directly or indirectly, with at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105 In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule interacts, for example, directly or indirectly, with at least one, two, three, four or five residues within residues 206-215 of SEQ ID. NO: 105. In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule interacts, for example, directly or indirectly, with at least one, two, three, four or five residues within residues 368-387 from SEQ ID NO: 105 or 106. In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule interacts, for example, directly or indirectly, with at least one, two, three, four or five residues in within residues 87-104 of SEQ ID NO: 105.

In one embodiment, the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105. In one embodiment, the antibody molecule binds to at least one, two, three, four or five residues within residues 206-215 of SEQ ID NO: 105.

Alternatively, or in combination with an embodiment described herein, the antibody molecule provides a reduction in the level of tandem mass spectrometry (TMT) labeling at residue K136 (numbered according to SEQ ID NO: 105) of a protein containing the amino acid the sequence of residues 27-547 of SEQ ID NO: 105, when bound, for example, when examining the antibody molecule as a bivalent antibody molecule using TMT isotopic labeling, for example, using the methods described in example 9, for example, with using TMT isotopic labeling for a labeling time of 30 seconds, wherein optionally the antibody molecule further provides a reduction in the level of TMT labeling at one or more of residues K133, K162, K179, K206, K214, K285, K291, and K341 (numbered as SEQ ID NO: 105) of the protein, for example, one or more of residues K162, K206, K214, K285, K291, and K341 (numbered as SEQ ID NO: 105) of the protein. In one embodiment, the antibody molecule provides increased levels of TMT labeling at one or both of residues K262 and K274 (numbered in accordance with SEQ ID NO: 105) of the protein when bound to it, for example, when the antibody molecule is examined as a bivalent antibody molecule using TMT isotopic labeling, for example using the methods described in Example 9, for example using TMT isotope labeling carried out over a labeling time of 30 seconds. In one embodiment, the antibody molecule provides reduced tandem mass spectrometry (TMT) labeling at residues K206 and K214 (numbered as SEQ ID NO: 105) of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105, when bound, the reduction at residue K214 being at least 90, 80, 70, 60 or 50% of the reduction at residue K206, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using isotopic labeling with TMT, for example, using the methods described in Example 9, for example, wherein the reduction at residue K214 is at least 90, 80, 70, 60 or 50% of the reduction at residue K206 using isotopic labeling using TMT, carried out within labeling time of 30 s, for example, the reduction at residue K214 being at least 90, 80, 70, 60, 50, 40 or 30% of the reduction at residue K206 using TMT isotopic labeling carried out during the labeling time , amounting to 300 s. In one embodiment, the antibody molecule provides reduction in tandem mass spectrometry (TMT) labeling at residue K162 (numbered as SEQ ID NO: 105) of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105, when bound during research

- 10 047335 development of an antibody molecule using TMT isotopic labeling for a labeling time of 30 seconds, wherein (i) the antibody molecule does not reduce the level of TMT labeling at residue K162 in a TMT isotopic labeling study TMT over a 300 s labeling time, or (ii) the antibody molecule provides a reduction in TMT labeling at residue K162 in a TMT isotopic labeling assay over a 300 s labeling time, wherein the reduction at residue K162 at a labeling time of 300 s is no more than 20, 30, 40 or 50% of the decrease at residue K162 at a labeling time of 30 s, for example, when studying the antibody molecule as a bivalent antibody molecule, for example, using methods described in example 9.

Alternatively, or in combination with an embodiment described herein, the antibody molecule binds to one or more residues of CD73, for example, through electrostatic interaction and/or hydrogen bonding, where one or more residues is selected from the group consisting of residues Y110, K136, L132, L157, K162, S155 and T209, numbered in accordance with SEQ ID NO: 105, as determined, for example, using crystal structure analysis, for example, using the methods described in Example 8. In one embodiment, the antibody molecule contains a heavy chain variable region and a light chain variable region, wherein the antibody molecule has one or more (e.g., 1, 2, 3, 4, or all) of the following properties:

(i) an antibody molecule (e.g., a heavy chain variable region, e.g., R54 of a heavy chain variable region numbered according to Kabat numbering) binds to Y110 (e.g., a backbone carbonyl of Y110) or K136 (e.g., a backbone carbonyl chains K136) from CD73 (numbered according to SEQ ID NO: 105), for example, through electrostatic interaction, as determined, for example, using crystal structure analysis, for example, using the methods described in example 8, (ii) antibody molecule ( for example, a heavy chain variable region, such as R31 from a heavy chain variable region numbered according to Kabat numbering) binds to L132 (eg, the main chain carbonyl of L132) or L157 (eg, the main chain carbonyl of L157) of CD73 ( numbered in accordance with SEQ ID NO: 105), for example, through electrostatic interaction, which, for example, is determined using crystal structure analysis, for example using the methods described in example 8, (iii) an antibody molecule (for example, a heavy chain variable region , e.g., S99 (e.g., the main chain carbonyl of S99), R31 (e.g., the main chain carbonyl of R31), or E95 (e.g., the side chain of E95) from the heavy chain variable region numbered according to Kabat numbering) binds to K162 (e.g., side chain K162) of CD73 (numbered in accordance with SEQ ID NO: 105), for example, through electrostatic interaction, as determined, for example, using crystal structure analysis, for example, using the methods described in example 8, (iv) antibody molecule (e.g., a heavy chain variable region, e.g., E98 from a heavy chain variable region numbered according to Kabat numbering) binds to S155 (e.g., a side chain of S155) of CD73 (numbered according to SEQ ID NO: 105), e.g. through a hydrogen bond, as determined, for example, using crystal structure analysis, for example, using the methods described in Example 8, and (v) an antibody molecule (for example, a light chain variable region, for example W32 (for example, a W32 side chain) of the variable light chain region numbered according to Kabat numbering) binds to T209 (e.g., T209 side chain) of CD73 (numbered according to SEQ ID NO: 105), for example, by hydrogen bonding, as determined, for example, using an assay crystal structure, for example using the methods described in example 8.

In one embodiment, the antibody molecule binds to one or more regions of CD73, for example, through shape complementarity and/or van der Waals interactions, wherein one or more regions is selected from the group consisting of residues 155-170, 136-138 and 209-210, numbered in accordance with SEQ ID NO: 105, as determined, for example, using crystal structure analysis, for example, using the methods described in Example 8. In one embodiment, the antibody molecule contains a heavy chain variable region and a light chain variable region, wherein an antibody molecule is characterized by one or more (e.g., 1, 2, or all) of the following properties:

(i) an antibody molecule (e.g., a heavy chain variable region, e.g., heavy chain variable region residues 33, 50, 52, 56, 97, 98, 100, or 100a numbered according to Kabat numbering) binds to residues 155-170 of CD73 (numbered according to SEQ ID NO: 105), for example, through shape complementarity and/or van der Waals interactions, as determined, for example, using crystal structure analysis, e.g.

- 11 047335 using the methods described in Example 8, (ii) an antibody molecule (eg, heavy chain variable region, eg heavy chain variable region residues 30 or 31 numbered according to Kabat numbering) binds to residues 136-138 of CD73 (numbered in accordance with SEQ ID NO: 105), for example, through shape complementarity and/or van der Waals interactions, as determined, for example, using crystal structure analysis, for example, using the methods described in example 8, and (iii) the molecule an antibody (e.g., a light chain variable region, e.g., residues 30 or 32 of the Kabat numbered light chain variable region) binds to residues 209-210 of CD73 (numbered according to SEQ ID NO: 105), which, for example , determined using crystal structure analysis, for example using the methods described in Example 8.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein the antibody molecule comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all CDRs) of a variable region heavy and/or light chain variable region comprising the amino acid sequence shown in Table 1 (e.g., from the heavy and light chain variable region sequences of the antibody disclosed in Table 1, e.g., antibodies 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398), or the encoded nucleotide sequence shown in Table 1. In some embodiments, CDRs are defined in accordance with the Kabat numbering scheme (eg, as set forth in Table 1). In some embodiments, the CDRs are defined in accordance with the Chothia numbering scheme (eg, as set forth in Table 1). In some embodiments, CDRs are defined according to a combined numbering scheme based on Kabat numbering and Chothia numbering (eg, as set forth in Table 1). In some embodiments, CDRs are defined in accordance with the IMGT numbering scheme (eg, as set forth in Table 1). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequence, shown in Table 1, or the encoded nucleotide sequence shown in Table 1.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73 comprising a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, comprising:

(i) a heavy chain variable region (VH) containing one, two or three of the amino acid sequence X ₁ X ₂ AMS from heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X1 represents R, Y or S, and X ₂ represents Y or N; amino acid sequence X1IX ₂ GX ₃ GX ₄ X ₅ TYYADSVKG from VHCDR2 (SEQ ID NO: 89), where X1 is A or S, X ₂ is S or T, X ₃ is S or T, X4 is M, G or S, and X ₅ represents N, S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL from VHCDR3 (SEQ ID NO: 37); and/or (ii) a light chain variable region (VL) comprising one, two or three of the amino acid sequence RASQSVGSNLA from light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence GASTRAT from VLCDR2 (SEQ ID NO: 49); and the amino acid sequence QQHNAFPYT from VLCDR3 (SEQ ID NO: 50).

In some embodiments, the anti-CD73 antibody molecule comprises: (i) a VH comprising one, two, or three of the VHCDR1 amino acid sequence of SEQ ID NO: 38, the VHCDR2 amino acid sequence of SEQ ID NO: 36, and the VHCDR3 amino acid sequence of SEQ ID NO: 37 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions); and VL comprising one, two, or three of the VLCDR1 amino acid sequence of SEQ ID NO: 48, the VLCDR2 amino acid sequence of SEQ ID NO: 49, and the VLCDR3 amino acid sequence of SEQ ID NO: 50 (or a sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity with it and/or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions);

(ii) a VH comprising one, two, or three of the VHCDR1 amino acid sequence of SEQ ID NO: 72, the VHCDR2 amino acid sequence of SEQ ID NO: 71, and the VHCDR3 amino acid sequence of SEQ ID NO: 37 (or a sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity with it and/or contained

- 12 047335 involving one, two, three or more substitutions, insertions or deletions, for example conservative substitutions); and VL comprising one, two, or three of the VLCDR1 amino acid sequence of SEQ ID NO: 48, the VLCDR2 amino acid sequence of SEQ ID NO: 49, and the VLCDR3 amino acid sequence of SEQ ID NO: 50 (or a sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity with it and/or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions);

(iii) a VH comprising one, two, or three of the VHCDR1 amino acid sequence of SEQ ID NO: 38, the VHCDR2 amino acid sequence of SEQ ID NO: 71, and the VHCDR3 amino acid sequence of SEQ ID NO: 37 (or a sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions); and VL comprising one, two, or three of the VLCDR1 amino acid sequence of SEQ ID NO: 48, the VLCDR2 amino acid sequence of SEQ ID NO: 49, and the VLCDR3 amino acid sequence of SEQ ID NO: 50 (or a sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity with it and/or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions);

(iv) a VH comprising one, two, or three of the VHCDR1 amino acid sequence of SEQ ID NO: 137, the VHCDR2 amino acid sequence of SEQ ID NO: 136, and the VHCDR3 amino acid sequence of SEQ ID NO: 37 (or a sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions); and VL comprising one, two, or three of the VLCDR1 amino acid sequence of SEQ ID NO: 48, the VLCDR2 amino acid sequence of SEQ ID NO: 49, and the VLCDR3 amino acid sequence of SEQ ID NO: 50 (or a sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity with it and/or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions);

(v) a VH comprising one, two or three of the VHCDR1 amino acid sequence of SEQ ID NO: 137, the VHCDR2 amino acid sequence of SEQ ID NO: 146, and the VHCDR3 amino acid sequence of SEQ ID NO: 37 (or a sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions); and VL comprising one, two, or three of the VLCDR1 amino acid sequence of SEQ ID NO: 48, the VLCDR2 amino acid sequence of SEQ ID NO: 49, and the VLCDR3 amino acid sequence of SEQ ID NO: 50 (or a sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity with it and/or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions); or (vi) a VH comprising one, two, or three of the VHCDR1 amino acid sequence of SEQ ID NO: 137, the VHCDR2 amino acid sequence of SEQ ID NO: 154, and the VHCDR3 amino acid sequence of SEQ ID NO: 37 (or a sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions); and VL comprising one, two, or three of the VLCDR1 amino acid sequence of SEQ ID NO: 48, the VLCDR2 amino acid sequence of SEQ ID NO: 49, and the VLCDR3 amino acid sequence of SEQ ID NO: 50 (or a sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity with it and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 44, 77, 84, 142, 151, or 159, or an amino acid sequence characterized by at least about 85%, 90%, 95% , or 99% sequence identity to SEQ ID NO: 44, 77, 84, 142, 151 or 159.

In some embodiments, the anti-CD73 antibody molecule comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 55.

In some embodiments, the anti-CD73 antibody molecule comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 46, 79, 86, 114, 116, or 117, or an amino acid sequence characterized by at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 46, 79, 86, 114, 116 or 117.

In some embodiments, the anti-CD73 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence having at least about 85%, 90%, 95%, or 99% identity

- 13 047335 sequences with SEQ ID NO: 57.

In some embodiments, the anti-CD73 antibody molecule comprises:

(i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 44 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain variable region, comprising the amino acid sequence of SEQ ID NO: 55 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(ii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 77 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain variable region, comprising the amino acid sequence of SEQ ID NO: 55 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(iii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 84 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain variable region, comprising the amino acid sequence of SEQ ID NO: 55 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(iv) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 142 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain variable region, comprising the amino acid sequence of SEQ ID NO: 55 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(v) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 151 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain variable region, comprising the amino acid sequence of SEQ ID NO: 55 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto); or (vi) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 159 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto) and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto).

In some embodiments, the anti-CD73 antibody molecule comprises:

(i) a heavy chain containing the amino acid sequence of SEQ ID NO: 46 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto) and a light chain containing the amino acid sequence of SEQ ID NO: 57 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(ii) a heavy chain containing the amino acid sequence of SEQ ID NO: 114 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence of SEQ ID NO: 57 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(iii) a heavy chain containing the amino acid sequence of SEQ ID NO: 79 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence of SEQ ID NO: 57 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(iv) a heavy chain containing the amino acid sequence of SEQ ID NO: 116 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence of SEQ ID NO: 57 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(v) a heavy chain containing the amino acid sequence of SEQ ID NO: 86 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence

- 14 047335 under SEQ ID NO: 57 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto); or (vi) a heavy chain containing the amino acid sequence of SEQ ID NO: 117 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence under SEQ ID NO: 57 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73 comprising a heavy chain variable region (VH) containing the amino acid sequence ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, comprising:

(i) a heavy chain variable region (VH) containing the amino acid sequence X1X2YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X1 is R, G or S, and X2 is Y or R; the amino acid sequence of YIYX1X2GSTX ₃ YNPSLKS VHCDR2 (SEQ ID NO: 91), where X ₁ is G or S, X ₂ is R, S or T, and X ₃ is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and/or (ii) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In some embodiments, the anti-CD73 antibody molecule comprises:

(i) a VH comprising one, two, or three of the VHCDR1 amino acid sequence of SEQ ID NO: 61, the VHCDR2 amino acid sequence of SEQ ID NO: 60, and the VHCDR3 amino acid sequence of SEQ ID NO: 3 (or a sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions); and VL comprising one, two, or three of the VLCDR1 amino acid sequence of SEQ ID NO: 14, the VLCDR2 amino acid sequence of SEQ ID NO: 15, and the VLCDR3 amino acid sequence of SEQ ID NO: 16 (or a sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity with it and/or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions);

(ii) a VH comprising one, two, or three of the VHCDR1 amino acid sequence of SEQ ID NO: 4, the VHCDR2 amino acid sequence of SEQ ID NO: 26, and the VHCDR3 amino acid sequence of SEQ ID NO: 3 (or a sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions); and VL comprising one, two, or three of the VLCDR1 amino acid sequence of SEQ ID NO: 14, the VLCDR2 amino acid sequence of SEQ ID NO: 15, and the VLCDR3 amino acid sequence of SEQ ID NO: 16 (or a sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity with it and/or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions);

(iii) a VH comprising one, two, or three of the VHCDR1 amino acid sequence of SEQ ID NO: 4, the VHCDR2 amino acid sequence of SEQ ID NO: 2, and the VHCDR3 amino acid sequence of SEQ ID NO: 3 (or a sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions); and VL comprising one, two, or three of the VLCDR1 amino acid sequence of SEQ ID NO: 14, the VLCDR2 amino acid sequence of SEQ ID NO: 15, and the VLCDR3 amino acid sequence of SEQ ID NO: 16 (or a sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity with it and/or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions); or (iv) a VH comprising one, two, or three of the VHCDR1 amino acid sequence of SEQ ID NO: 163, the VHCDR2 amino acid sequence of SEQ ID NO: 162, and the VHCDR3 amino acid sequence of SEQ ID NO: 3 (or a sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions); and VL comprising one, two, or three of the VLCDR1 amino acid sequence of SEQ ID NO: 14, the VLCDR2 amino acid sequence of SEQ ID NO: 15, and the VLCDR3 amino acid sequence of SEQ ID NO: 16 (or a sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity with it and/or containing one,

- 15 047335 two, three or more substitutions, insertions or deletions, for example conservative substitutions).

In some embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 66, 31, 10, or 168, or an amino acid sequence having at least 85%, 90%, 95%, or 99% identity sequences with SEQ ID NO: 66, 31, 10 or 168.

In some embodiments, the anti-CD73 antibody molecule comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21 or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: : 21.

In some embodiments, the anti-CD73 antibody molecule comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 68, 33, 12, 115, 113, or 112, or an amino acid sequence characterized by at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 68, 33, 12, 115, 113 or 112.

In some embodiments, the anti-CD73 antibody molecule comprises a light chain comprising an amino acid sequence of SEQ ID NO: 23 or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 23 .

In some embodiments, the anti-CD73 antibody molecule comprises:

(i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 66 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain variable region, comprising the amino acid sequence of SEQ ID NO: 21 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(ii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain variable region, comprising the amino acid sequence of SEQ ID NO: 21 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(iii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain variable region, comprising the amino acid sequence of SEQ ID NO: 21 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto); or (iv) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 168 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto) and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto).

In some embodiments, the anti-CD73 antibody molecule comprises:

(i) a heavy chain containing the amino acid sequence of SEQ ID NO: 68 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence of SEQ ID NO: 23 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(ii) a heavy chain containing the amino acid sequence of SEQ ID NO: 115 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence of SEQ ID NO: 23 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(iii) a heavy chain containing the amino acid sequence of SEQ ID NO: 33 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence of SEQ ID NO: 23 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto);

(iv) a heavy chain containing the amino acid sequence of SEQ ID NO: 113 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence of SEQ ID NO: 23 (or a sequence characterized by at least approximately

- 16 047335

85%, 90%, 95%, or 99% sequence identity with it);

(v) a heavy chain containing the amino acid sequence of SEQ ID NO: 12 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence of SEQ ID NO: 23 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto); or (vi) a heavy chain containing the amino acid sequence of SEQ ID NO: 112 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto), and a light chain containing the amino acid sequence under SEQ ID NO: 23 (or a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto).

In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH3-23 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a light chain variable region having an amino acid sequence derived from the human VK3-15 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH3-23 germline sequence and a light chain variable region having an amino acid sequence derived from the human VK3-15 germline sequence.

In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH4-59 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a light chain variable region having an amino acid sequence derived from the human VK1-12 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH4-59 germline sequence and a light chain variable region having an amino acid sequence derived from the human VK1-12 germline sequence.

In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH3-23 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a light chain variable region having an amino acid sequence derived from the human VK1-05 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH3-23 germline sequence and a light chain variable region having an amino acid sequence derived from the human VK1-05 germline sequence.

In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH1-02 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a light chain variable region having an amino acid sequence derived from the human VK1-12 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH1-02 germline sequence and a light chain variable region having an amino acid sequence derived from the human VK1-12 germline sequence.

In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH3-07 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a light chain variable region having an amino acid sequence derived from the human VK4-01 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH3-07 germline sequence and a light chain variable region having an amino acid sequence derived from the human VK4-01 germline sequence.

In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH1-69 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a light chain variable region having an amino acid sequence derived from the human VK3-15 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having

- 17 047335 an amino acid sequence derived from the human VH1-69 germline sequence, and a light chain variable region having an amino acid sequence derived from the human VK3-15 germline sequence.

In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH4-34 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a light chain variable region having an amino acid sequence derived from the human VK1-12 germline sequence. In certain embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region having an amino acid sequence derived from the human VH4-34 germline sequence and a light chain variable region having an amino acid sequence derived from the human VK1-12 germline sequence.

In certain embodiments, the anti-CD73 antibody molecule is a monoclonal antibody or a single-specificity antibody. In certain embodiments, the anti-CD73 antibody molecule is a bispecific or multispecific antibody. The heavy and light chains of an anti-CD73 antibody molecule may be full-length (e.g., the antibody may contain at least one or at least two complete heavy chains, and at least one or at least two complete light chains) or may contain an antigen-binding moiety ( e.g. Fab, F(ab')2, Fv, single chain Fv fragment, single domain antibody, diabody (dAb), bivalent or bispecific antibody or fragment thereof, single domain variant thereof or camel antibody).

In certain embodiments, the anti-CD73 antibody molecule has a heavy chain constant region (Fc) selected, for example, from the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; in particular selected, for example, from the heavy chain constant regions of IgG1, IgG2, IgG3 and IgG4, more particularly the heavy chain constant region of IgG4. In some embodiments, the heavy chain constant region is that of human IgG4. In some embodiments, the anti-CD73 antibody molecule comprises a light chain constant region selected from, for example, kappa or lambda light chain constant regions. In some embodiments, the light chain constant region is such a kappa chain (eg, human kappa chain). In some embodiments, the constant region is altered, such as mutated, to modify properties of the anti-CD73 antibody molecule (eg, increasing or decreasing one or more of Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, or complement function). In some embodiments, the heavy chain constant region of an IgG4, eg human IgG4, is mutated at position 228 according to Eu numbering (eg, S to P), for example, as shown in Table 3. In certain embodiments, the anti-CD73 antibody molecules comprise human IgG4 mutated at position 228 according to Eu numbering (eg, S to P), for example, as shown in Table. 3; and a kappa light chain constant region, for example as shown in Table. 3. In some embodiments, the heavy chain constant region of an IgG4, e.g., human IgG4, is mutated at position 228 (e.g., S to P) and at position 235 (e.g., L to E) according to Eu numbering, e.g., as shown in Table 3. In certain embodiments, anti-CD73 antibody molecules comprise human IgG4 mutated at position 228 (eg, S to P) and at position 235 (eg, L to E) according to Eu numbering, for example, as shown in Table 1. 3; and a kappa light chain constant region, for example as shown in Table. 3. In yet another embodiment, the heavy chain constant region of an IgG1, e.g., human IgG1, is mutated at one or more of position 297 (e.g., N to A), position 265 (e.g., D to A), position 329 (e.g., P to A), position 234 (eg L to A) or position 235 (eg L to A), all in accordance with Eu numbering, for example, as shown in table. 3. In certain embodiments, the anti-CD73 antibody molecules comprise human IgG1 mutated at one or more of the above positions, for example, as shown in Table 3; and a kappa light chain constant region, for example as shown in Table. 3.

In some embodiments, the anti-CD73 antibody molecule comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, and IgG4, and a light chain constant region selected from kappa or lambda light chain constant regions. In some embodiments, an anti-CD73 antibody molecule comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92-103, 119 and 120, and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 104.

In one aspect, the present invention provides an antibody molecule that competes with a monoclonal antibody, such as an antibody molecule described herein, for binding to human CD73. The present invention also provides an antibody molecule that binds to the same (or substantially the same) epitope as a monoclonal antibody, such as an antibody molecule

- 18 047335 described herein to, or overlapping (or substantially overlapping) human CD73.

In one embodiment, the monoclonal antibody comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In certain embodiments, the monoclonal antibody comprises:

(i) a heavy chain variable region (VH) containing the amino acid sequence X|X2AMS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X ₁ is R, Y or S, and X 2 is Y or N; amino acid sequence X ₁ IX2GX ₃ GX ₄ X ₅ TYYADSVKG

VHCDR2 (SEQ ID NO: 89), where X ₁ is A or S, X ₂ is S or T, X ₃ is S or T, X ₄ is M, G or S, and X ₅ is N , S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); and/or (ii) a light chain variable region (VL) comprising the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ ID NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In certain embodiments, the monoclonal antibody comprises:

(i) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(ii) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(iii) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(iv) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(v) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (vi) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50.

In one embodiment, the monoclonal antibody comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence ESQESPYNNWFDP (SEQ ID NO: 3).

In certain embodiments, the monoclonal antibody comprises:

(i) a heavy chain variable region (VH) containing the amino acid sequence X1X2YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X1 is R, G or S, and X2 is Y or R; the amino acid sequence of YIYX1X2GSTX ₃ YNPSLKS VHCDR2 (SEQ ID NO: 91), where X is G or S, X2 is R, S or T, and X3 is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and/or (ii) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

- 19 047335

In certain embodiments, the monoclonal antibody comprises:

(i) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(ii) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(iii) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (iv) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one aspect, the present invention provides a nucleic acid molecule that contains one or both nucleotide sequences that encode the heavy and light chain variable regions, CDRs, hypervariable loops, framework regions of the anti-CD73 antibody molecules described herein. In certain embodiments, the nucleotide sequence that encodes the anti-CD73 antibody molecule is codon optimized. For example, the present invention relates to first and second nucleic acids encoding the variable regions, respectively, of the heavy and light chains of an anti-CD73 antibody molecule selected, for example, from any of 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430 or 398, collectively presented in table. 1, or a sequence essentially identical to them. For example, the nucleic acid may contain a nucleotide sequence such as set out in table. 1, or a sequence substantially identical thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity, or that differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 1).

In one aspect, nucleic acids are disclosed comprising nucleotide sequences that encode heavy and light chain variable regions and CDRs of the anti-CD73 antibody molecules described herein. For example, the present invention provides first and second nucleic acids encoding, respectively, the heavy and light chain variable regions of the anti-CD73 antibody molecule according to Table 1, or sequences substantially identical thereto. For example, the nucleic acid may comprise a nucleotide sequence encoding an anti-CD73 antibody molecule according to Table 1, or a sequence substantially identical to that nucleotide sequence (e.g., a sequence having at least about 85%, 90%, 95%, or 99 % sequence identity or which differs by no more than 3, 6, 15, 30 or 45 nucleotides from the above nucleotide sequence).

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two or three CDRs or hypervariable loops from a heavy chain variable region having the amino acid sequence set forth in Table. 1, or a sequence substantially homologous thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions, or deletions, such as conservative substitutions).

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two or three CDRs or hypervariable loops from a light chain variable region having the amino acid sequence set forth in Table. 1, or a sequence substantially homologous thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions, or deletions, such as conservative substitutions).

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs, or hypervariable loops, of heavy and light chain variable regions having an amino acid

- 20 047335 sequence set out in table. 1, or a sequence substantially homologous thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions, or divisions, such as conservative substitutions).

In certain embodiments, the nucleic acid encodes a heavy chain variable region, wherein the nucleic acid comprises a nucleotide sequence of SEQ ID NO: 45, 78, 85, 143, 152, 160, 67, 32, 11, or 169, or a nucleotide sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 45, 78, 85, 143, 152, 160, 67, 32, 11, or 169.

In certain embodiments, the nucleic acid encodes a heavy chain, wherein the nucleic acid comprises a nucleotide sequence of SEQ ID NO: 47, 80, 87, 69, 34, or 13, or a nucleotide sequence characterized by at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 47, 80, 87, 69, 34 or 13.

In certain embodiments, the nucleic acid encodes a light chain variable region, wherein the nucleic acid comprises a nucleotide sequence of SEQ ID NO: 56, 144, 22, or 170, or a nucleotide sequence characterized by at least about 85%, 90%, 95%, or 99 % sequence identity to SEQ ID NO: 56, 144, 22 or 170.

In certain embodiments, the nucleic acid encodes a light chain, wherein the nucleic acid comprises a nucleotide sequence of SEQ ID NO: 58 or 24, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 58 or 24.

In one aspect, this disclosure relates to host cells and vectors containing the nucleic acids described herein. The nucleic acids may be present in a single vector or separate vectors present in the same host cell or a separate host cell. Also provided herein is a method for producing an anti-C73 antibody molecule, the method comprising culturing a host cell disclosed herein under conditions suitable for expression of the gene.

In one aspect, the present invention provides a method for producing the antibody molecule described herein. The method may include: providing a CD73 antigen (eg, an antigen containing at least a portion of a CD73 epitope, eg, the N-terminal domain of a CD73 antigen); providing an antibody molecule that binds to the CD73 antigen; and assessing whether the antibody molecule binds to CD73 antigen, or assessing the effectiveness of the antibody molecule in modulating, eg promoting or inhibiting, CD73 activity. The method may further include administering the antibody molecule to a subject, such as a human or non-human animal.

In one aspect, the present invention provides compositions, for example pharmaceutical compositions, that contain a pharmaceutically acceptable carrier, excipient or stabilizer and at least one of the anti-CD73 antibody molecules described herein. In one embodiment, the composition, such as a pharmaceutical composition, contains a combination of an antibody molecule and one or more agents, such as a therapeutic agent or another antibody molecule, described herein. In some embodiments, the antibody molecule is conjugated to a label or therapeutic agent. In some embodiments, the compositions, such as pharmaceutical compositions, comprise a combination of an antibody molecule and a second agent, such as a therapeutic agent or two or more of the aforementioned antibody molecules further described herein.

The anti-CD73 antibody molecules disclosed herein can inhibit, reduce or neutralize one or more activities of CD73, for example adenosine monophosphate (AMP) to adenosine provides inhibition or reduction of CD73 enzymatic activity; inhibiting the level of conversion or reducing its level; increasing the level of proliferation of anti-CD3/anti-CD28-stimulated T cells, such as CD4+ T cells, in the presence of adenosine monophosphate (AMP); inhibition of proliferation of regulatory T cells; increased levels of effector T cell responses; and/or inhibition of migration, infiltration or proliferation of myeloid-derived suppressor cells. Thus, such antibody molecules can be used to treat or prevent disorders that require enhancing the immune response in a subject.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second antigen binding domain binds to auto

- 21 047335 the third monomer of CD73, for example, when studied using size exclusion chromatography; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215, or residues 297-309 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule with using hydrogen-deuterium exchange mass spectrometry, for example as described in Example 2, for example hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than at residues 158,172 of SEQ ID NO: 105 and at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105. 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID

NO: 105. In one embodiment, binding of the antibody reduces the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105, at residues 206- 215 from SEQ ID NO: 105 and for residues 297-309 from SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105, residues 368-387 of SEQ ID NO: 105, or residues 297-309 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example , pH 7.5) and room temperature.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 in greater than at residues 206215 of SEQ ID NO: 105 and at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105. 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 368-387 of SeQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average water level

- 22 047335 rhodium-deuterium exchange for residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 206-215 of SEQ ID NO: 105, for residues 368-387 of SEQ ID NO: 105 and for residues 297 -309 from SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; and (ii) the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171) , upon binding, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87-104 of SEQ ID NO: 105, wherein the region having the greatest decrease average level of hydrogen-deuterium exchange among one or more regions, does not represent residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), results in a decrease in the average hydrogen-deuterium level exchange amounting to more than, for example, 0.02, 0.03, 0.04, 0.05 or 0.06 Da per residue, for residues 368-387 of SEQ ID NO: 105, for example, when examining an antibody molecule in form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5 ) and room temperature.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), results in a decrease in the average hydrogen-deuterium level exchange amounting to less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example, when studying the antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example as described in Example 2, for example hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature .

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of

- 23 047335 amino acid sequence under SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second antigen binding domain binds to the second CD73 monomer, e.g. using size exclusion chromatography; and (ii) the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105, and/or to at least one, two, three, four, or five residues within within residues 206-215 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; and (ii) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is assayed as a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay ), for example, as described in example 1.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2AMS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X1 is R, Y or S, and _X2 is Y or N ; amino acid sequence X1IX ₂ GX ₃ GX4X ₅ TYYADSVKG VHCDR2 (SEQ ID NO: 89), where X ₁ is A or S, X ₂ is S or T, X ₃ is S or T, X4 is M, G or S, and X ₅ represents N, S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ GO NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; And

- 24 047335 (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(d) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(e) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (f) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence ESQESPYNNWFDP (SEQ ID NO: 3).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X1 is R, G or S, and _X2 is Y or R ; the amino acid sequence of YIYX1X2GSTX3YNPSLKS VHCDR2 (SEQ ID NO: 91), where Xi is G or S, X2 is R, S or T, and X3 is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and amino acid aftertaste

- 25 047335 activity QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer (e.g., each monomer contains an amino acid sequence of residues 27-547 of SEQ ID NO: 105, for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second the antigen binding domain binds to a second monomer of CD73, for example, in a size exclusion chromatography assay; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (d) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215, or residues 297-309 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule with using hydrogen-deuterium exchange mass spectrometry, for example as described in Example 2, for example hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than residues 158,172 of SEQ ID NO: 105 and residues 206-215 of SEQ ID NO: 105. In one embodiment, the connection

- 26 047335 antibody calling provides a decrease in the average level of hydrogen-deuterium exchange at residues 368-387 from SEQ ID NO: 105 to a greater extent than at residues 158-172 from SEQ ID NO: 105 and at residues 297-309 from SEQ ID NO : 105. In one embodiment, antibody binding reduces the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding reduces the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105, residues 368-387 of SEQ ID NO: 105, or residues 297-309 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example , pH 7.5) and room temperature.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 in greater than at residues 206215 of SEQ ID NO: 105 and at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105. 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 368-387 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105, residues 368-387 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound

- 27 047335 antibody molecules), for example, as described in example 2; and (ii) the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171) , upon binding, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87-104 of SEQ ID NO: 105, wherein the region having the greatest decrease average level of hydrogen-deuterium exchange among one or more regions, does not represent residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), results in a decrease in the average hydrogen-deuterium level exchange amounting to more than, for example, 0.02, 0.03, 0.04, 0.05 or 0.06 Da per residue, for residues 368-387 of SEQ ID NO: 105, for example, when examining an antibody molecule in form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5 ) and room temperature.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), results in a decrease in the average hydrogen-deuterium level exchange amounting to less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example, when studying the antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example as described in Example 2, for example hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature .

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% , 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in the specified composition bind to di-

- 28 047335 measure of CD73 to form a complex, where each of these complexes consists of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of molecules antibodies that bind to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105, and/or to at least one, two, three, four, or five residues within within residues 206-215 of SEQ ID NO: 105.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is assayed as a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay ), for example, as described in example 1.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein (i) each of the antibody molecules comprises a plurality of the same first antigen binding domain and the same second antigen binding domain of at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2AMS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X1 is R, Y or S, and _X2 is Y or N ; amino acid sequence XiIX ₂ GX ₃ GX ₄ X ₅ TYYADSVKG VHCDR2 (SEQ ID NO: 89), where X ₁ is A or S, X ₂ is S or T, X ₃ is S or T, X4 is M, G or S, and X ₅ represents N, S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); And

- 29 047335 (b) a light chain variable region (VL) containing the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ ID NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(d) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(e) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (f) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule contains a heavy chain variable region (VH) containing an amino acid

- 30 047335 heavy chain complementarity determining region 3 (VHCDR3) sequence lot ESQESPYNNWFDP (SEQ ID NO: 3).

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X ₁ X ₂ YWS heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X 1 is R, G or S, and X ₂ is is Y or R; the amino acid sequence of YIY.X-.X-GST.WNTSl.KS VHCDR2 (SEQ ID NO: 91), where X1 is G or S, _X2 is R, S or T, and _X3 is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, at least 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, where each of said complexes consists of from one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (d) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one aspect, this document discloses a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first mo

- 31 047335 number of CD73 and a second CD73 monomer, each monomer containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of several antibody molecules contains the same first antigen-binding domain and the same second antigen-binding domain, no more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% of the antibody molecules in said composition bind to a CD73 dimer to form a complex, wherein each of said complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in Example 2; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215, or residues 297-309 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule with using hydrogen-deuterium exchange mass spectrometry, for example as described in Example 2, for example hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than at residues 158,172 of SEQ ID NO: 105 and at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105. 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 158-172 of SEQ ID NO: 105, residues 206-215 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), e.g. , as described in example 2; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105, residues 368-387 of SEQ ID NO: 105, or residues 297-309 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example , pH 7.5) and room temperature.

In one embodiment, binding of the antibody causes the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to be reduced to a greater extent than at

- 32 047335 tatkam 206-215 of SEQ ID NO: 105. In one embodiment, binding of the antibody reduces the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, binding of the antibody reduces the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one In one embodiment, binding of the antibody reduces the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206215 of SEQ ID NO: 105 and at residues 368-387 of SEQ ID NO: 105. In one In an embodiment, antibody binding reduces the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding reduces the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. SEQ ID NO: 105. In one embodiment, binding of the antibody reduces the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105, at residues 368-387 from SEQ ID NO: 105 and for residues 297-309 from SEQ ID NO: 105.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), e.g. , as described in example 2; and (ii) the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171) , upon binding, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87-104 of SEQ ID NO: 105, wherein the region having the greatest decrease average level of hydrogen-deuterium exchange among one or more regions, does not represent residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), e.g. , as described in example 2; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), results in a decrease in the average hydrogen-deuterium level exchange amounting to more than, for example, 0.02, 0.03, 0.04, 0.05 or 0.06 Da per residue, for residues 368-387 of SEQ ID NO: 105, for example, when examining an antibody molecule in form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5 ) and room temperature.

- 33 047335

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), e.g. , as described in example 2; and (ii) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), results in a decrease in the average hydrogen-deuterium level exchange amounting to less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example, when studying the antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example as described in Example 2, for example hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature .

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), e.g. , as described in example 2; and (ii) the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105, and/or to at least one, two, three, four, or five residues within within residues 206-215 of SEQ ID NO: 105.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), e.g. , as described in example 2; and (ii) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is assayed as a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay ), for example, as described in example 1.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer with

- 34 047335 by forming a complex, wherein each of said complexes contains two or more antibody molecules and two or more CD73 dimers, for example when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of molecules antibodies that bind to CD73 (excluding unbound antibody molecules), for example, as described in example 2; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), e.g. , as described in example 2; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X ₁ X2AMS heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X ₁ is R, Y or S, and X ₂ is Y or N; amino acid sequence X ₁ IX ₂ GX ₃ GX ₄ X ₅ TYYADSVKG VHCDR2 (SEQ ID NO: 89), where X1 is A or S, X ₂ is S or T, X ₃ is S or T, X4 is M , G or S, and X ₅ represents N, S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ ID NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), e.g. , as described in example 2; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

- 35 047335 (d) VH containing the amino acid sequence of VHCDR1 under SEQ ID NO: 137, the amino acid sequence of VHCDR2 under SEQ ID NO: 136 and the amino acid sequence of VHCDR3 under SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(e) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (f) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50.

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), e.g. , as described in example 2; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence ESQESPYNNWFDP (SEQ ID NO: 3).

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in the composition bind to the CD73 dimer to form a complex, where each of these complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), e.g. , as described in example 2; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X1 is R, G or S, and _X2 is Y or R ; the amino acid sequence of YIY.X-.X-GST.WNTSl.KS VHCDR2 (SEQ ID NO: 91), where X1 is G or S, _X2 is R, S or T, and _X3 is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQSVLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In one aspect, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., each monomer consists of the amino acid sequence of SEQ ID NO: 171), where (i) if each of the multiple antibody molecules contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25%, 30%, 35%, 40%, 45%,

- 36 047335

50%, 55%, 60%, 65%, or 70% of the antibody molecules in said composition bind to a CD73 dimer to form a complex, wherein each of said complexes contains two or more antibody molecules and two or more CD73 dimers, e.g. using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, as described in Example 2; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (d) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), provides a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 from SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215, or residues 297-309 from SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is assayed as a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay ), for example, as described in example 1.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than at residues 158,172 of SEQ ID NO: 105 and at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105. 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 158-172 of SEQ ID NO: 105, residues 206-215 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein

- 37 047335 (i) an antibody molecule, when bound to a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen- deuterium exchange for residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 206-215 of SEQ ID NO: 105, for residues 368-387 of SEQ ID NO: 105, or for residues 297-309 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is assayed as a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay ), for example, as described in example 1.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 in greater than at residues 206215 of SEQ ID NO: 105 and at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105. 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 368-387 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105, residues 368-387 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), when bound, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87 -104 of SEQ ID NO: 105, wherein the region having the greatest decrease in the average level of hydrogen-deuterium exchange among one or more regions is not residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as bivalent antibody molecules using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is assayed as a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay ), for example, as described in example 1.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of greater than, for example, 0.02, 0.03, 0.04, 0.05, or 0.06 Da per residue, over residues 368 -387 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is assayed as a bivalent antibody molecule using a modified Cell Titer assay

- 38 047335

Glo (CTG), for example, as described in example 1.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is assayed as a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay ), for example, as described in example 1.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105, and/ or with at least one, two, three, four or five residues within residues 206-215 of SEQ ID NO: 105; and (ii) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is assayed as a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay ), for example, as described in example 1.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), provides a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 from SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215, or residues 297-309 from SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than at residues 158,172 of SEQ ID NO: 105 and at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105. 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 158-172 of SEQ ID NO: 105, residues 206-215 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange for residues 158-172 from SEQ ID NO: 105 to a greater extent than for residues 206-215 from SEQ ID NO: 105,

- 39 047335 for residues 368-387 of SEQ ID NO: 105 or for residues 297-309 of SEQ ID NO: 105, for example, when studying the antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 in greater than at residues 206215 of SEQ ID NO: 105 and at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105. 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 368-387 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105, residues 368-387 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), when bound, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87 -104 of SEQ ID NO: 105, wherein the region having the greatest decrease in the average level of hydrogen-deuterium exchange among one or more regions is not residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as bivalent antibody molecules using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of greater than, for example, 0.02, 0.03, 0.04, 0.05, or 0.06 Da per residue, over residues 368 -387 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ

- 40 047335

ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105, and/ or with at least one, two, three, four or five residues within residues 206-215 of SEQ ID NO: 105; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), provides a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 from SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215, or residues 297-309 from SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2AMS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X1 is R, Y or S, and _X2 is Y or N ; amino acid sequence X ₁ IX ₂ GX3GX ₄ X ₅ TYYADSVKG VHCDR2 (SEQ ID NO: 89), where X1 is A or S, X ₂ is S or T, X ₃ is S or T, X4 is M, G or S, and X ₅ represents N, S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ ID NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than at residues 158,172 of SEQ ID NO: 105 and at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105. 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 158-172 of SEQ ID NO: 105, residues 206-215 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange for residues 158-172 from SEQ ID NO: 105 to a greater extent than for residues 206-215 from SEQ ID NO: 105,

- 41 047335 for residues 368-387 of SEQ ID NO: 105 or for residues 297-309 of SEQ ID NO: 105, for example, when studying the antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X|X2AMS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X ₁ is R, Y or S, and X ₂ is Y or N; amino acid sequence X ₁ IX ₂ GX ₃ GX ₄ X ₅ TYYADSVKG VHCDR2 (SEQ ID NO: 89), where X ₁ is A or S, X ₂ is S or T, X ₃ is S or T, X4 is M, G or S, and X ₅ represents N, S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ ID NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 in greater than at residues 206215 of SEQ ID NO: 105 and at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105. 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 368-387 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105, residues 368-387 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), when bound, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87 -104 of SEQ ID NO: 105, wherein the region having the greatest decrease in the average level of hydrogen-deuterium exchange among one or more regions is not residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as bivalent antibody molecules using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X ₁ X2AMS heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X ₁ is R, Y or S, and X ₂ is Y or N; amino acid sequence X1IX2GX3GX4X5TYYADSVKG VHCDR2 (SEQ ID NO: 89), where X1 is A or S, X2 is S or T, X3 is S or T, X4 is M, G or S, and X5 is N, S , L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ ID NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171) results in a reduction in the average hydrogen-deuterium exchange rate of greater than, for example, 0.02, 0.03, 0.04, 0.05 or 0.06 Da per residue , at residues 368-387 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry , carried out with the exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence XiX ₂ AMS heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X ₁ is R, Y or S, and X ₂ is Y or N; amino acid sequence X1IX ₂ GX ₃ GX ₄ X ₅ TYYADSVKG VHCDR2 (SEQ ID NO: 89), where X ₁ is A or S, X ₂ is S or T, X ₃ is S or T, X4 is M, G or S, and X5 is N, S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ ID NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2AMS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X1 is R, Y or S, and _X2 is Y or N ; amino acid sequence X ₁ IX ₂ GX ₃ GX ₄ X ₅ TYYADSVKG VHCDR2 (SEQ ID NO: 89), where X ₁ is A or S, X ₂ is S or T, X ₃ is S or T, X4 is M, G or S, and X ₅ represents N, S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ ID NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105, and/ or with at least one, two, three, four or five residues within residues 206-215 of SEQ ID NO: 105; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2AMS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X1 is R, Y or S, and _X2 is Y or N ; amino acid sequence X1IX ₂ GX ₃ GX ₄ X ₅ TYYADSVKG VHCDR2 (SEQ ID NO: 89), where X1 is A or S, X ₂ is S or T, X ₃ is S or T, X4 is M, G or S, and X ₅ represents N, S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ ID NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein

- 43 047335 (i) an antibody molecule, when bound to a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a decrease in the average level of hydrogen- deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215, or residues 297-309 of SEQ ID NO: 105, for example, when studying an antibody molecule as a bivalent molecule antibodies using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(d) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(e) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (f) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than at residues 158,172 of SEQ ID NO: 105 and at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105. 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 158-172 of SEQ ID NO: 105, residues 206-215 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence

- 44 047335 of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 206-215 of SEQ ID NO: 105, for residues 368-387 of SEQ ID NO: 105 or at residues 297-309 of SEQ ID NO: 105, for example, when studying the antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(d) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(e) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (f) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 in greater than at residues 206215 of SEQ ID NO: 105 and at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105. 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 368-387 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105, residues 368-387 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO:

- 45 047335

171), upon binding, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87-104 of SEQ ID NO: 105, wherein the region characterized the largest decrease in the average hydrogen-deuterium exchange rate among one or more regions is not residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(d) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(e) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (f) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of greater than, for example, 0.02, 0.03, 0.04, 0.05, or 0.06 Da per residue, over residues 368 -387 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(c) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71, and the amino acid sequence

- 46 047335

VHCDR3 under SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(d) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(e) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (f) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105, and/ or with at least one, two, three, four or five residues within residues 206-215 of SEQ ID NO: 105; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(d) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(e) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or

- 47 047335 (f) VH containing the amino acid sequence of VHCDR1 under SEQ ID NO: 137, the amino acid sequence of VHCDR2 under SEQ ID NO: 154 and the amino acid sequence of VHCDR3 under SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), provides a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 from SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215, or residues 297-309 from SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence ESQESPYNNWFDP (SEQ ID NO: 3).

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than at residues 158,172 of SEQ ID NO: 105 and at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105. 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 158-172 of SEQ ID NO: 105, residues 206-215 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 206-215 of SEQ ID NO: 105, for residues 368-387 of SEQ ID NO: 105 or at residues 297-309 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry exchange carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence ESQESPYNNWFDP (SEQ ID NO: 3).

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 in greater than residues 206215 of SEQ ID NO: 105 and residues 368-387 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at the residue

- 48 047335 cam 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 368-387 of SEQ ID NO: 105 and for residues 297-309 of SEQ ID NO: 105. In one embodiment binding of the antibody reduces the average level of hydrogen-deuterium exchange at residues 158-172 from SEQ ID NO: 105 to a greater extent than at residues 206-215 from SEQ ID NO: 105, at residues 368-387 from SEQ ID NO: 105 and for residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), when bound, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87 -104 of SEQ ID NO: 105, wherein the region having the greatest decrease in the average level of hydrogen-deuterium exchange among one or more regions is not residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as bivalent antibody molecules using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence ESQESPYNNWFDP (SEQ ID NO: 3).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of greater than, for example, 0.02, 0.03, 0.04, 0.05, or 0.06 Da per residue, over residues 368 -387 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence ESQESPYNNWFDP (SEQ ID NO: 3).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence ESQESPYNNWFDP (SEQ ID NO: 3).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105, and/ or with at least one, two, three, four or five residues within residues 206-215 of SEQ ID NO: 105; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence ESQESPYNNWFDP (SEQ ID NO: 3).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence

- 49 047335 of SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215 or residues 297- 309 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry, carried out with exchange in for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X1 is R, G or S, and _X2 is Y or R ; the amino acid sequence of YIYX1X2GSTX3YNPSLKS VHCDR2 (SEQ ID NO: 91), where Xi is G or S, X2 is R, S or T, and _X3 is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than at residues 158,172 of SEQ ID NO: 105 and at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105. 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 158-172 of SEQ ID NO: 105, residues 206-215 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 206-215 of SEQ ID NO: 105, for residues 368-387 of SEQ ID NO: 105 or at residues 297-309 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry exchange carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X1 is R, G or S, and _X2 is Y or R ; the amino acid sequence of YIYXjX ₂ GSTX ₃ YNPSLKS VHCDR2 (SEQ ID NO: 91), where X1 is G or S, X ₂ is R, S or T, and X ₃ is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, the bonds

- 50 047335 binding of an antibody reduces the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of an antibody reduces the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206215 of SEQ ID NO: 105 and at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction in the average the level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, the coupling antibodies provide a decrease in the average level of hydrogen-deuterium exchange at residues 158-172 from SEQ ID NO: 105 to a greater extent than at residues 368-387 from SEQ ID NO: 105 and at residues 297-309 from SEQ ID NO: 105. B In one embodiment, antibody binding reduces the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105, and at residues 368-387 of SEQ ID NO: : 105 and for residues 297-309 from SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), when bound, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87 -104 of SEQ ID NO: 105, wherein the region having the greatest decrease in the average level of hydrogen-deuterium exchange among one or more regions is not residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as bivalent antibody molecules using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X1 is R, G or S, and _X2 is Y or R ; the amino acid sequence of YIYX1X2GSTX3YNPSLKS VHCDR2 (SEQ ID NO: 91), where Xi is G or S, X2 is R, S or T, and _X3 is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of greater than, for example, 0.02, 0.03, 0.04, 0.05, or 0.06 Da per residue, over residues 368 -387 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X ₁ is R, G or S, and X ₂ is Y or R; the amino acid sequence of YIYXjX ₂ GSTX ₃ YNPSLKS VHCDR2 (SEQ ID NO: 91), where X1 is G or S, X ₂ is R, S or T, and X ₃ is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule upon binding to a protein comprising an amino acid sequence

- 51 047335 from residues 27-547 of SEQ ID NO: 105 (for example, a protein consisting of the amino acid sequence of SEQ ID NO: 171), leads to a decrease in the average level of hydrogen-deuterium exchange of less than, for example, 0.05 , 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example, when studying the antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X1 is R, G or S, and _X2 is Y or R ; the amino acid sequence of YIYX1X2GSTX3YNPSLKS VHCDR2 (SEQ ID NO: 91), where Xi is G or S, X2 is R, S or T, and _X3 is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105, and/ or with at least one, two, three, four or five residues within residues 206-215 of SEQ ID NO: 105; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X1 is R, G or S, and _X2 is Y or R ; the amino acid sequence of YIYXjX ₂ GSTX ₃ YNPSLKS VHCDR2 (SEQ ID NO: 91), where X1 is G or S, X ₂ is R, S or T, and X ₃ is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), provides a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 from SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215, or residues 297-309 from SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (d) a VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162, and the amino acid sequence

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VHCDR3 under SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 in greater than at residues 158,172 of SEQ ID NO: 105 and at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average hydrogen-deuterium exchange rate at residues 368-387 of SEQ ID NO: 105. 105 to a greater extent than at residues 158-172 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding causes a reduction in the average level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105 and residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange across residues 368-387 of SEQ ID NO: 105 to a greater extent than residues 158-172 of SEQ ID NO: 105, residues 206-215 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), provides a decrease in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 206-215 of SEQ ID NO: 105, for residues 368-387 of SEQ ID NO: 105 or at residues 297-309 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry exchange carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (d) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one embodiment, antibody binding provides a reduction in the average hydrogen-deuterium exchange rate at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105. In one embodiment, antibody binding provides a reduction the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 368-387 of SEQ ID NO: 105. In one embodiment, antibody binding causes a decrease in the average level of hydrogen-deuterium exchange across residues 158-172 of SEQ ID NO: 105 to a greater extent than for residues 297-309 of SEQ ID NO: 105. In one embodiment, antibody binding results in a reduction in the average level of hydrogen-deuterium exchange for residues 158-172 of SEQ ID NO: 105 in to a greater extent than for residues 206

- 53 047335

215 of SEQ ID NO: 105 and at residues 368-387 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 in greater than at residues 368-387 of SEQ ID NO: 105 and at residues 297-309 of SEQ ID NO: 105. In one embodiment, binding of the antibody results in a reduction in the average level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than residues 206-215 of SEQ ID NO: 105, residues 368-387 of SEQ ID NO: 105, and residues 297-309 of SEQ ID NO: 105.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), when bound, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87 -104 of SEQ ID NO: 105, wherein the region having the greatest decrease in the average level of hydrogen-deuterium exchange among one or more regions is not residues 206-215 of SEQ ID NO: 105, for example, when examining an antibody molecule as bivalent antibody molecules using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (d) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of greater than, for example, 0.02, 0.03, 0.04, 0.05, or 0.06 Da per residue, over residues 368 -387 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in Example 2, for example, hydrogen-deuterium exchange mass spectrometry for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence

- 54 047335

VHCDR3 under SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (d) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule, upon binding to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence under SEQ ID NO: 171), results in a reduction in the average hydrogen-deuterium exchange rate of less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example, when studying an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, for example, as described in example 2, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7-8 (for example, pH 7.5) and room temperature; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (d) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule binds to at least one, two, three, or four residues within residues 158-172 of SEQ ID NO: 105, and/ or with at least one, two, three, four or five residues within residues 206-215 of SEQ ID NO: 105; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence

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VHCDR3 under SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (d) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, e.g. antibody molecules in the form of a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay, for example, as described in Example 1; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence GGLYGSGSYLSDFDL (SEQ ID NO: 37).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, e.g. antibody molecules in the form of a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay, for example, as described in Example 1; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence X1X2AMS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 88), where X1 is R, Y or S, and _X2 is Y or N ; amino acid sequence X ₁ IX ₂ GX ₃ GX ₄ X ₅ TYYADSVKG VHCDR2 (SEQ ID NO: 89), where X1 is A or S, X ₂ is S or T, X ₃ is S or T, X4 is M , G or S, and X ₅ represents N, S, L or Y; and the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37); and (b) a light chain variable region (VL) comprising the amino acid sequence RASQSVGSNLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 48); amino acid sequence of GASTRAT VLCDR2 (SEQ ID NO: 49); and the amino acid sequence of QQHNAFPYT VLCDR3 (SEQ ID NO: 50).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, e.g. antibody molecules in the form of a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay, for example, as described in Example 1; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

(d) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50;

- 56 047335 (e) VH containing the amino acid sequence of VHCDR1 under SEQ ID NO: 137, the amino acid sequence of VHCDR2 under SEQ ID NO: 146 and the amino acid sequence of VHCDR3 under SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (f) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50.

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, e.g. antibody molecules in the form of a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay, for example, as described in Example 1; and (ii) the antibody molecule comprises a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence ESQESPYNNWFDP (SEQ ID NO: 3).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, e.g. antibody molecules in the form of a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay, for example, as described in Example 1; and (ii) the antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence XiX ₂ YWS of heavy chain complementarity determining region 1 (VHCDR1) (SEQ ID NO: 90), where X1 is R, G or S, and X ₂ is Y or R; the amino acid sequence of YIYX1X2GSTX3YNPSLKS VHCDR2 (SEQ ID NO: 91), where X1 is G or S, _X2 is R, S or T, and _X3 is N or K; and the amino acid sequence of ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3); and/or (b) a light chain variable region (VL) comprising the amino acid sequence RASQGISSWLA of light chain complementarity determining region 1 (VLCDR1) (SEQ ID NO: 14); amino acid sequence AASSLQS VLCDR2 (SEQ ID NO: 15); and the amino acid sequence of QQGNSFPRT VLCDR3 (SEQ ID NO: 16).

In one aspect, disclosed herein is an antibody molecule that binds to human CD73, wherein (i) the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, e.g. antibody molecules in the form of a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay, for example, as described in Example 1; and (ii) the antibody molecule contains:

(a) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16;

(c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16; or (d) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 under SEQ ID NO: 14, the amino acid sequence of VLCDR2 under SEQ ID NO: 15 and the amino acid after

- 57 047335 VLCDR3 activity under SEQ ID NO: 16.

Routes of application of anti-CD73 antibody molecules

The antibody molecules disclosed herein can modulate (eg, enhance, stimulate, increase, inhibit, decrease, or neutralize) one or more activities of CD73. In some embodiments, the antibody molecule causes one or more of inhibition or reduction of CD73 enzymatic activity; inhibiting the conversion of adenosine monophosphate (AMP) to adenosine or reducing its level; and increasing the level of proliferation of T cells stimulated by anti-CD3 antibody/anti-CD28 antibody, eg CD4+ T cells, in the presence of adenosine monophosphate (AMP).

In some embodiments, the antibody molecule inhibits or reduces the enzymatic activity of CD73 (e.g., soluble human CD73 or membrane-bound human CD73), e.g., human CD73-mediated conversion of adenosine monophosphate (AMP) to adenosine, as measured, for example, using a method described herein. for example, by quantitation of phosphate by the malachite green (MG) reaction or a modified Cell Titer Glo (CTG) assay, for example, as described in example 1.

In some embodiments, the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is assayed as a bivalent antibody molecule using a modified Cell Titer Glo (CTG) assay ), for example, as described in Example 1. In one embodiment, the antibody molecule inhibits the enzymatic activity of membrane-bound human CD73 by at least about 60%, 70%, 80%, or 90%, for example, when the antibody molecule is tested as a bivalent molecule antibodies using a modified Cell Titer Glo (CTG) assay, including the following steps:

(i) incubating a titrated dose of the antibody molecule (eg, 1000 ng/ml) with 20,000 cells/ml of a human cancer cell line expressing human CD73 (eg, human breast cancer cell line MDA-MB-231 or human ovarian cancer cell line SKOV3 ) for 240 minutes at 37°C in the presence of 100 μM AMP;

(ii) measuring the level of AMP disappearance using a modified Cell Titer Glo (CTG) assay as described in Example 1; and (iii) calculating the percentage of inhibition mediated by the antibody molecule using the time zero control as 100% inhibition and the no antibody control as 0% inhibition.

In some embodiments, the antibody molecule increases the level of proliferation of anti-CD3 antibody/anti-CD28 antibody-stimulated T cells, e.g., CD4+ T cells, in the presence of adenosine monophosphate (AMP), as measured, for example, by a method described herein, e.g. CellTrace Violet (CTV) cell proliferation assay, such as the assay from Example 1.

In certain aspects, a method is provided for modulating (eg, promoting or inhibiting) an immune response in a subject. The method involves administering to a subject an anti-CD73 antibody molecule disclosed herein (e.g., a therapeutically effective amount of an anti-CD73 antibody molecule), alone or in combination with one or more agents or procedures (e.g., in combination with antineoplastic therapies, e.g., chemotherapy, radiation therapy and/or other immunomodulatory agents) in a manner that modulates the immune response in the subject. In some embodiments, the antibody molecule inhibits, reduces, or neutralizes an immune response in a subject.

The subject may be a mammal, such as a monkey, a primate, preferably a great ape, such as a human (eg, a patient with or at risk for a disorder described herein). In some embodiments, the subject needs to enhance the immune response, and in some embodiments, the subject needs to inhibit the immune response. In one embodiment, the subject has a disorder or is at risk for a disorder described herein, such as cancer, as described herein. In certain embodiments, the subject has or is at risk of developing an immune deficiency. For example, the subject is or has been treated with chemotherapy and/or radiation therapy.

In one aspect, there is provided a method of stimulating an immune response in a subject. The method involves administering to a subject an anti-CD73 antibody molecule described herein, eg, a therapeutically effective amount of an anti-CD73 antibody molecule, alone or in combination with one or more agents or procedures.

In one aspect, there is provided a method of treating (eg, one or more of reducing the intensity, inhibiting, or delaying the progression) of a cancer or tumor in a subject. The method involves administering to a subject an anti-CD73 antibody molecule described herein, for example, a therapeutically effective amount of an anti-CD73 antibody molecule, alone or in combination with one

- 58 047335 with it or several means or procedures.

In some embodiments, the antibody molecule is administered in combination with a second therapeutic agent or procedure. In some embodiments, the second therapeutic agent or procedure is selected from one or more of chemotherapy, targeted cancer therapy, oncolytic drug, cytotoxic agent, immunotherapy, cytokine, surgical procedure, radiation treatment procedure, costimulatory molecule activator, inhibitory molecule inhibitor (e.g. checkpoint inhibitor), vaccine or cell therapy. In some embodiments, the second therapeutic agent is selected from one or more of 1) a protein kinase C (PKC) inhibitor; 2) heat shock protein 90 (HSP90) inhibitor; 3) phosphoinositide 3-kinase (PI3K) and/or target of rapamycin (mTOR) inhibitor; 4) a cytochrome P450 inhibitor (for example, a CYP17 inhibitor or a 17-alpha-hydroxylase/C17-20-lyase inhibitor); 5) iron chelating agent; 6) aromatase inhibitor; 7) a p53 inhibitor, for example a p53/Mdm2 interaction inhibitor; 8) apoptosis inducer; 9) angiogenesis inhibitor; 10) aldosterone synthase inhibitor; 11) smoothened receptor inhibitor (SMO); 12) prolactin receptor inhibitor (PRLR); 13) Wnt signaling inhibitor; 14) CDK4/6 inhibitor; 15) fibroblast growth factor receptor 2 (FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor; 16) macrophage colony-stimulating factor (M-CSF) inhibitor; 17) an inhibitor of one or more of c-KIT, histamine release, Flt3 (eg FLK2/STK1) or PKC; 18) an inhibitor of one or more of VEGFR-2 (eg, FLK-1/KDR), PDGFR-beta, cKIT or Raf kinase C; 19) a somatostatin agonist and/or growth hormone release inhibitor; 20) anaplastic lymphoma kinase (ALK) inhibitor; 21) inhibitor of insulin-like growth factor 1 receptor (IGF-1R); 22) P-glycoprotein 1 inhibitor; 23) vascular endothelial growth factor receptor (VEGFR) inhibitor; 24) BCR-ABL kinase inhibitor; 25) FGFR inhibitor; 26) CYP11B2 inhibitor; 27) an HDM2 inhibitor, for example an HDM2-p53 interaction inhibitor; 28) tyrosine kinase inhibitor; 29) c-MET inhibitor; 30) JAK inhibitor; 31) DAC inhibitor; 32) inhibitor of 11 β-hydroxylase; 33) IAP inhibitor; 34) PIM kinase inhibitor; 35) cupin pore inhibitor; 36) a BRAF inhibitor, for example BRAF V600E or wild type BRAF; 37) HER3 inhibitor; 38) MEK inhibitor; or 39) a lipid kinase inhibitor.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is selected from the group consisting of PDR001, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, and AMP-224. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In some embodiments, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 250 mg to 350 mg, about 350 mg to 450 mg, or about 450 mg to 550 mg, such as at a dose of about 300 mg or about 400 mg, eg once every three weeks (Q3W) or once every four weeks (Q4W), eg at a dose of approximately 300 mg Q3W or at a dose of approximately 400 mg Q4W. In one embodiment, the anti-PD-1 antibody molecule is administered, for example, by infusion over a period of 30 minutes or a period of no more than 2 hours. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of from about 5 mg to 100 mg, from about 100 mg to 500 mg, from about 500 mg to 1000 mg, from about 1000 mg to 1500 mg, from about 1500 mg to 2000 mg, from about 2000 mg to 2500 mg, from about 2500 mg to 3000 mg, from about 3000 mg to 3500 mg, or from about 3500 mg to 4000 mg, for example at a dose of about 6 mg, about 20 mg, about 60 mg, about 200 mg, about 600 mg, about 1200 mg, about 2400 mg, about 3000 mg or about 3600 mg, for example once a week (QW), every two weeks (Q2W) or every four weeks (Q4W), for example Q2W. In one embodiment, the anti-CD73 antibody molecule is administered, for example by infusion, over a period of 30 minutes, a period of 1 hour, or a period of no more than 2 hours. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 5 mg to 100 mg, such as 20 mg, Q2W, and the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg , for example 400 mg, Q4W. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 5 mg to 100 mg, such as 60 mg, Q2W, and the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg , for example 400 mg, Q4W. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 100 mg to 500 mg, such as 200 mg, Q2W, and the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg , for example 400 mg, Q4W. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 500 mg to 1000 mg, such as 600 mg, Q2W, and the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg , for example 400 mg, Q4W. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 1000 mg to 1500 mg, such as 1200 mg, Q2W, and the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg , for example 400 mg, Q4W. In some countries

- 59 047335 ant implementation, the anti-CD73 antibody molecule is administered, for example intravenously, at a dose of from about 2000 mg to 2500 mg, for example 2400 mg, Q2W, and the anti-PD-1 antibody molecule is administered, for example intravenously, at a dose from about 350 mg to 450 mg, for example 400 mg, Q4W. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 3000 mg to 3500 mg, such as 3000 mg, Q2W, and the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg , for example 400 mg, Q4W. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 3500 mg to 4000 mg, such as 3600 mg, Q2W, and the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg , for example 400 mg, Q4W.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a PD-L1 inhibitor. In some embodiments, the PD-L1 inhibitor is selected from the group consisting of FAZ053, atezolizumab, avelumab, durvalumab, and BMS-936559.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a CTLA-4 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab or tremelimumab.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is selected from MGB453, TSR-022, or LY3321367.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is selected from the group consisting of LAG525, BMS-986016, TSR-O33, MK-4280, and REGN3767.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a GITR agonist. In some embodiments, the GITR agonist is selected from the group consisting of GWN323 (Novartis), BMS-986156 (BMS), MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte/Agenus), AMG 228 (Amgen) and INBRX-110 (Inhibrx).

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a multispecific anti-CD3 antibody molecule. In some embodiments, the multispecific anti-CD3 antibody molecule is a bispecific anti-CD3 x anti-CD123 antibody molecule (eg, XENP14045) or a bispecific anti-CD3 x anti-CD20 antibody molecule (eg, XENP13676).

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a cytokine molecule. In some embodiments, the cytokine molecule is IL-15 complexed with a soluble form of IL-15 receptor alpha (IL-15Ra).

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a STING agonist.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a macrophage colony-stimulating factor (M-CSF) inhibitor, optionally the M-CSF inhibitor being MCS110.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a CSF-1R inhibitor, wherein the CSF-1R inhibitor is optionally BLZ945.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with an indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) inhibitor.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a TGF-β inhibitor.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with an A2AR adenosine receptor antagonist. In some embodiments, the adenosine A2AR receptor antagonist is selected from the group consisting of PBF509, CPI444, AZD4635, Vipadent, GBV-2034, and AB928. In some embodiments, the adenosine A2AR receptor antagonist is selected from the group consisting of 5-bromo-2,6-di-(N-pyrazol-1-yl)pyrimidin-4-amine; ^)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2 ,3]triazolo[4,5D]pyrimidin-5-amine; (R)7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2, 3]tri-azolo[4,5D]pyrimidin-5-amine or racemate thereof; 7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4 ,5D]pyrimidin-5-amine and 6-(2-chloro-6-methyl pyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine. In some embodiments, the adenosine A2AR receptor antagonist is administered, for example orally, at a dose of from about 20 mg to 60 mg, from about 60 mg to 100 mg, from about 100 mg to 140 mg, from about 140 mg to 180 mg, from about 180 mg to 220 mg, about 220 mg to 260 mg, about 260 mg to 300 mg, about 300 mg to 340 mg, about 340 mg to 380 mg, about 380 mg to 480 mg, about 480 mg to 580 mg, or from about 580 mg to 680 mg, for example at a dose of about 40 mg, about 80 mg, about 160 mg, about 320 mg, about 480 mg or about 620 mg, for example, once daily (QD), twice daily day (BID) or three times a day (TID), for example BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 5 mg to 100 mg, about 100 mg to 500 mg, about 500 mg to 1000 mg, about 1000 mg to 1500 mg , from about 1500 mg to 2000 mg, from about 2000 mg to 2500 mg, from about 2500 mg to 3000 mg, from about 3000 mg to 3500 mg, or from about 3500 mg to 4000 mg, for example at a dose of about 6 mg, about 20 mg, approximately 60 mg, approximately 200 mg, approximately 600 mg, approximately 1200 mg, approximately 2400 mg, approximately 3000 mg, or approximately 3600 mg, e.g. once weekly (QW), once every two weeks (Q2W), or once every four weeks (Q4W), for example Q2W. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 20 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 20 mg to 60 mg, e.g. 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 20 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 60 mg to 100 mg, e.g. 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 20 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 140 mg to 180 mg, e.g. 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 20 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 300 mg to 340 mg, e.g. 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 5 mg to 100 mg, such as 60 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, for example, orally, at a dose of about 20 mg to 60 mg, e.g. 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 60 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 60 mg to 100 mg, e.g. 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 60 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 140 mg to 180 mg, e.g. 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 60 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 300 mg to 340 mg, e.g. 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 100 mg to 500 mg, e.g., 200 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 20 mg to 60 mg, e.g. 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 100 mg to 500 mg, e.g., 200 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 60 mg to 100 mg, e.g. 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 100 mg to 500 mg, e.g., 200 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 140 mg to 180 mg, e.g. 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 100 mg to 500 mg, e.g., 200 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 300 mg to 340 mg, e.g. 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 500 mg to 1000 mg, e.g., 600 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 20 mg to 60 mg, e.g. 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 500 mg to 1000 mg, e.g., 600 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 60 mg to 100 mg, e.g. 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 500 mg to 1000 mg, e.g., 600 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 140 mg to 180 mg, e.g. 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 500 mg to 1000 mg, e.g., 600 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 300 mg to 340 mg, e.g. 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 1000 mg to 1500 mg, e.g., 1200 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 20 mg to 60 mg, e.g. 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 1000 mg to 1500 mg, e.g., 1200 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 60 mg to 100 mg, e.g. 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example intravenously, at a dose of about

- 61 047335 particularly 1000 mg to 1500 mg, eg 1200 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 140 mg to 180 mg, eg 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 1000 mg to 1500 mg, e.g., 1200 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 300 mg to 340 mg, e.g. 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 20 mg to 60 mg, e.g. 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 60 mg to 100 mg, e.g. 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 140 mg to 180 mg, e.g. 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 300 mg to 340 mg, e.g. 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 480 mg to 580 mg, e.g. 480 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 580 mg to 680 mg, e.g. 620 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3000 mg to 3500 mg, e.g., 3000 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 300 mg to 340 mg, e.g. 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3000 mg to 3500 mg, e.g., 3000 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 480 mg to 580 mg, e.g. 480 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3000 mg to 3500 mg, e.g., 3000 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 580 mg to 680 mg, e.g. 620 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3500 mg to 4000 mg, e.g., 3600 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 300 mg to 340 mg, e.g. 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3500 mg to 4000 mg, e.g., 3600 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 480 mg to 580 mg, e.g. 480 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3500 mg to 4000 mg, e.g., 3600 mg, Q2W, and the adenosine A2AR receptor antagonist is administered, e.g., orally, at a dose of about 580 mg to 680 mg, e.g. 620 mg, BID.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a PD-1 inhibitor and an A2AR adenosine receptor antagonist. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of from about 5 mg to 100 mg, from about 100 mg to 500 mg, from about 500 mg to 1000 mg, from about 1000 mg to 1500 mg, from about 1500 mg to 2000 mg, from about 2000 mg to 2500 mg, from about 2500 mg to 3000 mg, from about 3000 mg to 3500 mg, or from about 3500 mg to 4000 mg, for example at a dose of about 6 mg, about 20 mg, about 60 mg, about 200 mg, about 600 mg, about 1200 mg, about 2400 mg, about 3000 mg or about 3600 mg, for example once a week (QW), every two weeks (Q2W) or every four weeks (Q4W), for example Q2W. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In some embodiments, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 250 mg to 350 mg, about 350 mg to 450 mg, or about 450 mg to 550 mg, such as at a dose of about 300 mg or about 400 mg, eg once every three weeks (Q3W) or once every four weeks (Q4W), eg at a dose of approximately 300 mg Q3W or at a dose of approximately 400 mg Q4W. In some embodiments, the adenosine A2AR receptor antagonist is administered, for example orally, at a dose of about 20 mg to 60 mg, about 60 mg to 100 mg, about 100 mg to 140 mg, about 140 mg to 180 mg, about 180 mg up to 220 mg, from about 220 mg to 260 mg, from about 260 mg to 300 mg, from about 300 mg to 340 mg, from about 340 mg to 380 mg, from about 380 mg to 480 mg, from about 480 mg to 580 mg or from about 580 mg to 680 mg, for example at a dose of about 40 mg, about 80 mg, about 160 mg, about

- 62 047335

320 mg, about 480 mg, or about 620 mg, eg once daily (QD), twice daily (BID) or three times daily (TID), eg BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 20 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 20 mg to 60 mg, eg 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 20 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 60 mg to 100 mg, eg 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 20 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 140 mg to 180 mg, eg 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 5 mg to 100 mg, e.g., 20 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 300 mg to 340 mg, eg 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 5 mg to 100 mg, such as 60 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 20 mg to 60 mg, eg 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 5 mg to 100 mg, such as 60 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 60 mg to 100 mg, eg 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 5 mg to 100 mg, such as 60 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 140 mg to 180 mg, eg 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 5 mg to 100 mg, such as 60 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 300 mg to 340 mg, eg 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 100 mg to 500 mg, such as 200 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 20 mg to 60 mg, eg 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 100 mg to 500 mg, such as 200 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 60 mg to 100 mg, eg 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 100 mg to 500 mg, such as 200 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 140 mg to 180 mg, eg 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of from about 100 mg to 500 mg, such as 200 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of from about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 300 mg to 340 mg, eg 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 500 mg to 1000 mg, such as 600 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 20 mg to 60 mg, eg 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 500 mg to 1000 mg, such as 600 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg, eg, 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 60 mg to 100 mg, eg 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 500 mg to 1000 mg, e.g., 600 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at

- 63 047335 at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 140 mg to 180 mg, eg 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, for example, intravenously, at a dose of about 500 mg to 1000 mg, such as 600 mg, Q2W, the anti-PD-1 antibody molecule is administered, for example, intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 300 mg to 340 mg, eg 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 1000 mg to 1500 mg, e.g., 1200 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 20 mg to 60 mg, eg 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 1000 mg to 1500 mg, e.g., 1200 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 60 mg to 100 mg, eg 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 1000 mg to 1500 mg, e.g., 1200 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 140 mg to 180 mg, eg 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 1000 mg to 1500 mg, e.g., 1200 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 300 mg to 340 mg, eg 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 20 mg to 60 mg, eg 40 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 60 mg to 100 mg, eg 80 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 140 mg to 180 mg, eg 160 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 300 mg to 340 mg, eg 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 480 mg to 580 mg, eg 480 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 2000 mg to 2500 mg, e.g., 2400 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 580 mg to 680 mg, eg 620 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3000 mg to 3500 mg, e.g., 3000 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 300 mg to 340 mg, eg 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3000 mg to 3500 mg, e.g., 3000 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 480 mg to 580 mg, eg 480 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3000 mg to 3500 mg, e.g., 3000 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 580 mg to 680 mg, eg 620 mg, BID. In some embodiments, an anti-CD73 antibody molecule

- 64 047335 administered, for example intravenously, at a dose of from about 3500 mg to 4000 mg, for example 3600 mg, Q2W, an anti-PD-1 antibody molecule is administered, for example intravenously, at a dose of from about 350 mg to 450 mg, for example 400 mg, Q4W , and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 300 mg to 340 mg, eg 320 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3500 mg to 4000 mg, e.g., 3600 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 480 mg to 580 mg, eg 480 mg, BID. In some embodiments, the anti-CD73 antibody molecule is administered, e.g., intravenously, at a dose of about 3500 mg to 4000 mg, e.g., 3600 mg, Q2W, the anti-PD-1 antibody molecule is administered, e.g., intravenously, at a dose of about 350 mg to 450 mg, eg 400 mg, Q4W, and the adenosine A2AR receptor antagonist is administered, eg orally, at a dose of about 580 mg to 680 mg, eg 620 mg, BID.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a PD-L1 inhibitor and an A2AR adenosine receptor antagonist.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with a chimeric antigen receptor (CAR) T-cell therapy. In some embodiments, the CAR T cell therapy is CTL019.

In some embodiments, the anti-CD73 antibody molecule is administered in combination with one or more of the agents described in Table 18, for example, one or more of 1) a protein kinase C (PKC) inhibitor; 2) heat shock protein 90 (HSP90) inhibitor; 3) phosphoinositide 3-kinase (PI3K) and/or target of rapamycin (mTOR) inhibitor; 4) a cytochrome P450 inhibitor (for example, a CYP17 inhibitor or a 17-alpha-hydroxylase/C17-20-lyase inhibitor); 5) iron chelating agent; 6) aromatase inhibitor; 7) a p53 inhibitor, for example a p53/Mdm2 interaction inhibitor; 8) apoptosis inducer; 9) angiogenesis inhibitor; 10) aldosterone synthase inhibitor; 11) smoothened receptor inhibitor (SMO); 12) prolactin receptor inhibitor (PRLR); 13) Wnt signaling inhibitor; 14) CDK4/6 inhibitor; 15) fibroblast growth factor receptor 2 (FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor; 16) macrophage colony-stimulating factor (M-CSF) inhibitor; 17) an inhibitor of one or more of c-KIT, histamine release, Flt3 (eg FLK2/STK1) or PKC; 18) an inhibitor of one or more of VEGFR-2 (eg, FLK-1/KDR), PDGFR-beta, c-KIT or Raf kinase C; 19) a somatostatin agonist and/or growth hormone release inhibitor; 20) anaplastic lymphoma kinase (ALK) inhibitor; 21) inhibitor of insulin-like growth factor 1 receptor (IGF-1R); 22) P-glycoprotein 1 inhibitor; 23) vascular endothelial growth factor receptor (VEGFR) inhibitor; 24) BCR-ABL kinase inhibitor; 25) FGFR inhibitor; 26) CYP11B2 inhibitor; 27) an HDM2 inhibitor, for example an HDM2-p53 interaction inhibitor; 28) tyrosine kinase inhibitor; 29) c-MET inhibitor; 30) JAK inhibitor; 31) DAC inhibitor; 32) 11β-hydroxylase inhibitor; 33) IAP inhibitor; 34) PIM kinase inhibitor; 35) porcupine inhibitor; 36) a BRAF inhibitor, for example BRAF V600E or wild type BRAF; 37) HER3 inhibitor; 38) MEK inhibitor; or 39) a lipid kinase inhibitor described herein and in Table. 18.

In certain embodiments, the cancer treated with the anti-CD73 antibody molecule alone or in combination with a second therapeutic agent or procedure includes, but is not limited to, solid tumor, hematologic cancer (eg, leukemia, lymphoma, myeloma, eg, multiple myeloma), and metastatic disease. In some embodiments, the cancer is selected from lung cancer (eg, non-small cell lung cancer), pancreatic cancer (eg, pancreatic ductal adenocarcinoma), breast cancer (eg, triple negative breast cancer), melanoma, head and neck cancer (eg , squamous cell carcinoma of the head and neck), colorectal cancer (eg, microsatellite stable (MSS) colorectal cancer), ovarian cancer, or kidney cancer (eg, renal cell carcinoma). In certain embodiments, the anti-CD73 antibody molecule, used alone or in combination with a second therapeutic agent or procedure, controls tumor growth, reduces the rate of metastasis, and/or improves survival.

In certain embodiments, the antibody molecule is administered at a dose of from about 100 mg to 1600 mg, from about 100 mg to 1400 mg, from about 100 mg to 1200 mg, from about 100 mg to 1000 mg, from about 100 mg to 800 mg, from about 100 mg to 600 mg, about 100 mg to 400 mg, about 100 mg to 200 mg or about 100 mg, about 180 mg or about 200 mg, for example once every two weeks. In one embodiment, the antibody molecule is administered at a dose of at least about 180 mg every two weeks.

In certain embodiments, the antibody molecule is administered, for example, intravenously, at a dose of from about 5 mg to 100 mg, from about 100 mg to 500 mg, from about 500 mg to 1000 mg, from about 1000 mg to 1500 mg, from about 1500 mg to 2000 mg, about 2000 mg to 2500 mg, about 2500 mg to 3000 mg, about 3000 mg to 3500 mg, or

- 65 047335 from approximately 3500 mg to 4000 mg, for example once a week (QW), every two weeks (Q2W) or every four weeks (Q4W). In certain embodiments, the antibody molecule is administered, for example, intravenously, at a dose of about 6 mg, about 20 mg, about 60 mg, about 200 mg, about 600 mg, about 1200 mg, about 2400 mg, about 3000 mg, or about 3600 mg, for example QW, Q2W or Q4W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 60 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 200 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 600 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 1200 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 2400 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 3000 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 3600 mg Q2W.

In addition, the present invention provides methods for enhancing an immune response to an antigen in a subject, comprising administering to the subject (i) an antigen; and (ii) an anti-CD73 antibody molecule disclosed herein such that the immune response to the antigen is enhanced in the subject. The antigen may be, for example, a tumor antigen, a viral antigen, a bacterial antigen, or an antigen from a pathogen.

The anti-CD73 antibody molecule can be administered to a subject systemically (eg, orally, parenterally, subcutaneously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or intracavitary administration) or locally. In one embodiment, the anti-CD73 antibody molecule is administered intravenously.

The anti-CD73 antibody molecule may be used alone in unconjugated form, or it may be associated with a substance, such as a cytotoxic agent or fragment (eg, a therapeutic drug; a radiation-emitting compound; molecules of plant, fungal or bacterial origin, or a biological protein (eg, a protein toxin) or particle (eg, a recombinant viral particle, eg via a viral envelope protein). For example, an anti-CD73 antibody may be coupled to a radioactive isotope such as an α, β or γ emitter, or a β and γ emitter.

Dosages and therapeutic regimens for the anti-CD73 antibody molecule can be determined by one skilled in the art.

In another aspect, a method is provided for detecting CD73 in a biological sample or subject. In one embodiment, the method comprises (i) contacting a sample or subject (and optionally a reference sample or subject) with an antibody molecule according to any one of claims 1 to 57 under conditions that allow the antibody molecule to interact with CD73, and (ii) detecting forming a complex between the antibody molecule and the sample or subject (and optionally a reference sample or subject).

The antibody molecules described herein are preferred for use in the methods described herein, although other anti-CD73 antibodies may be used instead of or in combination with the anti-CD73 antibody molecule of the present invention.

Brief description of graphic materials

In fig. 1 is a graph depicting the level of binding of anti-CD73 antibodies or isotype control antibodies to CD8+ T cells as measured by flow cytometry. MFI values are plotted against antibody concentration. The antibodies tested are CD73 antibodies 350, 356, 358, 373, 374, 377 and 379, as well as an isotype control antibody, all expressed in format.B.

In fig. 2A and 2B are graphs showing the results of a malachite green inorganic phosphate assay that examines the ability of an anti-CD73 antibody to inhibit the CD73-mediated conversion of adenosine monophosphate (AMP) to adenosine. The rate of inorganic phosphate (Pi) release is plotted against the AMP concentrations tested. In fig. 2A, recombinant human CD73 was incubated with AMP substrate in buffer alone (Km hCD73) or in the presence of an IgG1 isotype control antibody (ISO.C). In fig. 2B, recombinant CD73 was incubated with AMP buffer alone (Km hCD73) or in the presence of anti-CD73 antibody 350.C at the indicated concentrations (1 μg/ml 350.C, 0.3 μg/ml 350.C, or 0.1 μg/ ml 350.C).

In fig. 3A, 3B and 3C are graphs showing the results of a malachite green (MG) phosphate assay that determines the ability of an anti-CD73 antibody to inhibit the enzymatic activity of recombinant soluble human or cynomolgus CD73. % INH phosphate formation is plotted against anti-CD73 antibody concentrations for studies using recombinant human CD73 (FIGS. 3A and 3B) or cynomolgus CD73 (FIG. 3C). The antibodies tested are anti-CD73 350, 356,

- 66 047335

373 and 374, expressed in .A or .B format.

In fig. 4 is a graph showing the results of a modified Cell Titer Glo (CTG) assay testing the enzyme inhibitory activity of anti-CD73 antibodies against CD73 isolated from the MDA-MB-231 breast cancer cell line. %INH is plotted against a range of anti-CD73 antibody concentrations. The antibodies tested are CD73 antibodies 350 and 373 expressed in either .A or .B format, an isotype control antibody of IgG4 S228P (ISO.A), and an isotype control antibody of IgG4 S228P/L235E- (ISOB ).

In fig. 5 is a graph showing the results of a modified Cell Titer Glo (CTG) assay that examines the ability of anti-CD73 antibodies to inhibit CD73 enzymatic activity in serum from a patient with pancreatic cancer. % INH AMP conversion is plotted against anti-CD73 antibody concentrations. The CD73 antibodies tested are antibodies 350, 356, 358, 373, 374, 377 and 379, all expressed in format.B.

In fig. 6 is a graph showing the level of inhibition of CD73 expressed on the surface of the breast cancer cell line MDA-MB-231 measured using phosphate quantitation by the malachite green reaction. % INH conversion of AMH is plotted against a range of anti-CD73 antibody concentrations. The CD73 antibodies tested are antibodies 350, 356, 358, 373, 374, 377 and 379, all in .B format.

Fig. 7A, 7B, 7C and 7D are bar graphs showing the results of a modified Cell Titer Glo (CTG) assay that examines the ability of anti-CD73 antibodies to inhibit the enzymatic activity of CD73 expressed on the surface of the human breast cancer cell line MDA-MB-231 (Figs. 7A and 7C) or the mouse breast cancer cell line 4T1 (Figs. 7B and 7D). The Y-axis shows the percentage of inhibition relative to the control without antibodies (full conversion) and the control at time zero (no conversion). For each antibody, bars from left to right represent doses of 10, 3, 1, and 0.3 μg/mL. The antibodies tested were line 1 antibodies 918, 350, 356, and 358 (FIGS. 7A and 7B) and line 3 antibodies 930, 373, 374, 376, 377, and 379 (FIGS. 7C and 7D).

Fig. 8A and 8B are graphs showing the enzyme inhibition activity of anti-CD73 antibodies against surface CD73 expressed on the human breast cancer cell line MDA-MB-231 or the human ovarian cancer cell line SKOV3, measured using a modified Cell Titer assay Glo (CTG). %INH is plotted against a range of anti-CD73 antibody concentrations. The anti-CD73 antibodies tested are antibodies 350 and 373, expressed in .A or .B format.

Fig. 9A and 9B are graphs similar to those in FIG. 8A and 8B. The antibodies tested are anti-CD73 350, 356, 373 and 374 format. A or.B.

Fig. 10 is a graph showing the level of inhibition of human CD73 overexpressed on HEK 293 cells by anti-CD73 antibodies as measured by a modified Cell Titer Glo (CTG) assay. %INH conversion of AMH is plotted against a range of anti-CD73 antibody concentrations. The antibodies tested are anti-CD73 350, 356, 373 and 374 in .A or .B format.

Fig. 11A and 11B are graphs showing the level of inhibition of CD73 expressed on primary human PBMCs isolated from two separate donors by anti-CD73 antibodies as measured by a modified Cell Titer Glo (CTG) assay. %INH is plotted against a range of anti-CD73 antibody concentrations. The CD73 antibodies tested are antibodies 350, 356 and 358, all in .B format.

Fig. 12A and 12B are graphs showing the level of proliferation of CD4+ T cells stimulated with anti-CD3/28 antibody in the presence of AMP and anti-CD73 antibody. The proliferation index, a measure of T cell division, is plotted against a range of antibody concentrations. In fig. 12A shows the results of a study examining anti-CD73 antibodies 350, 356, 358, 374, 377, and 379, all in the format.B. In fig. 12B shows the results of a study using antibodies 350 and 372 expressed in .A or .B format.

Fig. 13 is a bar graph showing the results of a xenograft study examining the ability of an anti-CD73 antibody to inhibit CD73 enzymatic activity in vivo. The y-axis shows serum levels of adenosine and inosine in immune-compromised mice implanted with a high-expressing CD73 breast cancer cell line (MDA-MB-231), measured by mass spectrometry. Antibodies to CD73 350, 356, 373 and 374, expressed in format.A or.B, were administered intraperitoneally at a dose of 20 or 200 μg/mouse. A control antibody, human polyclonal IgG, was administered at a dose of 200 μg/mouse.

Fig. 14 is a graph showing a comparison of the protection profiles of 373.A and 373.B measured by hydrogen-deuterium exchange fragmentation mass spectrometry (HDx-MS). In fig. Figure 14 shows the results for exchange for 1 minute at pH 7.5 and room temperature.

- 67 047335 temperature.

Fig. 15 is a graph showing a comparison of the protection profiles of 350.A2 and 350.B measured using hydrogen-deuterium exchange fragmentation mass spectrometry (HDx-MS). In fig. Figure 15 shows the results for 1 minute exchange at pH 7.5 and room temperature.

Fig. 16A is a graphical representation showing the conformational change of CD73 between a closed/active (Protein Structure Database (PDB) 4H2I) and an open/inactive conformation (PDB 4H2F). Fig. 16B is a graphical representation showing the open/open conformation of a CD73 dimer constructed from two PDB 4H2F units after alignment of the C-terminal domains with PDB 4H1S.

Fig. 17A and 17B are graphs showing SEC profiles of CD73-373.A and CD73-373.B complexes, respectively.

Fig. 18A and 18B are graphs showing SEC profiles of CD73-350.A2 and CD73-350.B complexes, respectively.

Fig. 19 is a graph showing the relative percentage values of CD73/mAb species calculated using the integration method.

Fig. 20 is a schematic graphical representation showing an oligomerization model for combining HDx and SEC interpretations.

Fig. 21A and 21B are graphs showing the level of CD73 expression in subsets of stromal cells analyzed by flow cytometry in 4T1 tumors from mice treated with a pan-anti-TGFP antibody or hIgG2 isotype control. In fig. 21A CD73 expression is plotted as fluorescence intensity compared to samples stained with appropriate isotopic controls. One representative sample is shown. In fig. 21B shows a quantification of CD73 expression level measured as mean fluorescence intensity. Each symbol represents a pattern. P-values are reported where significant. CAF=cancer associated fibroblasts.

Fig. 22A, 22B and 22C are graphs showing the results of an assay evaluating the effect of anti-CD73 antibody on immunoglobulin class switching recombination in B cells. Intact (CD19'CD27 ^- IgM'IgD') CD73' and CD73 ^B cells were isolated from the peripheral blood of healthy donors, labeled with CFSE and stimulated in vitro with CpG 2006, antibodies to CD40, IL-2, IL-21 and transferrin. Cells were cultured in the presence of anti-CD73 350.B antibody or isotype control antibody (IgG4) at three different concentrations: 1, 10 and 100 ng/ml. In fig. 22A measured IgM secretion in 7-day cell culture supernatant using an ELISA assay. In fig. 22B, the level of B cell proliferation was measured on day 7, and the numbers of dividing cells counted after electronic gating of the diluted CFSE population were plotted for the three different concentrations tested. In fig. 22C IgG secreting cells (IgG SC) were counted by ELISPOT assay at the same time point. Data were collected from two independent experiments.

Fig. 23 is a panel of graphs showing individual tumor volumes for the indicated groups. Isotype control mice were sacrificed on day 25. In the anti-PD-1 antibody-treated group, mice received 300 μg/mouse for all doses. In the 350.B treated group, mice received 600 μg/mouse for the first dose and then 400 μg/mouse for the remaining four doses. The same dosing schedules were used for the combination group. All mice were treated on days 2, 5, 9, 12, and 17.

Fig. 24A is a pair of graphs showing the detection of biotinylated 373.A on blood samples from two donors pretreated with unlabeled 373.A. FIG. 24B is a graph showing the percentage of target occupancy on CD8+ T cells by antibody 373.A.

Fig. 25A and 25B are panel graphs showing that proliferation of CD4+ and CD8+ T cells was suppressed by AMP during TCR-mediated activation, and this suppression could be reversed by antibody 373.A.

In fig. 26A and 26B show the CD73 residues (bold, italics and single underline) that interact with the heavy chain of Fab 350.A2 through direct enthalpic interactions (Y110, L132, K136, S155, L157 and K162, numbered according to SEQ ID NO: 105) (FIG. 26A) or van der Waals and hydrophobic interactions (residues 136-138 and 155-170, numbered according to SEQ ID NO: 105) (FIG. 26B) measured in Example 8. FIG. 26C and 26D show heavy chain residues of Fab 350.A2 (bold, italics and single underline) that interact with CD73 through direct enthalpic interactions (R31, R54, E95, E98 and S99, numbered according to Kabat, or R31, R54 , E98, E101 and S102, numbered according to their linear positions in SEQ ID NO: 331 (Fig. 26C) or van der Waals and hydrophobic interactions (residues 30, 31, 33, 50, 52, 56, 97, 98, 100 , and 100a, numbered according to Kabat numbering, or residues 30, 31, 33, 50, 52, 56, 100, 101, 103, and 104, numbered according to their linear

- 68047335 positions in SEQ ID NO: 331) (FIG. 26D) measured in Example 8. In FIG. 26E and 26F show CD73 residues (bold, italics and single underline) that interact with the light chain of Fab 350.A2 through direct enthalpic interactions (T209 numbered according to SEQ ID NO: 105) (Fig. 26E) or van der Waals and hydrophobic interactions (residues 209 and 210 numbered according to SEQ ID NO: 105) (FIG. 26F) measured in Example 8. FIG. 26G and 26H show the light chain residues of Fab 350.A2 (bold, italics and single underline) that interact with CD73 through direct enthalpy interactions (W32, numbered according to Kabat numbering by their linear positions in SEQ ID NO: 23) ( Fig. 26G) or van der Waals and hydrophobic interactions (residues 30 and 32, numbered according to Kabat numbering or their linear positions in SEQ ID NO: 23) (Fig. 26H) measured in Example 8. The signal peptide is underlined by a double line in fig. 26A, 26B, 26E and 26F.

Fig. 27A and 27B are graphs showing the difference between the labeling levels observed for CD73/mAb complexes and CD73 alone after a 30 s labeling pulse.

Fig. 28A and 28B are graphs showing the difference between the labeling levels observed for CD73/mAb complexes and CD73 alone after a 300 s labeling pulse.

Brief description of tables

In table 1 shows the amino acid and nucleotide sequences for exemplary CD73 antibodies.

In table 2 shows consensus CDR sequences for exemplary CD73 antibodies.

In table Figure 3 shows the amino acid sequences of human IgG heavy chains and human kappa light chains.

In table 4 shows exemplary CD73 sequences.

In table 5 and 6 show the amino acid and/or nucleotide sequences of exemplary anti-PD-1 antibody molecules.

In table 7 and 8 show the amino acid and/or nucleotide sequences of exemplary anti-PD-L1 antibody molecules.

In table 9 and 10 show the amino acid and/or nucleotide sequences of exemplary anti-LAG-3 antibody molecules.

In table 11 and 12 show the amino acid and/or nucleotide sequences of exemplary anti-TIM-3 antibody molecules.

In table 13 and 14 show the amino acid and/or nucleotide sequences of exemplary anti-GITR antibody molecules.

In table 15 shows the amino acid sequences of exemplary anti-CD3 bispecific antibody molecules.

In table 16 and 17 show the amino acid sequences of exemplary IL15/IL-15Ra complexes.

Table 18 is a summary of selected therapeutic agents that can be administered in combination with the anti-CD73 antibody molecules described herein. In table 18, from left to right, shows the following: the compound designation of the second therapeutic agent, the structure of the compound, and the publication of the patent(s) disclosing said compound.

In table 19 shows the designations for two lines of antibodies to CD73.

In table 20 shows binding affinities for anti-CD73 antibodies.

In table 21 shows the binding affinity values for Fab antibodies to CD73.

In table Figure 22 shows preliminary dose levels for 373.A.

In table Figure 23 shows preliminary dose levels for 373.A in combination with PBF509.

In table Figure 24 shows preliminary dose levels for 373.A in combination with BAP049-clone-E.

In table Figure 25 shows preliminary dose levels for PBF509 in combination with 373.A and BAP049clone-E.

In table 26 shows the corresponding anti-CD73 germline sequences.

Detailed Description of the Invention

As used herein, the term CD73 refers to cluster of differentiation 73, also known as 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase. The term CD73 includes mutants, fragments, variants, isoforms, and homologs of full-length wild-type CD73. In one embodiment, the CD73 protein is encoded by the NT5E gene. Exemplary CD73 sequences are available in the Uniprot database under accession numbers Q6NZX3 and P21589. Exemplary amino acid sequences of immature CD73 are provided under SEQ ID NO: 105-107. CD73 monomer refers to a polypeptide containing the extracellular domain of CD73. In one embodiment, the CD73 monomer is full-length CD73. A CD73 dimer refers to two polypeptides (e.g., two non-covalently linked polypeptides) consisting of two CD73 monomers (e.g., two identical CD73 monomers) interacting with each other to form a stable dimer, e.g., a dimer formed through protein-protein interactions between C

- 69 047335 terminal domains of CD73 monomers. In one embodiment, the CD73 dimer is a naturally occurring CD73 dimer.

Without being limited by theory, human CD73 contains two domains. A conserved N-terminal domain (corresponding to approximately residues 29-310 of SEQ ID NO: 105) and a conserved C-terminal domain (corresponding to approximately residues 343-513 of SEQ ID NO: 105), which are linked by a single α-helix (corresponding approximately to residues 318-336 from SEQ ID NO: 105). The active site is found mainly in a closed conformation and is formed between the C- and N-terminal domains. In terms of enzymatic catalysis, movement of the N-terminal domain by ~100° relative to the C-terminal domain can enable substrate binding and release, which occurs in an open (catalytically inactive) conformation. Human CD73 forms a dimer through protein-protein interactions between the C-terminal domains. The recessed surface area as well as the molecular interactions at the dimer interface differ significantly between the active and inactive conformations of the enzyme. See, for example, Kparr K, et al., Structure 20:2161-73 (2012), incorporated herein by reference in its entirety.

Accordingly, the present invention provides, at least among other things, antibody molecules that bind to CD73 with high affinity and specificity. In one embodiment, human antibodies are disclosed herein that bind to CD73. In one embodiment, disclosed herein are antibody molecules that are capable of inhibiting or reducing the enzymatic activity of CD73, such as human CD73, such as soluble human CD73 or membrane-bound human CD73. In one embodiment, disclosed herein are antibody molecules that are capable of inhibiting or reducing the level of CD73-mediated conversion of adenosine monophosphate (AMP) to adenosine. Additional aspects of the present invention include nucleic acid molecules encoding antibody molecules, expression vectors, host cells, and methods for producing antibody molecules. Also provided are immunoconjugates, poly- or bispecific antibody molecules, and pharmaceutical compositions containing antibody molecules. The anti-CD73 antibody molecules disclosed herein can be used for the treatment, prevention, and/or diagnosis of cancers or malignant disorders, such as solid tumors and liquid tissue tumors, such as lung cancer (e.g., non-small cell lung cancer), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), breast cancer (eg, triple negative breast cancer), melanoma, head and neck cancer (eg, head and neck squamous cell carcinoma), colorectal cancer (eg, microsatellite stable (MSS) colorectal cancer), ovarian cancer or kidney cancer (eg, renal cell carcinoma). The anti-CD73 antibody molecules disclosed herein can be used for the treatment, prevention and/or diagnosis of an infectious disease. Thus, methods for detecting CD73 are disclosed herein, as well as methods for treating various disorders, including cancer and infectious diseases, using anti-CD73 antibody molecules.

Additional terms are defined below and throughout this application.

As used herein, singular forms refer to one or more than one (eg, at least one) grammatical object of the form. As used herein, the term multiple means two or more.

The term or is used herein to refer to the term and/or and is used interchangeably with it unless the context clearly indicates otherwise.

The terms approximately and approximate will generally mean an acceptable degree of error for the quantity being measured, given the nature or accuracy of the measurements. Illustrative error rates are within 20 percent (%), typically within 10%, and in most cases within 5% of a specified value or range of values.

The compositions and methods disclosed herein cover polypeptides and nucleic acids having the specified sequences or sequences substantially identical or similar thereto, such as sequences having at least about 85%, 90% or 95% identity with the specified sequence . In the context of an amino acid sequence, the term substantially identical is used herein to mean a first amino acid sequence that contains a sufficient or minimal number of amino acid residues that are i) identical to aligned amino acid residues in a second amino acid sequence or ii) conservative substitutions thereof such that the first and the second amino acid sequences may have the same structural domain and/or the same functional activity. For example, amino acid sequences that contain the same structural domain are characterized by at least about 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a reference sequence, such as the sequence provided herein.

In the context of a nucleotide sequence, the term essentially identical is used in this book.

- 70 047335 document to designate a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in the second nucleic acid sequence such that the first and second nucleotide sequences encode or encode a polypeptide having the same functional activity a domain of a polypeptide with the same structure or a polypeptide with the same functional activity. For example, nucleotide sequences have at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a reference sequence, such as the sequence provided in this document.

The term functional variant refers to polypeptides that have an amino acid sequence substantially identical to a naturally occurring sequence, or are encoded by a substantially identical nucleotide sequence, and are capable of exhibiting one or more of the activities of the naturally occurring sequence.

Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows.

To determine the percentage identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for the purpose of optimal comparison (for example, gaps may be introduced into one or both of the first and second amino acid sequences or nucleic acid sequences for optimal alignment, and non-homologous sequences may not be included in the for comparison purposes). In a preferred embodiment, the length of the reference sequence aligned for comparison purposes is at least 30%, for example at least 40%, 50%, 60%, for example at least 70%, 80%, 90%, 100% of the length of the reference sequences. The amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are then compared. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.

The percentage identity of two sequences depends on the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that must be introduced for optimal alignment of the two sequences.

Comparing sequences and determining the percentage identity of two sequences can be done using a mathematical algorithm. In some embodiments, the percentage identity of two amino acid sequences is determined using the Needleman-Wunsch algorithm ((1970) J. Mol. Biol. 48:444-453), which was included in the GAP program as part of the GCG software package (available at http: //www.gcg.com), using either the Blossom 62 matrix or the RAM250 matrix, and a gap opening penalty of 16, 14, 12, 10, 8, 6 or 4, and a gap extension penalty of 1, 2, 3, 4, 5, or 6. In certain embodiments, the percentage identity between two nucleotide sequences is determined using the GAP program within the GCG software package (available at http://www.gcg.com) using the NWSgapdna.CMP matrix and a gap opening penalty of 40, 50, 60, 70, or 80, and a gap extension penalty of 1, 2, 3, 4, 5, or 6. One suitable set of parameters (and the one that should be applied if not otherwise stated) is a Blossum 62 scoring matrix with a penalty for opening a gap of 12, a penalty for extending a gap of 4, and a penalty for shifting the frame of a gap 5.

The percentage identity of two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17), which was included in the ALIGN program (version 2.0), using the PAM120 residue substitution weight table , penalty for extending gap 12 and penalty for opening gap 4.

The nucleic acid and protein sequences described herein can be used as query sequences to search public databases, for example, to identify other members of the family or related sequences. Such searches can be performed using the programs NBLAST and XBLAST (version 2.0) Altschul, et al. (1990) J. Mol. Biol. 215:403-10. Nucleotide BLAST searches can be performed using the NBLAST program, score=100, word length=12, to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. Protein BLAST searches can be performed using the XBLAST program, score=50, word length=3, to obtain amino acid sequences homologous to the protein molecules described herein. Gapped BLAST can be used to obtain gap alignments for comparison purposes, as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389–3402. When using the BLAST and Gapped BLAST programs, you can use the default settings from the corresponding programs (for example, XBLAST and NBLAST). See http://www.ncbi.nlm.nih.gov.

As used herein, the term hybridizes under low stringency, moderate stringency, high stringency, or very high stringency conditions describes the hybridization conditions and

- 71 047335 washing. Guidance for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which is incorporated herein by reference. This reference describes methods using an aqueous medium and a non-aqueous medium, and either method can be used. The specific hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions in 6X sodium chloride/sodium citrate (SSC) at approximately 45°C, followed by two washes in 0.2X SSC, 0.1% SDS at at least 50°C (washing temperature may be increased to 55°C for low severity conditions); 2) moderate stringency hybridization conditions - in 6X SSC at approximately 45°C, then one or more washes in 0.2X SSC, 0.1% SDS at 60°C; 3) high stringency hybridization conditions - 6X SSC at approximately 45°C, then one or more washes in 0.2X SSC, 0.1% SDS at 65°C; and preferably 4) very high stringency hybridization conditions are 0.5 M sodium phosphate, 7% SDS at 65°C, followed by one or more washes at 0.2X SSC, 1% SDS at 65°C. Very high stringency conditions (4) are suitable conditions and are those that should be used unless otherwise stated.

It should be understood that the molecules of the present invention may have additional conservative or non-essential amino acid substitutions that do not significantly affect their functions.

The term amino acid is intended to cover all molecules, both natural and synthetic, that contain both an amino functional group and an acid functional group, and can be incorporated into a polymer of naturally occurring amino acids. Exemplary amino acids include naturally occurring amino acids; their analogs, derivatives and related compounds; amino acid analogues having variant side chains; and all stereoisomers of any of the above. As used herein, the term amino acid includes both D- and L-optical isomers and peptidomimetics.

A conservative amino acid substitution is a substitution in which an amino acid residue is replaced by an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been identified in the prior art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g. threonine, valine, isoleucine) and aromatic side chains (e.g. tyrosine, phenylalanine , tryptophan, histidine).

The terms polypeptide, peptide, and protein (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be interrupted by molecules other than amino acids. The terms also cover a polymer of amino acids that has been modified; for example, through disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation or any other manipulation such as conjugation to a labeling moiety. The polypeptide may be isolated from natural sources, may be obtained by recombination-based techniques from a eukaryotic or prokaryotic host, or may be the product of synthetic procedures.

The terms nucleic acid, nucleic acid sequence, nucleotide sequence or polynucleotide sequence and polynucleotide are used interchangeably. They refer to the polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or their analogues. The polynucleotide can be either single-stranded or double-stranded, and if single-stranded, it can be a coding strand or a non-coding (antisense) strand. The polynucleotide may contain modified nucleotides, such as methylated nucleotides and nucleotide analogues. The nucleotide sequence may be interrupted by non-nucleotide components. The polynucleotide may be further modified after polymerization, for example, by conjugation with a labeling moiety. The nucleic acid may be a recombinant polynucleotide or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin that is either not naturally occurring or is linked to another polynucleotide in a non-natural location.

As used herein, the term isolated refers to material that has been removed from its original or native environment (eg, the natural environment if it occurs in nature). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide isolated through human intervention from some or all of the co-existing materials in a natural system is isolated. Such polynucleotides may be part of a vector, and/or such polynucleotides or polypeptides may be part of a composition and still be isolated

- 72 047335 lenient because such a vector or composition is not part of the environment in which it occurs naturally.

The term chimeric antigen receptor or alternatively CAR refers to a set of polypeptides, typically two in the simplest embodiments, which, when found in an immune effector cell, endow the cell with specificity for a target cell, typically a cancer cell, and the ability to form intracellular signal. In some embodiments, the CAR comprises at least an extracellular antigen binding domain, a transmembrane domain, and a cytoplasmic signaling domain (also referred to herein as an intracellular signaling domain) comprising a functional signaling domain derived from a stimulatory molecule and/or a co-stimulatory molecule as defined herein below . In some aspects, the polypeptides of the set are contiguous to each other. In some embodiments, the set of polypeptides includes a dimerization switch that, in the presence of a dimerization molecule, can link the polypeptides to each other, for example, can link an antigen binding domain to an intracellular signaling domain. In one aspect, the stimulatory molecule is a zeta chain associated with a T cell receptor complex. In one aspect, the cytoplasmic signaling domain further comprises one or more functional signaling domains derived from at least one co-stimulatory molecule, as defined below. In one aspect, the costimulatory molecule is selected from the costimulatory molecules described herein, for example, 4-1BB (ie, CD137), CD27, and/or CD28. In one aspect, the CAR provides a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain, and an intracellular signaling domain comprising a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR provides a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain, and an intracellular signaling domain comprising a functional signaling domain derived from a co-stimulatory molecule and a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR provides a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain, and an intracellular signaling domain comprising two functional signaling domains derived from one or more co-stimulatory molecules and a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR provides a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain, and an intracellular signaling domain comprising at least two functional signaling domains derived from one or more co-stimulatory molecules and a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR contains an optional leader sequence at the amino terminus (N-terminus) of the CAR fusion protein. In one aspect, the CAR further comprises a leader sequence at the N-terminus of the extracellular antigen binding domain, wherein the leader sequence is optionally cleaved from the antigen binding domain (eg, scFv) during cellular processing and localization of the CAR to the cell membrane.

The term signaling domain refers to the functional part of a protein that acts by transmitting information within a cell to regulate cellular activity through certain signaling pathways, forming second messengers or functioning as effectors by responding to such messengers.

As used herein, the term intracellular signaling domain refers to the intracellular portion of the molecule. The intracellular signaling domain generates a signal that promotes the immune effector function of a cell containing a CAR, such as a CART cell. Examples of immune effector functions, such as those of a CART cell, include cytolytic activity and helper activity, including cytokine secretion.

In an embodiment, the intracellular signaling domain may include a primary intracellular signaling domain. Exemplary primary intracellular signaling domains include domains derived from molecules responsible for primary stimulation or antigen-dependent stimulation. In an embodiment, the intracellular signaling domain may include a co-stimulatory intracellular domain. Exemplary co-stimulatory intracellular signaling domains include those derived from molecules responsible for co-stimulatory signaling or antigen-independent stimulation. For example, in the case of CART, the primary intracellular signaling domain may comprise the cytoplasmic sequence of a T cell receptor, and the costimulatory intracellular signaling domain may comprise the cytoplasmic sequence of a coreceptor or costimulatory molecule.

The primary intracellular signaling domain may contain a signaling motif that is known as an immunoreceptor tyrosine activating motif or ITAM. Examples of primary cytoplasmic signal sequences containing ITAMs include, but are not limited to, sequences derived from CD3-zeta, common FcR gamma chain (FCER1G), Fc-gamma RIIa, FcR-beta (Fc-epsilon R1b), CD3-gamma, CD3- delta, CD3 epsilon, CD79a, CD79b, DAP10 and DAP12.

- 73 047335

The term zeta, or alternatively zeta chain, CD3-g3ema, or TCR-zeta, is defined as the protein represented by GenBank Accession No. BAG36664.1, or equivalent residues from a non-human species, e.g., mouse, rodent, non-human ape, ape, etc., and the zeta stimulatory domain or alternatively the CD3-zeta stimulatory domain or the TCR-zeta stimulatory domain is defined as the amino acid residues of the cytoplasmic zeta chain domain or functional derivatives thereof that are sufficient for the functional transmission of the original signal, necessary for T cell activation. In one aspect, the cytoplasmic zeta domain comprises residues 52-164 of GenBank Accession No. BAG36664.1 or equivalent residues from a non-human species, e.g., mouse, rodent, ape, ape, etc., which are functional orthologues thereof .

The term costimulatory molecule refers to a cognate binding partner on a T Cell that binds to a costimulatory ligand, thereby mediating a costimulatory T cell response, such as without limitation proliferation. Costimulatory molecules are cell surface molecules, other than antigen receptors or their ligands, that promote an effective immune response. Costimulatory molecules include, but are not limited to, MHC class I molecule, BTLA and Toll-like receptor ligand, as well as OX40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278) and 4-1BB ( CD137). Additional examples of such costimulatory molecules include CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, CD4, CD8-alpha, CD8-beta, III2R- running, IL2R-gamma, IL7R-alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM , Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a and a ligand that binds to CD83.

The costimulatory intracellular signaling domain may be an intracellular portion of a costimulatory molecule. The co-stimulatory molecule can be represented by the following protein families: TNF receptor family proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocyte activation molecules (SLAM proteins) and activating NK cell receptors. Examples of such molecules include CD27, CD28, 4-1BB (CD137), OX40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, ICAM-1, lymphocyte function-associated antigen-1 (LFA-1), CD2, CDS , CD7, CD287, LIGHT, NKG2C, NKG2D, SLAMF7, NKp80, NKp30, NKp44, NKp46, CD160, B7-H3 and a ligand that binds to CD83, etc.

An intracellular signaling domain may comprise all of the intracellular portion or all of the native intracellular signaling domain of the molecule from which it is derived, or a functional fragment or derivative thereof.

The term 4-1BB refers to a member of the TNFR superfamily with the amino acid sequence represented by GenBank accession No. AAA62478.2, or equivalent residues from a non-human species, such as mouse, rodent, ape, ape, etc.; and the 4-1BB co-stimulatory domain is defined as amino acid residues 214-255 of GenBank Accession No. AAA62478.2 or equivalent residues from a non-human species, e.g., mouse, rodent, non-human ape, great ape, and the like.

As used herein, the term immune effector cell refers to a cell that participates in an immune response, for example, contributing to an immune effector response. Examples of immune effector cells include T cells, such as alpha/beta T cells and gamma/delta T cells, B cells, natural killer (NK) cells, natural killer T cells (NKT), mast cells, and phagocytes of myeloid origin.

As used herein, the term immune effector function or immune effector response refers to a function or response, for example, of an immune effector cell that enhances or promotes an immune attack on a target cell. For example, immune effector function or response refers to a property of a T or NK cell that promotes the destruction or inhibition of growth or proliferation of a target cell. In the case of a T cell, primary stimulation and costimulation are examples of immune effector function or response.

The terms cancer-associated antigen or tumor antigen interchangeably refer to a molecule (typically a protein, carbohydrate or lipid) that is expressed on the surface of a cancer cell, either in whole or as a fragment (eg, MHC molecule/peptide), and which is useful for preferential targeting of a pharmacological agent to a cancer cell. In some embodiments, the tumor antigen is a marker expressed by both normal cells and cancer cells, such as a lineage marker, such as CD19 on B cells. In some embodiments, the tumor antigen is a cell surface molecule that is overexpressed in a cancer cell relative to

- 74 047335 normal cell, for example, is characterized by 1-fold overexpression, 2-fold overexpression, 3-fold or greater overexpression compared to a normal cell. In some embodiments, a tumor antigen is a cell surface molecule that is inappropriately synthesized in a cancer cell, such as a molecule that contains deletions, additions, or mutations compared to a molecule expressed on a normal cell. In some embodiments, the tumor antigen will be expressed exclusively on the cell surface of the cancer cell, either in whole or as a fragment (eg, MHC molecule/peptide), and will not be synthesized or expressed on the surface of a normal cell. In some embodiments, the CARs of the present invention include CARs comprising an antigen binding domain (eg, an antibody or antibody fragment) that binds to a peptide presented by an MHC molecule. Typically, peptides derived from endogenous proteins fill the pockets of major histocompatibility complex (MHC) class I molecules and are recognized by T cell receptors (TCRs) on CD8+ T lymphocytes. Complexes of MHC class I molecules are constitutively expressed by all nucleated cells. In cancer, virus-specific and/or tumor-specific peptide/MHC molecule complexes represent a unique class of cell surface targets for immunotherapy. TCR-like antibodies targeting peptides derived from viral or tumor antigens associated with human leukocyte antigen (HLA)-A1 or HLA-A2 have been described (see, for example, Sastry et al., J Virol. 2011 85(5). ):1935-1942; Sergeeva et al., Blood, 2011 117(16):4262-4272; Verma et al., J Immunol 2010 184(4):2156-2165; 21):1601-1608; Dao et al., Sci Transl Med 2013 5(176): 176ra33; Tassev et al., Cancer Gene Ther 2012 19(2):84-100). For example, a TCR-like antibody can be identified by screening a library, such as a human scFv phage display library.

Various aspects with respect to the compositions and methods presented herein are further described below in detail. Additional definitions are set forth throughout this specification.

Antibody molecules

In one embodiment, the antibody molecule binds to CD73 of a mammal, such as a human. For example, the antibody molecule binds to an epitope, such as a linear or conformational epitope, such as an epitope described herein, on CD73.

As used herein, the term antibody molecule refers to a protein, such as an immunoglobulin chain or fragment thereof, containing at least one immunoglobulin variable domain sequence. The term antibody molecule includes, for example, a monoclonal antibody (including a full-length antibody that contains an immunoglobulin Fc region). In one embodiment, the antibody molecule comprises a full-length antibody or a full-length immunoglobulin chain. In one embodiment, the antibody molecule comprises an antigen-binding or functional fragment of a full-length antibody or a full-length immunoglobulin chain.

As used herein, an antibody molecule binds to an antigen, as such binding is understood by one skilled in the art. In one embodiment, the antibody binds to the antigen with a dissociation constant (K _D ) of approximately 1 x 10 ^-3 M or less, 1 x 10 ^-4 M or less, or 1 x 10 ^-5 M or less.

In one embodiment, the antibody molecule is a monospecific antibody molecule and binds a single epitope, such as a monospecific antibody molecule comprising multiple immunoglobulin variable domain sequences, each of which binds the same epitope.

In one embodiment, the antibody molecule is a multispecific antibody molecule, for example, it contains multiple immunoglobulin variable domain sequences, wherein the first of several immunoglobulin variable domain sequences has a binding specificity for a first epitope, and the second of several immunoglobulin variable domain sequences has a binding specificity for a second epitope. epitope. In an embodiment, the first and second epitopes are on the same antigen, for example on the same protein (or subunit of a multimeric protein). In an embodiment, the first and second epitopes overlap or are substantially overlapping. In an embodiment, the first and second epitopes do not overlap or are substantially non-overlapping. In an embodiment, the first and second epitopes are on different antigens, for example on different proteins (or on different subunits of a multimeric protein). In one embodiment, the multispecific antibody molecule contains third, fourth or fifth immunoglobulin variable domains. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or a tetraspecific antibody molecule,

In an embodiment, the polyspecific antibody molecule is a molecule

- 75 047335 bispecific antibody. A bispecific antibody is characterized by specificity for no more than two antigens. The bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence that is characterized by binding specificity to a first epitope, and a second immunoglobulin variable domain sequence that is characterized by binding specificity to a second epitope. In an embodiment, the first and second epitopes are on the same antigen, for example on the same protein (or subunit of a multimeric protein). In an embodiment, the first and second epitopes overlap or are substantially overlapping. In an embodiment, the first and second epitopes do not overlap or are substantially non-overlapping. In an embodiment, the first and second epitopes are on different antigens, for example on different proteins (or on different subunits of a multimeric protein). In an embodiment, the bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence that have binding specificity to a first epitope, and a heavy chain variable domain sequence and a light chain variable domain sequence that have binding specificity to a second epitope. In an embodiment, the bispecific antibody molecule comprises a half-antibody having binding specificity to a first epitope and a half-antibody having binding specificity to a second epitope. In an embodiment, the bispecific antibody molecule comprises a half-antibody or fragment thereof having binding specificity to a first epitope and a half-antibody or fragment thereof having binding specificity to a second epitope. In an embodiment, the bispecific antibody molecule comprises a scFv or fragment thereof having binding specificity to a first epitope, and a scFv or fragment thereof having binding specificity to a second epitope.

In one embodiment, the antibody molecule includes a diabody and a single chain molecule, as well as an antigen binding fragment of the antibody (eg, Fab, F(ab')2 and Fv). For example, an antibody molecule may comprise a heavy (H) chain variable domain sequence (abbreviated herein as VH) and a light (L) chain variable domain sequence (abbreviated herein as VL). In one embodiment, the antibody molecule contains or consists of a heavy chain and a light chain (herein referred to as a semi-antibody). In another example, an antibody molecule contains two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequences, thereby forming two antigen binding regions such as Fab, Fab', F(ab')2, Fc , Fd, Fd', Fv, single chain antibodies (eg, scFv), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific) and chimeric (eg, humanized) antibodies, which can be obtained by modifying whole antibodies or such , synthesized de novo using recombinant DNA technologies. These functional antibody fragments retain the ability to selectively bind to their corresponding antigen or receptor. Antibodies and antibody fragments can be from any class of antibodies, including, but not limited to, IgG, IgA, IgM, IgD and IgE, and from any subclass (eg, IgG1, IgG2, IgG3 and IgG4) of antibodies. The antibody molecule preparation may be monoclonal or polyclonal. The antibody molecule may also be a human, humanized, CDR-grafted, or in vitro-derived antibody. The antibody may have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3 or IgG4. The antibody may also have a light chain selected from, for example, kappa or lambda. The term immunoglobulin (Ig) is used interchangeably herein with the term antibody.

Examples of antigen binding fragments of an antibody molecule include: (i) a Fab fragment, a monovalent fragment consisting of VL, VH, CL and CH1 domains; (ii) fragment F(ab') ₂ , a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of one arm of the antibody, (v) a diabody fragment (dAb) which consists of a VH domain; (vi) camelized or camelized variable domain; (vii) single chain Fv (scFv), see, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); (viii) single domain antibody. Such antibody fragments can be prepared using any suitable method, including conventional techniques known to those skilled in the art, and the fragments can be screened for suitability in the same manner as intact antibodies.

The term antibody includes intact molecules as well as functional fragments thereof. Antibody constant regions can be altered, eg mutated, to modify properties of the antibody (eg, to increase or decrease one or more of the level of Fc receptor binding, level of antibody glycosylation, number of cysteine residues, effector cell function, or complement function).

Antibodies disclosed herein may also be single domain antibodies. Single-domain antibodies may include antibodies whose complementarity-determining regions are part of a single-domain polypeptide. Examples include, but are not limited to, antibodies to

- 76 047335 based on heavy chains, antibodies naturally lacking light chains, single-domain antibodies derived from traditional 4-chain antibodies, engineered antibodies and single-domain frameworks other than those derived from antibodies. Single domain antibodies can be any antibodies known in the art or any single domain antibodies that will be known in the future. Single domain antibodies can be obtained from any species, including, but not limited to, mouse, human, camel, llama, fish, shark, goat, rabbit, and bovine. In another aspect, the single domain antibody is a naturally occurring single domain antibody known as a heavy chain antibody lacking light chains. Such single domain antibodies are disclosed in WO 9404678, for example. For purposes of clarity, this variable domain, derived from a heavy chain antibody that naturally lacks a light chain, is referred to herein as a VHH or nanobody to distinguish it from the traditional VH of four-chain immunoglobulins. Such a VHH molecule can be obtained from antibodies from Camelidae species, such as camel, llama, dromedary, alpaca and guanaco. Species other than Camelidae can produce heavy chain antibodies that naturally lack a light chain; such VHH are included within the scope of the present invention.

The VH and VL regions can be subdivided into regions of hypervariability called complementarity determining regions (CDRs), which alternate with regions that are more conserved called framework regions (FR or FW).

The dimensions of the framework region and CDR have been accurately determined using a number of methods (see Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 ; Chothia, C. et al. (1987) J. Mol. 196:901-917; and definitions of AbM used in Oxford Molecular's AbM software. See generally, e.g. Protein Sequence and Structure Analysis. of Antibody Variable Domains. B: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

The terms complementarity determining region and CDR as used herein refer to amino acid sequences in the variable regions of an antibody that confer antigen specificity and binding affinity. In some embodiments, three CDRs (HCDR1, HCDR2, and HCDR3) are present in each heavy chain variable region, and three CDRs (LCDR1, LCDR2, and LCDR3) are present in each light chain variable region.

The precise boundaries of the amino acid sequence of a given CDR can be determined using any of the well known schemes, including those described in Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (numbering scheme according to Kabat), Al-Lazikani et al., (1997) JMB 273,927-948 (numbering scheme according to Chothia). As used herein, CDRs defined according to the Chothia numbering scheme are also sometimes referred to as hypervariable loops.

For example, according to Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). According to Chothia, the CDR amino acids in VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2) and 91-96 (LCDR3). Combining the definitions of CDRs according to Kabat and according to Chothia, CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3) in human VL.

By all definitions, each of VH and VL typically contains three CDRs and four FRs, arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

In general, unless specifically stated otherwise, anti-CD73 antibody molecules may comprise any combination of one or more Kabat CDRs, Chothia CDRs, a combination of Kabat and Chothia CDRs, EVIGT CDRs, and/or an alternative definition such as those described in Table 1. 1.

As used herein, the term immunoglobulin variable domain sequence refers to an amino acid sequence that may form the structure of an immunoglobulin variable domain. For example, the sequence may comprise all or part of the amino acid sequence of a naturally occurring variable domain. For example, the sequence may or may not contain one, two or more N- or C-terminal amino acids, or may contain other changes that are compatible with the formation of a protein structure.

The term antigen-binding site refers to a portion of an antibody molecule that contains determinants that form an interaction site that binds to a CD73 polypeptide or an epitope thereof. In the case of proteins (or protein mimetics), the antigen binding region typically contains one or more loops (of at least, for example, four amino acids or amino acid mimetics) that form an interaction site that binds to the CD73 polypeptide. Typically, the antigen-binding region of an antibody molecule contains at least one or

- 77 047335 two CDRs and/or hypervariable loops or, more typically, at least three, four, five or six CDRs and/or hypervariable loops.

As used herein, the term Eu numbering refers to the Eu numbering convention for antibody constant regions as described in Edelman, G.M. et al., Proc. Natl. Acad. USA, 63, 7885 (1969) and Kabat et al., in Sequences of Proteins of Immunological Interest, U.S. Dept. Health and Human Services, 5th edition, 1991.

The terms compete or cross-compete are used interchangeably herein to refer to the ability of an antibody molecule to interfere with the binding of an anti-CD73 antibody molecule, such as the anti-CD73 antibody molecule provided herein, to a target, such as human CD73. Interference with binding may be direct or indirect (eg, through allosteric modulation of the antibody molecule or target). The extent to which an antibody molecule is able to interfere with the binding of another antibody molecule to a target, and therefore whether it can be said to compete, can be determined using a competitive binding assay, such as a flow cytometry assay, an ELISA assay, or a BIACORE assay. In some embodiments, the competitive binding assay is a quantitative competitive assay. In some embodiments, the first anti-CD73 antibody molecule competes for target binding with a second anti-CD73 antibody molecule if binding of the first antibody molecule to the target is reduced by 10% or more, such as by 20% or more, 30% or more, 40% or more more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more greater than, 98% or greater, 99% or greater in a competitive binding assay (eg, the competitive assay described herein).

As used herein, the term epitope refers to fragments of an antigen (eg, human CD73) that specifically interact with an antibody molecule. Such fragments, also referred to herein as epitope determinants, typically contain or are part of elements such as amino acid side chains or sugar side chains. The epitope determinant can be determined by methods known in the art or disclosed herein, for example, by crystallography or hydrogen-deuterium exchange analysis. At least one or more fragments in an antibody molecule that specifically interact with an epitope determinant are typically found in a CDR. Typically, an epitope has specific three-dimensional structural characteristics. Typically, an epitope has specific charge characteristics. Some epitopes are linear epitopes, while others are conformational epitopes.

In one embodiment, an epitope determinant is a fragment on an antigen, such as an amino acid side chain or a sugar side chain or a portion thereof, which, when the antigen molecule and antibodies co-crystallize, is within a predetermined distance, for example within 5 angstroms, from fragment of an antibody molecule referred to herein as a crystallographic epitope determinant. The crystallographic epitope determinants of an epitope are collectively called a crystallographic epitope.

A first antibody molecule binds to the same epitope as a second antibody molecule (e.g., a reference antibody molecule, such as an antibody molecule disclosed herein) if the first antibody interacts with the same epitope determinants on an antigen as the second antibody or the reference antibody , for example, if the interaction is measured in the same way for both the antibody and the second or reference antibody. Epitopes that overlap have at least one common epitope determinant. The first antibody molecule binds to an epitope that overlaps with an epitope of a second antibody molecule (eg, a reference antibody molecule, such as the antibody disclosed herein) if both antibody molecules interact with the same epitope determinant. A first and a second antibody molecule (e.g., a reference antibody molecule, such as an antibody molecule disclosed herein) bind substantially overlapping epitopes if at least half of the epitope determinants of the second or reference antibody are found to be epitope determinants in an epitope of the first antibody. A first and a second antibody molecule (e.g., a reference antibody molecule, such as an antibody molecule disclosed herein) bind substantially the same epitope if the first antibody molecule binds at least half of the core epitope determinants of the epitope of the second or reference antibody, wherein the core epitope epitope determinants are determined, for example, using crystallography or hydrogen-deuterium exchange.

As used herein, an antibody molecule reduces the level of hydrogen-deuterium exchange in an antigen fragment if the hydrogen-deuterium exchange in the antigen fragment in the presence of the antibody molecule becomes lower than the hydrogen-deuterium exchange in the antigen fragment in the absence of the antibody molecule, as measured by a hydrogen-deuterium exchange assay. -deuterium exchange.

As used herein, a decrease in the average hydrogen-deuterium vol.

- 78 047335 exchange is determined by the level of normalized hydrogen-deuterium exchange (Yes per residue) in the antigen fragment in the absence of the antibody minus the level of normalized hydrogen-deuterium exchange (Yes per residue) in the antigen fragment in the presence of the antibody.

As used herein, the terms monoclonal antibody or monoclonal antibody composition refer to a preparation of antibody molecules of a single molecular composition. A monoclonal antibody composition exhibits a single specificity and binding affinity for a particular epitope. A monoclonal antibody can be produced using hybridoma technology or using methods that do not use hybridoma technology (eg, recombination-based methods).

A human-effective protein is a protein that does not elicit a neutralizing antibody response, such as a human anti-mouse antibody (HAMA) response. HAMA can be problematic in a number of circumstances, for example, if the antibody molecule is administered repeatedly, such as in the treatment of a chronic or recurrent disease. The HAMA response can make repeated antibody administration potentially ineffective due to increased levels of antibody clearance from serum (see, e.g., Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)), and due to potential allergic reactions (see, for example, LoBuglio et al., Hybridoma, 5:5117-5123 (1986)).

The antibody molecule may be a polyclonal or monoclonal antibody. In other embodiments, the antibody may be produced by recombination, such as by yeast display, phage display, or combinatorial methods. Alternatively, such antibodies can be selected from synthetic yeast-based antibody presentation systems, such as those described, for example, in Y. Xu et al, Addressing polyspecificity of antibodies selected from an in vitro yeast presentation system: a FACS-based, high- throughput selection and analytical tool. PEDS 26.10, 663-70 (2013); WO2009036379; WO2010105256; and WO2012009568, incorporated herein by reference in their entirety.

In one embodiment, the antibody is a fully human antibody (e.g., a yeast-displayed antibody, a phage-displayed antibody, or a mouse-derived antibody that has been genetically engineered to produce an antibody from a human immunoglobulin sequence) or a non-human antibody, such as a rodent (mouse or rat), goat, primate (eg monkey) or camel antibody. Methods for producing rodent antibodies are known in the art.

Human monoclonal antibodies can preferably be produced using transgenic mice carrying human immunoglobulin genes rather than the murine system. Splenocytes from such transgenic mice immunized with the antigen of interest are used to produce hybridomas that secrete human mAbs with specific affinities for human protein epitopes (see, for example, Wood et al. WO 91/00906, Kucherlapati et al. . publication according to PCT WO 91/10741; international application WO 92/03917; Nature Genet. 7:13-21;Morrison, S.L. et al. Proc. Acad. Sci. USA 81:6851-6855; 90:3720-3724; Bruggeman et al. 1991 Eur J Immunol 21:1323-1326).

The antibody may be an antibody in which the variable region or part thereof, such as a CDR, is produced in a non-human organism, such as a rat or mouse. Chimeric antibodies, CDR grafted antibodies and humanized antibodies are included within the scope of the present invention. Antibodies produced in a non-human organism, such as a rat or mouse, and which are then modified, such as in the variable framework or constant region, to reduce antigenicity in humans are within the scope of the present invention.

Antibodies can be produced using any suitable DNA recombination techniques known in the art (see Robinson et al., International Patent Application Publication PCT/US86/02269; Akira, et al., European Patent Application 184187; Taniguchi , M., European patent application 171496; Morrison et al., European patent application 173494; Neuberger et al., international application WO 86/01533; US patent No. 4816567; Patent 125023; Better et al. (1988 Science 240:1041-1043); Liu et al. 84:3439-3443; al. (1987) PNAS 84:214-218; Cane Res. 47:999-1005; Nature 314:446-449; , J Natl Cancer Inst. 80:1553–1559).

In a humanized or grafted antibody, at least one or two, but typically all three, recipient CDRs (from the immunoglobulin heavy and light chains) are replaced by a donor CDR. The antibody may be replaced by at least a portion of the non-human CDRs, or only some of the CDRs may be replaced by non-human CDRs. It is only necessary to replace the number of CDRs required for binding of the humanized CD73 antibody. In some embodiments, the donor is a rodent antibody, such as an antibody

- 79 047335 rat or mouse, and the recipient is a human framework region or a human consensus framework region. Typically, the immunoglobulin from which the CDR is obtained is called donor, and the immunoglobulin from which the framework is obtained is called acceptor. In one embodiment, the donor immunoglobulin is a non-human immunoglobulin (eg, rodent immunoglobulin). An acceptor framework is a naturally occurring (eg, human) framework or consensus framework or sequence that is about 85% or greater, such as 90%, 95%, 99% or greater, identical thereto.

As used herein, the term consensus sequence refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related sequences (see, for example, Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family of proteins, each a position in a consensus sequence is occupied by the amino acid most frequently occurring at that position within a family. If two amino acids occur equally frequently, either one may be included in the consensus sequence. The consensus framework refers to the framework region in the immunoglobulin consensus sequence.

The antibody can be humanized using methods known in the art (see, for example, Morrison, S. L., 1985, Science 229:1202-1207, Oi et al., 1986, BioTechniques 4:214, and Queen et al. US patent no. 5,585,089, US Pat. No. 5,693,761, and US Pat. No. 5,693,762, each of which is incorporated herein by reference).

Humanized or CDR-grafted antibodies can be produced by CDR grafting or CDR replacement, where one, two or all of the immunoglobulin chain CDRs can be replaced. See, for example, US Pat. No. 5,225,539; Jones et al. 1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239:1534; Beidler et al. 1988 J. Immunol. 141:4053-4060; Winter U.S. Patent No. 5,225,539, the contents of each of which are expressly incorporated herein by reference.

Also included within the scope of the present invention are humanized antibodies in which certain amino acids have been substituted, deleted or added. Criteria for selecting amino acids from a donor are described in US Pat. No. 5,585,089, for example, sections 12-16 of US Pat. No. 5,585,089, for example, sections 12-16 of US Pat. No. 5,585,089, the contents of which are incorporated herein by reference. Other techniques for humanizing antibodies are described in Padlan et al. EP 519596 Al, published December 23, 1992.

The antibody molecule may be a single chain antibody. The single chain antibody (scFV) can be engineered (see, for example, Colcher, D. et al. (1999) Ann N Y Acad Sci 880:263-80; and Reiter, Y. (1996) Clin Cancer Res 2:245-52 ). A single chain antibody can be dimerized or multimerized to produce multivalent antibodies having specificity for different epitopes of the same target protein.

In still other embodiments, the antibody molecule comprises a heavy chain constant region selected, for example, from the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; in particular selected, for example, from the (eg human) heavy chain constant regions of IgG1, IgG2, IgG3 and IgG4. In another embodiment, the antibody molecule comprises a light chain constant region selected from, for example, the (eg, human) kappa light chain or lambda chain constant regions. The constant region may be altered, eg, mutated, to modify properties of the antibody (eg, to increase or decrease one or more of the level of Fc receptor binding, level of antibody glycosylation, number of cysteine residues, effector cell function, and/or complement function). In some embodiments, the antibody has effector function and can fix complement. In other embodiments, the antibody does not recruit effector cells or fix complement. In certain embodiments, the antibody has reduced or no ability to bind to the Fc receptor. For example, it may be an isotype or subtype, fragment, or other mutant that does not support Fc receptor binding, eg, it contains the Fc receptor binding region that has been mutagenized or the region has been deleted.

Methods for changing the constant region of an antibody are known in the art. Antibodies with altered function, for example altered affinity for an effector ligand, such as an FcR on a cell or complement component C1, can be obtained by replacing at least one amino acid residue in the constant portion of the antibody with another residue (see, for example, EP 388151 A1, US patent No. 5,624,821 and U.S. Patent No. 5,648,260, the contents of each of which are incorporated herein by reference). Also considered are amino acid mutations that stabilize the antibody structure, such as S228P (Eu numbering) in human IgG4. Similar types of changes may be described that, when applied to mouse immunoglobulin or other species, reduce or eliminate these functions.

The antibody molecule may be derivatized or linked to another functional molecule (eg, another peptide or protein). The term derivative used in this document

- 80 047335 zinc antibody molecule is a molecule that has been modified. Derivatization methods include, but are not limited to, the addition of a fluorescent moiety, radionucleotide, toxin, enzyme, or affinity ligand such as biotin. Accordingly, it is intended that the antibody molecules of the present invention include derivatized and otherwise modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule may be operably linked (via a chemical compound, genetic fusion, non-covalent association, or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or diabody), a detection agent, a cytotoxic agent , a pharmaceutical agent and/or a protein or peptide that can mediate the association of an antibody or portion of an antibody with another molecule (such as a streptavidin core region or a polyhistidine tag).

A derivatized antibody molecule of one type is produced by cross-linking two or more antibodies (of the same type or different types, for example to create bispecific antibodies). Suitable cross-linking agents include those that are heterobifunctional and contain two separately reacting groups separated by a suitable spacer (eg, m-maleimidobenzoyl-N-hydroxysuccinimide ester), or homobifunctional (eg, disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, Illinois.

Suitable detection means by which the antibody molecule of the present invention can be derivatized (or labeled) include fluorescent compounds, various enzymes, prosthetic groups, luminescent materials, bioluminescent materials, fluorescent emitting metal atoms such as europium (Eu), and others antanides, and radioactive materials (described below). Typical fluorescent detection agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1naphthalene sulfonyl chloride, phycoerythrin, etc. The antibody can also be derivatized with detection enzymes such as alkaline phosphatase, horseradish peroxidase, β-galactosidase, acetylcholinesterase , glucose oxidase, etc. If the antibody is derivatized by a detection enzyme, it is detected by adding additional reagents that are used by the enzyme to produce a detectable reaction product. For example, in the presence of the detection agent horseradish peroxidase, the addition of hydrogen peroxide and diaminobenzidine results in a colored reaction product that can be detected. The antibody molecule can also be derivatized with a prosthetic group (eg, streptavidin/biotin and avidin/biotin). For example, the antibody can be derivatized with biotin and detected by indirectly measuring the level of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, fluorescein dichlorotriazinylamine, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; and examples of bioluminescent materials include luciferase, luciferin and aequorin.

The labeled antibody molecule can be used, for example, for diagnostic and/or experimental purposes in a number of cases, including (i) to isolate a predetermined antigen using standard techniques such as affinity chromatography or immunoprecipitation; (ii) to detect a predetermined antigen (eg, in a cell lysate or cell supernatant) to assess the amount and pattern of protein expression; (iii) to monitor protein levels in tissue as part of a clinical trial procedure, for example to determine the effectiveness of a given treatment regimen.

The antibody molecule may be conjugated to another molecular entity, typically a tag or therapeutic (eg, immunomodulatory, immunostimulant, cytotoxic, or cytostatic) agent or moiety. Radioactive isotopes can be used in diagnostic or therapeutic applications. Radioactive isotopes that can be attached to anti-CD73 antibodies include, but are not limited to, α, β, or γ emitters or β and γ emitters. Such radioactive isotopes include, but are not limited to, iodine ( ¹³¹ I or ¹²⁵ I), yttrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), actinidium ( ²²⁵ Ac), praseodymium, astatine ( ²¹¹ At), rhenium ( ¹⁸⁶ Re), bismuth ( ²¹² Bi or ²¹³ Bi), indium (111In), technetium (99mTc), phosphorus ( ³² P), rhodium ( ¹⁸⁸ Rh), sulfur ( ³⁵ S), carbon ( ¹⁴ C), tritium ( ³ H), chromium ( ⁵¹ Cr ), chlorine ( ³⁶ Cl), cobalt ( ⁵⁷ Co or ⁵⁸ Co), iron ( ⁵⁹ Fe), selenium ( ⁷⁵ Se) or gallium ( ⁶⁷ Ga). Radioisotopes used as therapeutic agents include yttrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), sea anemone ( ²²⁵ Ac), praseodymium, astatine ( ²¹¹ At), rhenium ( ¹⁸⁶ Re), bismuth ( ²¹² Bi or ²¹³ Bi), and rhodium ( ¹⁸⁸ Rh). Radioisotopes used as tracers, for example for diagnostic applications, include iodine ( ^131I or ^125I ), indium (111In), technetium (mTc), phosphorus ( ^32P ), carbon ( ^14C ) and tritium ( ^3H ) or one or more isotopes for therapeutic use listed above.

The present invention relates to radiolabeled antibody molecules and methods for labeling them. In one embodiment, a method for labeling an antibody molecule is disclosed. The method involves contacting an antibody molecule with a chelating agent to thereby obtain a conjugated antibody. The conjugated antibody is labeled with a radioactive label using

- 81 047335 radioisotope, for example indium, yttrium and lutetium, thereby obtaining a labeled antibody molecule.

As discussed above, the antibody molecule can be conjugated to a therapeutic agent. Therapeutically active radioisotopes have already been mentioned. Examples of other therapeutic agents include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracinedione, mitoxantrone, mitramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine , tetracaine, lidocaine, propranolol, puromycin, maytansinoids, for example maytansinol (see US patent No. 5208020), CC-1065 (see US patent Nos. 5475092, 5585499, 5846545), and their analogs or homologues. Therapeutics include, but are not limited to, antimetabolites (eg, methotrexate, 6mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (eg, mechlorethamine, thiotepa, chlorambucil, CC-1065, melphalan, carmustine (BSNU), and lomustine (CCNU) ), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C and platinum(II) cis-dichlorodiamine (DDP), cisplatin), anthracyclines (eg, daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (eg, dactinomycin (formerly actinomycin), bleomycin, mithramycin and anthramycin (AMC)) and antimitotic agents (eg, vincristine, vinblastine, taxol and maytansinoids).

In one aspect, the present invention relates to a method for producing a target binding molecule that binds to the CD73 receptor. For example, the target binding molecule is an antibody molecule. The method involves: providing a target protein that contains at least a portion of the non-human protein, wherein that portion is homologous (identical in at least 70, 75, 80, 85, 87, 90, 92, 94, 95, 96, 97, 98, or 99%) of the corresponding portion of the human target protein, but differs by at least one amino acid (e.g., at least one, two, three, four, five, six, seven, eight, or nine amino acids); producing an antibody molecule that binds to an antigen; and assessing the effectiveness of the binding agent in modulating the activity of the target protein. The method may further comprise administering a binding agent (eg, an antibody molecule) or a derivative thereof (eg, a humanized antibody molecule) to a human subject.

In certain embodiments, the antibody molecule is a multispecific (eg, bispecific or trispecific) antibody molecule. Protocols for generating bispecific or heterodimeric antibody molecules are known in the art, including without limitation, for example, the prong-to-valve approach as described, for example, in US 5,731,168; Fc pairing using directed electrostatic interaction, as described, for example, in WO 09/089004, WO 06/106905 and WO 2010/129304; formation of heterodimers by strand exchange engineering domains (SEED), as described, for example, in WO 07/110205; exchange of Fab fragments as described, for example, in WO 08/119353, WO 2011/131746 and WO 2013/060867; double antibody conjugates, for example, obtained by cross-linking antibodies to create a bispecific structure using a heterobifunctional reagent containing a reactive amino group and a reactive sulfhydryl group, as described, for example, in US 4433059; bispecific antibody determinants created by recombination of half-antibodies (heavy-light chain pairs or Fabs) from different antibodies through a cycle of reduction and oxidation of disulfide bonds between two heavy chains, as described, for example, in US 4444878; trifunctional antibodies, for example, three Fab' fragments cross-linked using reactive sulfhydryl groups, as described, for example, in US5273743; biosynthetic binding proteins, for example pairs of scFvs cross-linked at the C-terminal tails, preferably by chemical cross-linking via disulfide bonds or reactive amino groups, as described, for example, in US5534254; bifunctional antibodies, for example, Fab fragments with different binding specificities dimerized with leucine zippers (eg c-fos and c-jun) replacing the constant domain, as described, for example, in US5582996; bispecific and oligospecific mono- and oligovalent receptors, for example, the VHCH1 regions of two antibodies (two Fab fragments), linked by a polypeptide spacer between the CH1 region of one antibody and the VH region of another antibody, usually with associated light chains, as described, for example, in US5591828 ; bispecific DNA-antibody conjugates, for example, obtained by cross-linking antibodies or Fab fragments with a double-stranded DNA fragment, as described, for example, in US5635602; bispecific fusion proteins, for example an expression construct containing two scFvs with a hydrophilic coiled-coil peptide linker between them and a complete constant region, as described, for example, in US5637481; multivalent and polyspecific binding proteins, for example, a dimer of polypeptides having a first domain with an Ig heavy chain variable region binding region and a second domain with an Ig light chain variable region binding region, generally called diabodies (higher order structures for creating bispecific, trispecific or tetraspecific molecules, as described, for example, in US5837242; miniantibody designs with linked VL and VH chains, additionally connected by peptide spacers to the antibody hinge region and CH3 region, which can be dimerized to form bispecific/multivalent molecules, as described. eg in US5837821;

- 82 047335

VH and VL domains linked by a short peptide linker (eg, 5 or 10 amino acids) or no linker at all, in any orientation, which can form dimers to form bispecific diabodies; trimers and tetramers, as described, for example, in US5844094; a thread of VH domains (or VL domains in members of the family), connected by peptide bonds with stitchable groups at the C-terminus, additionally associated with VL domains to form sequentially connected Fvs (or scFvs), as described, for example, in US5864019; and single chain binding polypeptides with both VH and VL domains linked by a peptide linker, combined into multivalent structures by non-covalent or chemical cross-linking to form, for example, homobivalent, heterobivalent, trivalent and tetravalent structures using both scFv-type format and and the type of diabody, as described, for example, in US5869620. Additional illustrative polyspecific and bispecific molecules and methods for their preparation are found, for example, in US5910573, US5932448, US6333396, US6476198, US6511663,

US5959083, US5989830, US6005079, US6239259, US6294353,

US6670453, US6743896, US6809185, US6833441, US7129330,

US7183076, US7521056, US7527787,

US2002103345A1,

US2004242847A1,

US2005100543A1,

US2006083747A1,

US2007087381A1,

US2008050370A1,

US2008254512A1,

US2009162359A1,

US2003207346A1,

US2005003403A1,

US2005136049A1,

US2006120960A1,

US2007128150A1,

US2008069820A1,

US2008260738A1,

US2009162360A1,

US7534866, US7612181, US2002004587A1,

US2003211078A1,

US2005004352A1,

US2005136051A1,

US2006204493A1,

US2007141049A1,

US2008152645A1,

US2009130106A1,

US2009175851A1,

US2004219643A1

US2005069552A1

US2005163782A1

US2006263367A1

US2007154901A1

US2008171855A1

US2009148905A1

US2009175867A1

US2002076406A1,

US2004220388A1,

US2005079170A1,

US2005266425A1,

US2007004909A1,

US2007274985A1,

US2008241884A1,

US2009155275A1,

US2009232811A1,

US2009234105A1, US2009263392A1, US2009274649A1, EP346087A2, WO0006605A2, WO02072635A2,

WO04081051A1, WO06020258A2, WO2007044887A2, WO2007095338A2, WO2007137760A2,

WO2008119353A1, WO2009021754A2, WO2009068630A1, WO9103493A1, WO9323537A1,

WO9409131A1, WO9412625A2, WO9509917A1, WO9637621A2, WO9964460A1. The contents of the foregoing applications are incorporated herein by reference in their entirety.

In other embodiments, the anti-CD73 antibody molecule (e.g., a monospecific, bispecific, or multispecific antibody molecule) is covalently linked, e.g., fused, to another partner, e.g., a protein, e.g., one, two, or more cytokines, e.g., as a fusion molecule, e.g., a fusion protein .

Fusion protein and fusion polypeptide refer to a polypeptide having at least two parts covalently linked to each other, where each part is a polypeptide having different properties. The property may be a biological property, such as in vitro or in vivo activity. The property may also be a simple chemical or physical property, such as binding to a target molecule, catalyzing a reaction, etc. Such two moieties may be linked directly by a single peptide bond or by a peptide linker, but are in the same reading frame.

The present invention provides an isolated nucleic acid molecule encoding any of the above antibody molecules, vectors and their host cells. The nucleic acid molecule includes, but is not limited to, RNA, genomic DNA, and cDNA.

Exemplary anti-CD73 antibody molecules

In some embodiments, the anti-CD73 antibody molecule comprises at least one antigen binding region, such as a variable region or an antigen binding fragment thereof, from an antibody described herein, such as an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table 1; or encoded by a nucleotide sequence from Table 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

In certain embodiments, the anti-CD73 antibody molecule comprises at least one, two, three, or four variable regions from an antibody described herein, such as an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376 , 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1; or encoded by the nucleotide sequence from the table. 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

In some embodiments, the anti-CD73 antibody molecule comprises at least one or two heavy chain variable regions from an antibody described herein, such as an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377 , 379, 363, 366, 407, 893, 939, 430, or 398; or described in table 1; or encoded by a nucleotide sequence from Table 1; or sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any

- 83 047335 from the above sequences.

In certain embodiments, the anti-CD73 antibody molecule comprises at least one or two light chain variable regions from an antibody described herein, such as an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377 , 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1; or encoded by the nucleotide sequence from the table. 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

In one embodiment, the anti-CD73 antibody molecule comprises an IgG4 heavy chain constant region, such as human IgG4. In another embodiment, human IgG4 contains a substitution (eg, a Ser to Pro substitution) at position 228 of the Eu numbering. In yet another embodiment, the anti-CD73 antibody molecule comprises an IgG1 heavy chain constant region, such as human IgG1. In one embodiment, human IgG1 contains a substitution (eg, an Asn to Ala substitution) at position 297 of the Eu numbering. In one embodiment, human IgG1 contains a substitution (eg, Asp to Ala substitution) at Eu numbering position 265, a substitution (eg, Pro to Ala substitution) at Eu numbering position 329, or both. In one embodiment, human IgG1 contains a substitution (eg, Leu to Ala substitution) at Eu numbering position 234, a substitution (eg, Leu to Ala substitution) at Eu numbering position 235, or both. In one embodiment, the heavy chain constant region contains the amino acid sequence set forth in table. 3, or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.

In yet another embodiment, the anti-CD73 antibody molecule comprises a kappa light chain constant region, such as a human kappa light chain constant region. In one embodiment, the light chain constant region contains the amino acid sequence set forth in table. 3, or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.

In another embodiment, the anti-CD73 antibody molecule comprises an IgG4 heavy chain constant region, such as human IgG4, and a kappa light chain constant region, such as a human kappa light chain constant region, such as a heavy and light chain constant region, comprising the amino acid sequence set forth in table 3, or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto. In yet another embodiment, an anti-CD73 antibody molecule comprises an IgG1 heavy chain constant region, such as human IgG1, and a kappa light chain constant region, such as a human kappa light chain constant region, such as a heavy and light chain constant region, comprising the amino acid sequence set forth in table 3, or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto. In one embodiment, human IgG1 contains a substitution at position 297 in accordance with Eu numbering (eg, replacing Asn with Ala). In one embodiment, human IgG1 comprises a substitution at position 265 according to Eu numbering, a substitution at position 329 according to Eu numbering, or both (eg, replacing Asp with Ala at position 265 and/or replacing Pro with Ala at position 329). In one embodiment, human IgG1 comprises a substitution at position 234 according to Eu numbering, a substitution at position 235 according to Eu numbering, or both (eg, a Leu to Ala substitution at position 234 and/or a Leu to Ala substitution at position 235).

In another embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region and constant region, a light chain variable region and constant region, or both, comprising an amino acid sequence of 918, 350, 356, 358, 930, 373, 374. 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1; or encoded by the nucleotide sequence from the table. 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

In some embodiments, the anti-CD73 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from the heavy chain variable region of an antibody described herein, such as an antibody selected from antibody 918, 350, 356, 358, 930 , 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1, or encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

In some embodiments, the anti-CD73 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region comprising the amino acid sequence shown in Table. 1, or encoded by nucleotide

- 84 047335 sequence from table. 1. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five or more changes, such as amino acid substitutions, insertions or deletions, compared to the amino acid sequence shown in Table 1, or the encoded nucleotide sequence shown in table. 1. In certain embodiments, the anti-CD73 antibody molecule contains a substitution in a heavy chain CDR, such as one or more substitutions in a heavy chain CDR1, CDR2, and/or CDR3.

In some embodiments, the anti-CD73 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from the light chain variable region of an antibody described herein, such as an antibody selected from antibody 918, 350, 356, 358, 930 , 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1, or encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

In certain embodiments, the anti-CD73 antibody molecule contains at least one, two, or three CDRs (or collectively all CDRs) from a light chain variable region comprising the amino acid sequence shown in table. 1 or encoded by the nucleotide sequence shown in table. 1. In some embodiments, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions, insertions or deletions, compared to the CDRs shown in Table 1 , or encoded by the nucleotide sequence shown in table. 1. In some embodiments, the anti-CD73 antibody molecule contains at least one, two or three CDRs (or collectively all CDRs) from a light chain variable region comprising the amino acid sequence shown in table. 1 or encoded by the nucleotide sequence shown in table. 1. In some embodiments, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions, insertions or deletions, compared to the CDRs shown in table. 1, or encoded by the nucleotide sequence shown in table. 1.

In some embodiments, an anti-CD73 antibody molecule comprises at least one, two, three, four, five, or six CDRs (or collectively all CDRs) from a heavy and light chain variable region comprising the amino acid sequence shown in Table 1. 1 or encoded by the nucleotide sequence shown in table. 1. In some embodiments, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions, insertions or deletions, compared to the CDRs shown in table. 1, or encoded by the nucleotide sequence shown in table. 1.

In certain embodiments, the anti-CD73 antibody molecule contains all six CDRs from an antibody described herein, for example, an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in Table 1, or encoded by a nucleotide sequence from Table 1, or closely related CDRs, for example, CDRs that are identical or that have at least one amino acid change, but no more than two, three or four changes (for example, substitutions, deletions or insertions, such as conservative substitutions). In certain embodiments, the anti-CD73 antibody molecule may comprise any CDR described herein. In certain embodiments, the anti-CD73 antibody molecule contains a substitution in a heavy chain CDR, such as one or more substitutions in a heavy chain CDR1, CDR2, and/or CDR3.

In some embodiments, the anti-CD73 antibody molecule contains at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two or three CDRs according to the Kabat numbering set forth in Table 1) from the heavy chain variable region of an antibody described herein, for example an antibody selected from antibody 918, 350, 356, 358 , 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table 1 or encoded by the nucleotide sequence shown in table 1; or a sequence substantially identical (eg, having at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the above sequences; or which has at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, such as conservative substitutions) compared to one, two or three CDRs according to Kabat et al., shown in table 1.

In certain embodiments, the anti-CD73 antibody molecule contains at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat numbering set forth in Table 1) from the light chain variable region of an antibody described herein, for example, an antibody selected from antibody 918, 350, 356, 358 , 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (e.g., having at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity

- 85 047335 importance) any of the above sequences; or which has at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, such as conservative substitutions) compared to one, two or three CDRs according to Kabat et al., shown in table 1.

In certain embodiments, the anti-CD73 antibody molecule contains at least one, two, three, four, five, or six CDRs in accordance with Kabat et al. (e.g., at least one, two, three, four, five or six CDRs in accordance with the Kabat numbering set forth in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody selected from antibodies 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1 or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences; or which has at least one amino acid change, but no more than two, three or four changes (for example, substitutions, deletions or insertions, such as conservative substitutions) compared to one, two, three, four, five or six CDRs in accordance with Kabat et al, shown in table. 1.

In some embodiments, the anti-CD73 antibody molecule contains all six CDRs according to Kabat et al. (e.g., all six CDRs according to Kabat numbering set forth in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody selected from antibody 918, 350, 356, 358, 930, 373 , 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1 or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences; or which has at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, eg conservative substitutions) compared to all six CDRs according to Kabat et al. shown in table. 1. In one embodiment, the anti-CD73 antibody molecule may comprise any CDR described herein.

In some embodiments, the anti-CD73 antibody molecule comprises at least one, two, or three Chothia hypervariable loops (e.g., at least one, two, or three hypervariable loops according to the Chothia numbering set forth in Table 1) from the variable region the heavy chain of an antibody described herein, for example an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1, or encoded by the nucleotide sequence from table. 1; or at least amino acids from these hypervariable loops that interact with CD73; or which have at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, such as conservative substitutions) compared to one, two or three hypervariable loops according to Chothia et al., shown in table 1.

In certain embodiments, the anti-CD73 antibody molecule contains at least one, two, or three Chothia hypervariable loops (e.g., at least one, two, or three hypervariable loops according to the Chothia numbering set forth in Table 1) from the variable region a light chain of an antibody described herein, for example an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1, or encoded by the nucleotide sequence from table. 1; or at least amino acids from these hypervariable loops that interact with CD73; or which have at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, such as conservative substitutions) compared to one, two or three hypervariable loops according to Chothia et al., shown in table 1.

In certain embodiments, the anti-CD73 antibody molecule contains at least one, two, three, four, five, or six hypervariable loops (e.g., at least one, two, three, four, five, or six hypervariable loops according to Chothia numbering set forth in Table 1) from the heavy and light chain variable regions of an antibody described herein, for example an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366 , 407, 893, 939, 430, or 398 or described in table. 1, or encoded by the nucleotide sequence from table. 1; or at least amino acids from these hypervariable loops that interact with CD73; or which have at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, such as conservative substitutions) compared to one, two, three, four, five or six Chothia hypervariable loops et al., shown in table. 1.

In some embodiments, the anti-CD73 antibody molecule comprises all six hypervariable loops (e.g., all six hypervariable loops according to the Chothia numbering set forth in Table 1) of an antibody described herein, e.g., an antibody selected

- 86 047335 from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398;, or closely related hypervariable loops, e.g. loops , which are identical or which have at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, such as conservative substitutions); or which have at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, eg conservative substitutions) compared to all six hypervariable loops of Chothia et al. shown in table. 1. In one embodiment, the anti-CD73 antibody molecule may comprise any hypervariable loop described herein.

In yet another embodiment, the anti-CD73 antibody molecule contains at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, for example, an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398, for example the same canonical structures as at least loop 1 and/or loop 2 variable domains of the heavy and/or light chains of the antibody described herein. See, for example, Chothia et al., (1992) J. Mol. Biol. 227:799-817; Tomlinson et al., (1992) J. Mol. Biol. 227:776-798 regarding descriptions of canonical hypervariable loop structures. These structures can be determined by reviewing the tables described in these references.

In certain embodiments, the anti-CD73 antibody molecule contains a combination of CDRs or hypervariable loops defined in accordance with Kabat et al. and Chothia et al.

In one embodiment, the anti-CD73 antibody molecule comprises at least one, two or three CDRs or hypervariable loops from the heavy chain variable region of an antibody described herein, for example an antibody selected from antibody 918, 350, 356, 358, 930, 373 , 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398, according to Kabat and Chothia numbering (e.g., at least one, two, or three CDRs or hypervariable loops according to with numbering according to Kabat and Chothia, set out in table 1); or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences; or which has at least one amino acid change, but no more than two, three or four changes (for example, substitutions, deletions or insertions, for example conservative substitutions) compared to one, two or three Kabat and/or Chothia CDRs or hypervariable loops , shown in table. 1.

In another embodiment, the anti-CD73 antibody molecule comprises at least one, two or three CDRs or hypervariable loops from the light chain variable region of an antibody described herein, for example an antibody selected from antibody 918, 350, 356, 358, 930, 373 , 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398, according to Kabat and Chothia numbering (e.g., at least one, two, or three CDRs or hypervariable loops according to numbered according to Kabat and Chothia, set out in table 1); or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences; or which has at least one amino acid change, but no more than two, three or four changes (for example, substitutions, deletions or insertions, for example conservative substitutions) compared to one, two or three Kabat and/or Chothia CDRs or hypervariable loops , shown in table. 1.

In some embodiments, the anti-CD73 antibody molecule comprises at least one, two, or three LMGT numbering CDRs (e.g., at least one, two, or three LMGT numbering CDRs set forth in Table 1) from the antibody heavy chain variable region, described herein, for example an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1 or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, having at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the above sequences; or which has at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, eg conservative substitutions) compared to one, two or three LMGT numbering CDRs shown in table. 1.

In certain embodiments, the anti-CD73 antibody molecule comprises at least one, two, or three LMGT numbering CDRs (e.g., at least one, two, or three LMGT numbering CDRs set forth in Table 1) from the antibody light chain variable region, described herein, for example an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (e.g., having at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any

- 87 047335 fight from the above sequences; or which has at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, eg conservative substitutions) compared to one, two or three LMGT numbering CDRs shown in table. 1.

In certain embodiments, the anti-CD73 antibody molecule comprises at least one, two, three, four, five, or six LMGT numbering CDRs (e.g., at least one, two, three, four, five, or six LMGT numbering CDRs set forth in table 1) from the variable regions of the heavy and light chains of an antibody described herein, for example an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407 , 893, 939, 430, or 398; or described in table. 1 or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences; or which has at least one amino acid change, but no more than two, three, or four changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) compared to one, two, three, four, five, or six LMGT numbering CDRs , shown in table. 1.

In some embodiments, an anti-CD73 antibody molecule comprises all six LMGT numbering CDRs (e.g., all six LMGT numbering CDRs set forth in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody selected from antibodies 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1; or encoded by the nucleotide sequence shown in table. 1; or or a sequence substantially identical (eg, having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the above sequences; or which has at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, eg conservative substitutions) compared to all six CDRs by LMGT numbering shown in table. 1. In one embodiment, the anti-CD73 antibody molecule may comprise any CDR described herein.

The anti-CD73 antibody molecule may contain any combination of CDRs or hypervariable loops according to Kabat and Chothia numbering.

In some embodiments, the anti-CD73 antibody molecule contains at least one, two, or three Chothia numbering hypervariable loops from the heavy chain variable region of an antibody described herein, such as the antibodies of Table 1. 1, or at least amino acids from these hypervariable loops that interact with CD73.

In some embodiments, the anti-CD73 antibody molecule contains at least one, two, or three Chothia numbering hypervariable loops from the light chain variable region of an antibody described herein, such as the antibodies of Table 1. 1, or at least amino acids from these hypervariable loops that interact with CD73.

In some embodiments, the anti-CD73 antibody molecule contains at least one, two, or three Kabat hypervariable loops from the heavy chain variable region of an antibody described herein, such as the antibodies of Table 1. 1, or at least amino acids from these hypervariable loops that interact with CD73.

In some embodiments, the anti-CD73 antibody molecule contains at least one, two, or three Kabat hypervariable loops from the light chain variable region of an antibody described herein, such as the antibodies of Table 1. 1, or at least amino acids from these hypervariable loops that interact with CD73.

In some embodiments, the anti-CD73 antibody molecule contains at least one, two, or three IMGT hypervariable loops from the heavy chain variable region of an antibody described herein, such as the antibodies of Table 1. 1, or at least amino acids from these hypervariable loops that interact with CD73.

In some embodiments, the anti-CD73 antibody molecule contains at least one, two, or three IMGT hypervariable loops from the light chain variable region of an antibody described herein, such as the antibodies of Table 1. 1, or at least amino acids from these hypervariable loops that interact with CD73.

In certain embodiments, the anti-CD73 antibody molecule contains at least one, two, three, four, five, or six hypervariable loops from the heavy and light chain variable regions of an antibody described herein, such as the antibodies of Table 1. 1, or at least amino acids from these hypervariable loops that interact with CD73.

In certain embodiments, the anti-CD73 antibody molecule contains all six hypervariable loops from the heavy and light chain variable regions of an antibody described herein, such as the antibodies of Table 1. 1, or at least amino acids from those hypervariable loops that interact with CD73, or closely related hypervariable loops, e.g.

- 88 047335 merhypervariable loops that are identical or have at least one amino acid change, but no more than two, three or four changes (for example, substitutions, for example conservative substitutions, deletions or insertions).

In some embodiments, the anti-CD73 antibody molecule contains at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of the antibody described herein, for example, the antibodies of Table 1. 1, for example the same canonical structures as at least loop 1 and/or loop 2 of the heavy and/or light chain variable domains of the antibody described herein. See, for example, Chothia et al., (1992) J. Mol. Biol. 227:799-817; Tomlinson et al., (1992) J. Mol. Biol. 227:776-798 regarding descriptions of canonical hypervariable loop structures. These structures can be determined by examining the tables described in these literature sources. In an embodiment, for example an embodiment providing a variable region, CDR (eg, Chothia, Kabat or LMGT CDR) or other sequence mentioned herein, for example in table. 1, the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, or is an antibody molecule that contains an antigen binding fragment of an antibody, such as a semi-antibody or an antigen binding fragment of a semi-antibody.

In some embodiments, the heavy or light chain variable domain, or both, of the anti-CD73 antibody molecules comprise an amino acid sequence that is substantially identical to the amino acid sequence disclosed herein, e.g., characterized by at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity to the variable region of an antibody disclosed herein, such as an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377 , 379, 363, 366, 407, 893, 939, 430, or 398; or described in table. 1, or encoded by the nucleotide sequence described in table. 1; or which differs by at least 1 or 5 residues, but less than 40, 30, 20 or 10 residues, from the variable region of an antibody described herein.

In certain embodiments, the heavy or light chain variable domain or both of an anti-CD73 antibody molecule comprises an amino acid sequence encoded by a nucleic acid sequence described herein or a nucleic acid that hybridizes to a nucleic acid sequence described herein (e.g., a sequence nucleic acid shown in Table 1), or a sequence complementary thereto, for example, under low stringency, medium stringency, high stringency or other hybridization conditions described herein.

In certain embodiments, the anti-CD73 antibody molecule contains at least one, two, three, or four antigen-binding regions, such as variable regions, having the amino acid sequence set forth in Table. 1, or a sequence substantially identical thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto, or that differs by no more than 1, 2, 5, 10 or 15 amino acid residues from the sequences shown in Table 1). In certain embodiments, the anti-CD73 antibody molecule contains a VH and/or VL domain encoded by a nucleic acid having a nucleotide sequence that encodes the antibody of Table 1. 1, or a sequence substantially identical thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto, or that differs by no more than 3, 6, 15, 30 or 45 nucleotides from the sequences shown in Table 1).

In certain embodiments, the anti-CD73 antibody molecule contains at least one, two, or three (eg, all) CDRs from a heavy chain variable region having the amino acid sequence set forth in Table. 1, or a sequence substantially homologous thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions, or deletions, such as conservative substitutions). In some embodiments, the anti-CD73 antibody molecule contains at least one, two, or three (eg, all) CDRs from a light chain variable region having the amino acid sequence set forth in Table. 1, or a sequence substantially homologous thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions, or deletions, such as conservative substitutions). In certain embodiments, an anti-CD73 antibody molecule comprises at least one, two, three, four, five, or six (eg, all) heavy and light chain variable region CDRs having the amino acid sequence set forth in Table 1. 1, or a sequence substantially homologous thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions, or deletions, such as conservative substitutions).

In some embodiments, the anti-CD73 antibody molecule comprises at least one

- 89 047335 two or three (for example, all) CDRs and/or hypervariable loops from a heavy chain variable region having the amino acid sequence of an antibody described herein, for example an antibody selected from antibody 918, 350, 356, 358, 930, 373 , 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398, generally presented in table. 1, or a sequence substantially identical thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions, or deletions, such as conservative substitutions). In certain embodiments, an anti-CD73 antibody molecule comprises at least one, two, or three (e.g., all) CDRs and/or hypervariable loops from a light chain variable region having the amino acid sequence of an antibody described herein, such as an antibody selected from antibody 918, 350, 356, 358, 930, 373, 374, 376, 377, 379, 363, 366, 407, 893, 939, 430, or 398, collectively presented in table. 1, or a sequence substantially identical thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or containing one, two, three or more substitutions, insertions, or deletions, such as conservative substitutions). In some embodiments, the anti-CD73 antibody molecule contains all six CDRs and/or hypervariable loops described herein, for example, those described in table. 1.

In some embodiments, the antibody molecule contains a variable region that is identical in sequence to, or that differs by 1, 2, 3, or 4 amino acids from the variable region described herein (eg, the FR region disclosed herein).

In one embodiment, the anti-CD73 antibody molecule comprises a heavy chain variable region (VH) containing the amino acid sequence GGLYGSGSYLSDFDL VHCDR3 (SEQ ID NO: 37). In one embodiment, the anti-CD73 antibody molecule comprises a heavy chain variable region (VH) containing the amino acid sequence ESQESPYNNWFDP VHCDR3 (SEQ ID NO: 3).

In one embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 88, the amino acid sequence of VHCDR2 of SEQ ID NO: 89, and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50, each of which is disclosed in Table 2. In one embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 90, the amino acid sequence of VHCDR2 of SEQ ID NO: 91, and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16, each of which is disclosed in Table 2.

In one embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 122, the amino acid sequence of VHCDR2 of SEQ ID NO: 123, and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 51, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 53, each of which is disclosed in Table 2. In one embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 124, the amino acid sequence of VHCDR2 of SEQ ID NO: 125, and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 17, the amino acid sequence of VLCDR2 of SEQ ID NO: 18, and the amino acid sequence of VLCDR3 of SEQ ID NO: 19, each of which is disclosed in Table 2.

In one embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 126, the amino acid sequence of VHCDR2 of SEQ ID NO: 89, and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50, each of which is disclosed in Table 2. In one embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 127, the amino acid sequence of VHCDR2 of SEQ ID NO: 91, and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 under SEQ ID NO: 14, amino acid sequence

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VLCDR2 under SEQ ID NO: 15 and the amino acid sequence of VLCDR3 under SEQ ID NO: 16, each of which is disclosed in table 2.

In one embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 128, the amino acid sequence of VHCDR2 of SEQ ID NO: 129, and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 54, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50, each of which is disclosed in Table 2. In one embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 130, the amino acid sequence of VHCDR2 of SEQ ID NO: 131, and the amino acid sequence of VHCDR3 of SEQ ID NO: 9; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 20, the amino acid sequence of VLCDR2 of SEQ ID NO: 18, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16, each of which is disclosed in Table 2.

In one embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 189, the amino acid sequence of VHCDR2 of SEQ ID NO: 89, and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50, each of which is disclosed in Table 2. In one embodiment, an anti-CD73 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 196, the amino acid sequence of VHCDR2 of SEQ ID NO: 91, and the amino acid sequence of VHCDR3 of SEQ ID NO: 9; and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16, each of which is disclosed in table. 2.

In one embodiment, the anti-CD73 antibody molecule comprises a VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36, and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 61, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 under SEQ ID NO:

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14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 under SEQ ID NO: 3; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 4, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 163, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one embodiment, the anti-CD73 antibody molecule comprises a VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 39, the amino acid sequence of VHCDR2 of SEQ ID NO: 40, and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 under SEQ ID NO: 51, amino acid sequence

VLCDR2 of SEQ ID NO: 52 and the amino acid sequence of VLCDR3 of SEQ ID NO: 53. In one embodiment, an anti-CD73 antibody molecule comprises a VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 73, the amino acid sequence of VHCDR2 of SEQ ID NO: 74, and amino acid sequence of VHCDR3 under SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 51, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 53. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 82, the amino acid sequence of VHCDR2 of SEQ ID NO: 74 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 51, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 53. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 138, the amino acid sequence of VHCDR2 of SEQ ID NO: 139 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 51, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 53. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 147, the amino acid sequence of VHCDR2 of SEQ ID NO: 148 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 51, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 53. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 155, the amino acid sequence of VHCDR2 of SEQ ID NO: 156 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 51, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 53. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 62, the amino acid sequence of VHCDR2 of SEQ ID NO: 63 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 17, the amino acid sequence of VLCDR2 of SEQ ID NO: 18, and the amino acid sequence of VLCDR3 of SEQ ID NO: 19. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 27, the amino acid sequence of VHCDR2 of SEQ ID NO: 28 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 17, the amino acid sequence of VLCDR2 of SEQ ID NO: 18, and the amino acid sequence of VLCDR3 of SEQ ID NO: 19. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 5, the amino acid sequence of VHCDR2 of SEQ ID NO: 6 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 under SEQ

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ID NO: 17, the amino acid sequence of VLCDR2 of SEQ ID NO: 18 and the amino acid sequence of VLCDR3 of SEQ ID NO: 19. In one embodiment, the anti-CD73 antibody molecule contains a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 164, the amino acid sequence of VHCDR2 under SEQ ID NO: 165 and the amino acid sequence of VHCDR3 under SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 17, the amino acid sequence of VLCDR2 of SEQ ID NO: 18 and the amino acid sequence of VLCDR3 of SEQ ID NO: 19.

In one embodiment, the anti-CD73 antibody molecule comprises a VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 35, the amino acid sequence of VHCDR2 of SEQ ID NO: 36, and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 70, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 81, the amino acid sequence of VHCDR2 under SEQ ID NO: 71 and the amino acid sequence of VHCDR3 under SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 135, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 145, the amino acid sequence of VHCDR2 under SEQ ID NO: 146 and the amino acid sequence of VHCDR3 under SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 153, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 59, the amino acid sequence of VHCDR2 of SEQ ID NO: 60 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 25, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 1, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 161, the amino acid sequence of VHCDR2 of SEQ ID NO: 162 and the amino acid sequence of VHCDR3 of SEQ ID NO: 3; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one embodiment, the anti-CD73 antibody molecule comprises a VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 41, the amino acid sequence of VHCDR2 of SEQ ID NO: 42, and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL containing the amino acid sequence of VLCDR1 under SEQ ID NO: 54, amino acid according to

- 93 047335 the VLCDR2 sequence of SEQ ID NO: 52 and the VLCDR3 amino acid sequence of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule contains a VH containing the VHCDR1 amino acid sequence of SEQ ID NO: 75, the VHCDR2 amino acid sequence of SEQ ID NO: 76 and the amino acid sequence of VHCDR3 under SEQ ID NO: 43; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 54, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 83, the amino acid sequence of VHCDR2 of SEQ ID NO: 76 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 54, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 140, the amino acid sequence of VHCDR2 of SEQ ID NO: 141 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 54, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 149, the amino acid sequence of VHCDR2 of SEQ ID NO: 150 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 54, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 157, the amino acid sequence of VHCDR2 of SEQ ID NO: 158 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 54, the amino acid sequence of VLCDR2 of SEQ ID NO: 52, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 64, the amino acid sequence of VHCDR2 of SEQ ID NO: 65 and the amino acid sequence of VHCDR3 of SEQ ID NO: 9; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 20, the amino acid sequence of VLCDR2 of SEQ ID NO: 18, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 29, the amino acid sequence of VHCDR2 of SEQ ID NO: 30 and the amino acid sequence of VHCDR3 of SEQ ID NO: 9; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 20, the amino acid sequence of VLCDR2 of SEQ ID NO: 18, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 7, the amino acid sequence of VHCDR2 of SEQ ID NO: 8 and the amino acid sequence of VHCDR3 of SEQ ID NO: 9; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 20, the amino acid sequence of VLCDR2 of SEQ ID NO: 18, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 166, the amino acid sequence of VHCDR2 of SEQ ID NO: 167 and the amino acid sequence of VHCDR3 of SEQ ID NO: 9; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 20, the amino acid sequence of VLCDR2 of SEQ ID NO: 18 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In one embodiment, an anti-CD73 antibody molecule comprises a VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 190, the amino acid sequence of VHCDR2 of SEQ ID NO: 36, and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 191, the amino acid sequence of VHCDR2 under SEQ ID NO: 71 and the amino acid sequence of VHCDR3 under SEQ ID NO: 43; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 192, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL containing the amino acid sequence of VLCDR1 under SEQ ID NO: 48, the amino acid sequence of VLCDR2 under SEQ ID NO: 49 and the amino acid sequence of VLCDR3 under

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SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 193, the amino acid sequence of VHCDR2 of SEQ ID NO: 136, and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 194, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 195, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 197, amino acid sequence of VHCDR2 of SEQ ID NO: 60 and amino acid sequence of VHCDR3 of SEQ ID NO: 9; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 198, the amino acid sequence of VHCDR2 of SEQ ID NO: 26 and the amino acid sequence of VHCDR3 of SEQ ID NO: 9; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 199, the amino acid sequence of VHCDR2 of SEQ ID NO: 2 and the amino acid sequence of VHCDR3 of SEQ ID NO: 9; and VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15, and the amino acid sequence of VLCDR3 of SEQ ID NO: 16. In one embodiment, the anti-CD73 antibody molecule comprises a VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 200, the amino acid sequence of VHCDR2 under SEQ ID NO: 162 and the amino acid sequence of VHCDR3 under SEQ ID NO: 9; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 14, the amino acid sequence of VLCDR2 of SEQ ID NO: 15 and the amino acid sequence of VLCDR3 of SEQ ID NO: 16.

In other embodiments, the aforementioned antibodies comprise a heavy chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with any of SEQ ID NO: 44, 77, 84, 142, 151, or 159. In other embodiments, the above-mentioned antibodies comprise a heavy chain variable region comprising an amino acid sequence characterized by at least 85% (e.g., at least 90%, 95 %, 97%, 98%, 99%, or 100%) sequence identity to any of SEQ ID NO: 66, 31, 10, or 168.

In other embodiments, the aforementioned antibodies comprise a light chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with any of SEQ ID NO: 55 or 21.

In other embodiments, the aforementioned antibodies comprise a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with any of SEQ ID NO: 46, 79, 86, 114, 116, or 117. In other embodiments, the above antibodies comprise a heavy chain comprising an amino acid sequence characterized by at least 85% (e.g., at least 90%, 95%, 97% , 98%, 99%, or 100%) sequence identity to any of SEQ ID NO: 68, 33, 12, 115, 113, or 112.

In other embodiments, the aforementioned antibodies comprise a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with any of SEQ ID NO: 57 or 23.

In other embodiments, the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 44; and a light chain variable region containing the amino acid sequence

- 95 047335 having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 55. In other embodiments, the molecule The antibody contains a heavy chain variable region containing an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 77 ; and a light chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 55. In other embodiments, the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 84; and a light chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 55. In other embodiments, the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 142; and a light chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 55. In other embodiments, the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 151; and a light chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 55. In other embodiments, the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 159; and a light chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 55. In other embodiments, the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 66; and a light chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 21. In other embodiments, the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 31; and a light chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 21. In other embodiments, the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 10; and a light chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 21. In other embodiments, the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 168; and a light chain variable region comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 21.

In other embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 46; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 57. In others In embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 79; and a light chain containing an amino acid sequence characterized by

- 96 047335 at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 57. In other embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (eg, at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 86; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 57. In others In embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 114; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 57. In others In embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 116; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 57. In others In embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 117; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 57. In others In embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 68; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 23. In others In embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 33; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 23. In others In embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 12; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 23. In others In embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 115; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 23. In others In embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 113; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 23. In others In embodiments, the antibody molecule comprises a heavy chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 112; and a light chain comprising an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 23.

In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 81, 201, 37, 205, 206 and 207, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 38, 201, 37, 205, 206 and 207, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 82, 202, 37, 208, 209 and 228, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 83, 203, 43, 229,

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209 and 207 respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 192, 201, 43, 205, 206 and 207, respectively. In other embodiments, the antibody molecule comprises VH and VL comprising the amino acid sequences of SEQ ID NOs: 204 and 230, respectively (or an amino acid sequence characterized by at least 85% (e.g., at least 90%, 95%, 97%, 98 %, 99%, or 100%) sequence identity with them).

In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 81, 231, 37, 205, 206 and 207, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 38, 231, 37, 205, 206 and 207, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 82, 232, 37, 208, 209 and 228, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 83, 233, 43, 229, 209 and 207, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 192, 231, 43, 205, 206 and 207, respectively. In other embodiments, the antibody molecule comprises VH and VL comprising the amino acid sequences of SEQ ID NOs: 234 and 230, respectively (or an amino acid sequence characterized by at least 85% (e.g., at least 90%, 95%, 97%, 98 %, 99%, or 100%) sequence identity with them).

In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 235, 236, 237, 246, 15 and 247, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 238, 236, 237, 246, 15 and 247, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 239, 240, 237, 248, 18 and 249, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 241, 242, 243, 250, 18 and 247, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 244, 236, 243, 246, 15 and 247, respectively. In other embodiments, the antibody molecule comprises VH and VL comprising the amino acid sequences of SEQ ID NOs: 245 and 251, respectively (or an amino acid sequence characterized by at least 85% (e.g., at least 90%, 95%, 97%, 98 %, 99%, or 100%) sequence identity with them).

In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 252, 253, 254, 262, 263 and 264, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 255, 253, 254, 262, 263 and 264, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 155, 256, 254, 265, 266 and 267, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 257, 258, 259, 268, 266 and 264, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 260, 253, 259, 262, 263 and 264, respectively. In other embodiments, the antibody molecule comprises VH and VL comprising the amino acid sequences of SEQ ID NOs: 261 and 269, respectively (or an amino acid sequence characterized by at least 85% (e.g., at least 90%, 95%, 97%, 98 %, 99%, or 100%) sequence identity with them).

In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 287, 288, 289, 298, 49 and 299, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 290, 288, 289, 298, 49 and 299, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 291, 292, 289, 300, 52 and 301, respectively.

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In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 293, 294, 295, 302, 52 and 299, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 296, 288, 295, 298, 49 and 299, respectively. In other embodiments, the antibody molecule comprises VH and VL comprising the amino acid sequences of SEQ ID NOs: 297 and 303, respectively (or an amino acid sequence characterized by at least 85% (e.g., at least 90%, 95%, 97%, 98 %, 99%, or 100%) sequence identity with them).

In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 304, 305, 306, 14, 15 and 314, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 61, 305, 306, 14, 15 and 314, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 307, 308, 306, 17, 18 and 315, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 309, 310, 311, 20, 18 and 314, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 312, 305, 311, 14, 15 and 314, respectively. In other embodiments, the antibody molecule comprises VH and VL comprising the amino acid sequences of SEQ ID NOs: 313 and 316, respectively (or an amino acid sequence characterized by at least 85% (e.g., at least 90%, 95%, 97%, 98 %, 99%, or 100%) sequence identity with them).

In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 317, 318, 319, 14, 15 and 328, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 320, 318, 319, 14, 15 and 328, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 321, 322, 319, 17, 18 and 329, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 323, 324, 325, 20, 18 and 328, respectively. In other embodiments, the antibody molecule comprises VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 containing the amino acid sequences of SEQ ID NO: 326, 318, 325, 14, 15 and 328, respectively. In other embodiments, the antibody molecule comprises VH and VL comprising the amino acid sequences of SEQ ID NOs: 327 and 330, respectively (or an amino acid sequence characterized by at least 85% (e.g., at least 90%, 95%, 97%, 98 %, 99%, or 100%) sequence identity with them).

In other embodiments, the aforementioned antibody molecules are selected from a full-length antibody, a bispecific antibody, a Fab, an F(ab')2, an Fv, or a single chain fragment Fv (scFv).

In other embodiments, the aforementioned antibody molecules comprise a heavy chain constant region selected from IgG1, IgG2, IgG3 and IgG4.

In other embodiments, the aforementioned antibody molecules comprise a light chain constant region selected from kappa or lambda light chain constant regions.

In some embodiments, the anti-CD73 antibody molecule comprises a heavy chain variable region, a light chain variable region, a heavy chain constant region, and/or a light chain constant region as disclosed in Table 1. 1. In some embodiments, the anti-CD73 antibody molecule comprises a heavy chain constant region and/or a light chain constant region as disclosed in Table. 3. In some embodiments, the anti-CD73 antibody molecule comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92-103, 119, and 120. In some embodiments, the anti-CD73 antibody molecule comprises a light chain constant region chain containing the amino acid sequence of SEQ ID NO: 104.

Exemplary sequences of antibodies to CD73 are described in table. 1 and 2 below.

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Table 1

Amino acid and nucleotide sequences for exemplary CD7 antibodies 3.

358 SEQ ID NO: 1 (combined) HCDR1 GGSISGRYWS SEQ ID NO: 2 (combined) HCDR2 YIYGTGSTNYNPSLKS SEQ ID NO: 3 (combined) HCDR3 ESQESPYNNWFDP SEQ ID NO: 4 (Kabat) HCDR1 GRYWS SEQ ID NO: 2 (Kabat) HCDR2 YIYGTGSTNYNPSLKS SEQ ID NO: 3 (Kabat) HCDR3 ESQESPYNNWFDP SEQ ID NO: 5 (Chothia) HCDR1 GGSISGR SEQ ID NO: 6 (Chothia) HCDR2 YGTGS SEQ ID NO: 3 (Chothia) HCDR3 ESQESPYNNWFDP SEQ ID NO: 7 (IMGT) HCDR1 GGSISGRY SEQ ID NO: 8 (IMGT) HCDR2 IYGTGST SEQ ID NO: 9 (IMGT) HCDR3 ARESQESPYNNWFDP SEQ ID NO: 199 (alternate) HCDR1 GSISGRYWS SEQ ID NO: 2 (alternate) HCDR2 YIYGTGSTNYNPSLKS SEQ ID NO: 9 (alternate) HCDR3 ARESQESPYNNWFDP SEQ ID NO: 10 VH QVQLQESGPGLVKPSETLSLTCTVSGGSISG RYWSWIRQPPGKGLEWIGYIYGTGSTNYN PSLKSRVTISVDTSKNQFSLKLSSVTAADTA VYYCARESQESPYNNWFDPWGQGTLVTVS S SEQ ID NO: 11 DNA encoding CAAGTGCAGCTGCAGGAATCTGGCCCTG GCCTGGTCAAGCCCTCCGAGACACTGTCC

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VH CTGACCTGCACCGTGTCCGGCGGCTCCAT CTCCGGCCGGTACTGGTCTTGGATCCGGC AGCCTCCCGGCAAGGGCCTGGAATGGAT CGGCTACATCTACGGCACCGGCTCCACC AACTACAACCCCAGCCTGAAGTCCAGAG TGACCATCTCCGTGGACACCTCCAAGAA CCAGTTCTCCCTGAAGCTGTCCTCCGTGA CCGCCGCTGACACCGCCGTGTACTACTGC GCCAGAGAGTCCCAGGAATCCCCCTTACA ACAATTGGTTCGACCCCTGGGGCCAGGG CACCCTGGTCACCGTGTCCTCT SEQ GO NO: 12 Heavy chain 358.A GLYSLSSVVTVP TKNQVSL TCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLG X, where X represents K or is absent. SEQ ID NO: 13 DNA encoding heavy chain 358.A CAAGTGCAGCTGCAGGAATCTGGCCCTG GCCTGGTCAAGCCCTCCGAGACACTGTCC CTGACCTGCACCGTGTCCGGCGGCTCCAT CTCCGGCCGGTACTGGTCTTGGATCCGGC AGCCTCCCGGCAAGGGCCTGGAATGGAT CGGCTACATCTACGGCACCGGCTCCACC AACTACAACCCCAGCCTGAAGTCCAGAG

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TGACCATCTCCGTGGACACCTCCAAGAA CCAGTTCTCCCTGAAGCTGTCCTCCGTGA CCGCCGCTGACACCGCCGTGTACTACTGC GCCAGAGAGTCCCAGGAATCCCTTACA ACAATTGGTTCGACCCCTGGGGCCAGGG CACCCTGGTCACCGTGTCCTCTGCTTCCA CCAAGGGCCCCTCCGTGTTCCCTCTGGCC CCTTGCTCCCGGTCCACCTCCGAGTCTAC TCTGGGCTGCCTCGTGAAGGACT ACTTCCCCGAGCCCGTGACCGTGTCCTGG AACTCTGGCGCCCTGACCTCCGGCGTGCA CACCTTCCCTGCCGTGCTGCAGTCCTCCG GCCTGTACTCCCTGTCCAGCGTCGTGACC GTGCCCTCCTCCAGCCTGGGCACCAAGA CCTACACCTGTAACGTGGACCACAAGCC CTCCAACACCAAAGTGGACAAGCGGGTG GAATCTAAGTACG GCCCTCCCTGCCCTCC TTGCCCTGCCCCTGAGTTCCTGGGCGGAC CTTCCGTGTTCCTGTTCCCTCCAAAGCCC AAGGACACCCTGATGATCTCCCGGACCC CTGAAGTGACCTGCGTGGTGGTGGACGT GTCCCAGGAAGATCCCGAAGTCCAGTTC AATTGGTACGTGGACGGCGTGGAAGTGC ACAACGCCAAGACCAAGCCCAGAGAGGA ACAGTTCAACTCCACCT ACCGGGTGGTGT CCGTGCTGACCGTGCTGCACCAGGACTG GCTGAACGGCAAAGAGTACAAGTGCAAA GTGTCCAACAAGGGCCTGCCCTCCAGCA TCGAAAAGACCATCTCAAGGCCAAGGG CCAGCCCCGCGAGCCCCAAGTGTACACC CTGCCTCCCAGCCAGGAAGATGACCA AGAATCAAGTGTCCCTGACTTGTCTGGTC AAGGGCTTCTACCCCTCCGATATCGCCG T GGAGTGGGAGTCCAACGGCCAGCCCGAG AACAACTACAAGACCACCCCTCCCGTGC

- 102 047335

TGGACTCCGACGGCTCCTTCTTCCTGTAC TCTCGGCTGACCGTGGACAAGTCCCGGT GGCAGGAAGGCAACGTCTTCTCCTGCTCC GTGATGCACGAGGCCCTGCACAACCACT ACACCCAGAAGTCCCTGTCCCTGTCTCTG GGCXiX ₂ X ₃ where Xi represents A, X2 represents A, and X3 represents G; or Xi is missing, X2 is missing and X3 is missing. SEQ GO NO: 112 Heavy chain 358.B GLYSLSSVVTVP TKNQVSLTC LVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLG X, where X represents K or is absent SEQ ID NO: 14 (combined) LCDR1 RASQGISSWLA SEQ ID NO: 15 (combined) LCDR2 AASSLQS SEQ ID NO: 16 (combined) LCDR3 QQGNSFPRT SEQ ID NO: 14 (Kabat) LCDR1 RASQGISSWLA SEQ ID NO: 15 (Kabat) LCDR2 AASSLQS

- 103 047335

SEQ S NO: 16 (Kabat) LCDR3 QQGNSFPRT SEQ ID NO: 17 (Chothia) LCDR1 SQGISSW SEQ ID NO: 18 (Chothia) LCDR2 A.A.S. SEQ ID NO: 19 (Chothia) LCDR3 GNSFPR SEQ ID NO: 20 (IMGT) LCDR1 QGISSW SEQ ID NO: 18 (IMGT) LCDR2 A.A.S. SEQ ID NO: 16 (IMGT) LCDR3 QQGNSFPRT SEQ ID NO: 14 (alternate) LCDR1 RASQGISSWLA SEQ ID NO: 15 (alternate) LCDR2 AASSLQS SEQ ID NO: 16 (alternate) LCDR3 QQGNSFPRT SEQ ID NO: 21 VL DIQMTQSPSSVSASVGDRVTITCRASQGISS WLAWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQG NSFPRTFGGGTKVEIK SEQ ID NO: 22 DNA encoding VL GACATCCAGATGACCCAGAGCCCCTCCT CCGTGTCCGCCTCCGTGGGCGACAGAGT GACCATCACCTGTCGGGCCTCCCAGGGC ATCTCCAGCTGGCTGGCCTGGTATCAGCA GAAGCCCGGCAAGGCCCCTAAGCTGCTG ATCTACGCCGCCTCCAGCCTGCAGTCCGG CGTGCCCTCCAGATTCTCCGGCTCTGGCT CCGGCACCGACTTCACCCTGACCATCAGC TCCCTGCAGCCCGAGGACTTCGCCACCTA CTACTGCCAGCAGGGCAACTCCTTTCCCTC GGACCTTCGGCGGAGGCACCAAAGTGGA AATCAAG SEQ ID NO: 23 Light chain DIQMTQSPSSVSASVGDRVTITCRASQGISS WLAWYQQKPGKAPKLLIYAASSLQSGVPS

- 104 047335

RFSGSGSGTDFTLTISSLQPEDFATYYCQQG NSFPRTFGGGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ GO NO: 24 DNA encoding the light chain GACATCCAGATGACCCAGAGCCCCTCCT CCGTGTCCGCCTCCGTGGGCGACAGAGT GACCATCACCTGTCGGGCCTCCCAGGGC ATCTCCAGCTGGCTGGCCTGGTATCAGCA GAAGCCCGGCAAGGCCCCTAAGCTGCTG ATCTACGCCGCCTCCAGCCTGCAGTCCGG CGTGCCCTCCAGATTCTCCGCTCTGGCT CCGGCACCGACTTCACCCTGACCATCAGC TCCCTG CAGCCCGAGGACTTCGCCACCTA CTACTGCCAGCAGGGCAACTCCTTCCCTC GGACCTTCGGCGGAGGCACCAAAGTGGA AATCAAGCGTACGGTGGCCGCTCCCTCC GTGTTCATCTTCCCACCCTCCGACGAGCA GCTGAAGTCCGGCACCGCCTCCGTCGTGT GCCTGCTGAACAACTTCTACCCTCGCGAG GCCAAAGTGCAGTGGAAAGTGGACAACG GCAACTCCCAGGAATC CGTCACCGAGCAGGACTCCAAGGACAGC ACCTACTCCCTGTCCTCACCCTGACCCT GTCCAAGGCCGACTACGAGAAGCACAAA GTGTACGCCTGCGAAGTGACCCACCAGG GCCTGTCCAGCCCCGTGACCAAGTCCTTC AACCGGGGCGAGTGC 356 SEQ ID NO: 25 (combined) HCDR1 GGSIEGRYWS SEQ ID NO: 26 (combined) HCDR2 YIYGSGSTKYNPSLKS SEQ ID NO: 3 HCDR3 ESQESPYNNWFDP

- 105 047335

(merged) SEQ GO NO: 4 (Kabat) HCDR1 GRYWS SEQ ID NO: 26 (Kabat) HCDR2 YIYGSGSTKYNPSLKS SEQ ID NO: 3 (Kabat) HCDR3 ESQESPYNNWFDP SEQ ID NO: 27 (Chothia) HCDR1 GGSIEGR SEQ ID NO: 28 (Chothia) HCDR2 YGSGS SEQ ID NO: 3 (Chothia) HCDR3 ESQESPYNNWFDP SEQ ID NO: 29 (IMGT) HCDR1 GGSIEGRY SEQ ID NO: 30 (IMGT) HCDR2 IYGSGST SEQ ID NO: 9 (IMGT) HCDR3 ARESQESPYNNWFDP SEQ ID NO: 198 (alternate) HCDR1 GSIEGRYWS SEQ ID NO: 26 (alternate) HCDR2 YIYGSGSTKYNPSLKS SEQ ID NO: 9 (alternate) HCDR3 ARESQESPYNNWFDP SEQ ID NO: 31 VH QVQLQESGPGLVKPSETLSLTCTVSGGSIEG RYWSWIRQPPGKGLEWIGYIYGSGSTKYNP SLKSRVTISVDTSKNQFSLKLSSVTAADTA VYYCARESQESPYNNWFDPWGQGTLVTVS S SEQ ID NO: 32 DNA encoding VH CAAGTGCAGCTGCAGGAATCTGGCCCTG GCCTGGTCAAGCCCTCCGAGACACTGTCC CTGACCTGCACCGTGTCCGGCGGCTCTAT CGAGGGCCGGTACTGGTCCTGGATCCGG CAGCCTCCTGGCAAGGGCCTGGAATGGA TCGGCTACATCTACGGCTCCGGCTCCACC AAGTACAACCCCAGCCTGAAGTCCAGAG TGACCATCTCCGTGGACACCTCCAAGAA CCAGTTCTCCCTGAAGCTGTCCTCCGTGA CCGCCGCTGACACCGCCGTGTACTACTGC

- 106 047335

GCCAGAGAGTCCCAGGAATCCCCCTTACA ACAATTGGTTCGACCCCTGGGGCCAGGG CACCCTGGTCACCGTGTCCTCT SEQ GO NO: 33 Heavy chain 356.A GLYSLSSVVT VPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQV SLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLG X, where X represents K or is absent SEQ ID NO: 34 DNA encoding heavy chain 356.A CAAGTGCAGCTGCAGGAATCTGGCCCTG GCCTGGTCAAGCCCTCCGAGACACTGTCC CTGACCTGCACCGTGTCCGGCGGCTCTAT CGAGGGCCGGTACTGGTCCTGGATCCGG CAGCCTCCTGGCAAGGGCCTGGAATGGA TCGGCTACATCTACGGCTCCGGCTCCACC AAGTACAACCCCAGCCTGAAGTCCAGAG TGACCATCTCCGTGGACACCTCCAAGAA CCCTGAAGCTGTCCTCCGTGA CCGCCGCTGACACCGCCGTGTACTACTGC GCCAGAGAGTCCCAGGAATCCCCTTACA ACAATTGGTTCGACCCCTGGGGCCAGGG CACCCTGGTCACCGTGTCCTCTGCCTCCA CCAAGGGCCCCTCCGTGTTCCCTCTGGCC CCTTGCTCCCGGTCCACCTCCGAGTCTAC

- 107 047335

CGCCGCTCTGGGCTGCCTCGTGAAGGACT ACTTCCCCGAGCCCGTGACCGTGTCCTGG AACTCTGGCGCCCTGACCTCCGGCGTGCA CACCTTCCCTGCCGTGCTGCAGTCCTCCG GCCTGTACTCCCTGTCCAGCGTCGTGACC GTGCCCTCCTCCAGCCTGGGCACCAAGA CCTACACCTGTAACGTGGACCACAAGCC CTCCAACACCAAAGTGGACAAGCGGGTG GAATCTAAGTACGGCCCTCCCTGCCCTCC TTGCCCTGCCCCTGAGTTCCCTGGGCGGAC CTTCCGTGTTCCTGTTCCCTCCAAAGCCC AAGGACACCCTGATGATCTCCCGGACCC CTGAAGTGACCTGCGTGGTGGTGGACGT GTCCCAGGAAGATCCCGAAGTCCAGTTC AATTGGTACGTGGACGGCGTGGAAGTGC ACAACGCCAAGACCAAGCCCAGAGAGGA ACAGTTCAACTCCACCTACCGGGTGGTGT CCGTGCTGACCGTGCTGCACCAGGACTG GCTGAACGGCAAAGAGTACAAGTGCAAA GTGTCCAACAAGGGCCTGCCCCTCCAGCA TCGAAAAGACCATCTCCAAAGGCCAAGGG CCAGCCCCGCGAGCCCCAAGTGTACACC CTGCCTCCCAGCCAGGAAGAGATGACCA AGAATCAAGTGTCCCTGACTTGTCTGGTC AAGGGCTTCTACCCCTCCGATATCGCCGT GGAGTGGGAGTCCAACGGCCAGCCCGAG AACAACTACAAGACCACCCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTGTAC TCTCGGCTGACCGTGGACAAGTCCCGGT GGCAGGAAGGCAACGTCTTCTCCTGCTCC GTGATGCACGAGGCCCTGCACAACCACT ACACCCAGAAGTCCCTGTCCCTGTCTCTG GGC X1X2X3, where Xi represents A, X2 represents A, and X3 represents G; or Xi

- 108 047335

absent, He absent and Xs absent. SEQ GO NO: 113 Heavy chain 356.B GLYSLSSVVT VPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFEGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSL TCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLG X, where X represents K or is absent SEQ ID NO: 14 (combined) LCDR1 RASQGISSWLA SEQ ID NO: 15 (combined) LCDR2 AASSLQS SEQ ID NO: 16 (combined) LCDR3 QQGNSFPRT SEQ ID NO: 14 (Kabat) LCDR1 RASQGISSWLA SEQ ID NO: 15 (Kabat) LCDR2 AASSLQS SEQ ID NO: 16 (Kabat) LCDR3 QQGNSFPRT SEQ ID NO: 17 (Chothia) LCDR1 SQGISSW SEQ ID NO: 18 (Chothia) LCDR2 A.A.S. SEQ ID NO: 19 (Chothia) LCDR3 GNSFPR SEQ ID NO: 20 (IMGT) LCDR1 QGISSW

- 109 047335

SEQ GO NO: 18 (IMGT) LCDR2 A.A.S. SEQ ID NO: 16 (IMGT) LCDR3 QQGNSFPRT SEQ ID NO: 14 (alternate) LCDR1 RASQGISSWLA SEQ ID NO: 15 (alternate) LCDR2 AASSLQS SEQ ID NO: 16 (alternate) LCDR3 QQGNSFPRT SEQ ID NO: 21 VL DIQMTQSPSSVSASVGDRVTITCRASQGISS WLAWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQG NSFPRTFGGGTKVEIK SEQ ID NO: 22 DNA encoding VL GACATCCAGATGACCCAGAGCCCCTCCT CCGTGTCCGCCTCCGTGGGCGACAGAGT GACCATCACCTGTCGGGCCTCCCAGGGC ATCTCCAGCTGGCTGGCCTGGTATCAGCA GAAGCCCGGCAAGGCCCCTAAGCTGCTG ATCTACGCCGCCTCCAGCCTGCAGTCCGG CGTGCCCTCCAGATTCTCCGGCTCTGGCT CCGGCACCGACTTCACCCTGACCATCAGC TCCCTGCAGCCCGAGGACTTCGCCACCTA CTACTGCCAGCAGGGCAACTCCTTTCCCTC GGACCTTCGGCGGAGGCACCAAAGTGGA AATCAAG SEQ ID NO: 23 Light chain SKADYE KHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 24 DNA encoding GACATCCAGATGACCCAGAGCCCCTCCT CCGTGTCCGCCTCCGTGGGCGACAGAGT

- 110 047335

light chain GACCATCACCTGTCGGGCCTCCCAGGGC ATCTCCAGCTGGCTGGCCTGGTATCAGCA GAAGCCCGGCAAGGCCCCTAAGCTGCTG ATCTACGCCGCCTCCAGCCTGCAGTCCGG CGTGCCCTCCAGATTCTCCGGCTCTGGCT CCGGCACCGACTTCACCCTGACCATCAGC TCCCTGCAGCCCGAGGACTTCGCCACCTA CTACTGCCAGCAGGGCAACTCCTTTCCCTC GGACCTTCGGCGGAGGCACCAAAGTGGA AATCAAGCGTACGGTGGCCGCTCCCTCC GTGTTCATCTTCCCACCCTCCGACGAGCA GCTGAAGTCCGGCACCGCCTCCGTCGTGT GCCTGCTGAACAACTTCTACCCTCGCGAG GCCAAAGTGCAGTGGAAAGTGGACAACG CCCTGCAGTCCGGCAACTCCCAGGAATC CGTCACCGAGCAGGACTCCAAGGACAGC ACCTACTCCCTGTCCTCCACCCCTGACCCT GTCCAAGGCCGACTACGAGAAGCACAAA GTGTACGCTGCGAAGTGACCCACCAGG GCCTGTCCAGCCCCGTGACCAAGTCCTTC AACCGGGGCGAGTGC 373 SEQ ID NO: 35 (combined) HCDR1 GFTFHRYAMS SEQ ID NO: 36 (combined) HCDR2 AISGSGMNTYYADSVKG SEQ ID NO: 37 (merged) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 38 (Kabat) HCDR1 RYAMS SEQ ID NO: 36 (Kabat) HCDR2 AISGSGMNTYYADSVKG SEQ ID NO: 37 (Kabat) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 39 (Chothia) HCDR1 GFTFHRY SEQ ID NO: 40 HCDR2 SGSGMN

- 111 047335

(Chothia) SEQ ID NO: 37 (Chothia) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 41 (IMGT) HCDR1 GFTFHRYA SEQ ID NO: 42 (IMGT) HCDR2 ISGSGMNT SEQ ID NO: 43 (IMGT) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 190 (alternate) HCDR1 FTFHRYAMS SEQ ID NO: 36 (alternate) HCDR2 AISGSGMNTYYADSVKG SEQ ID NO: 43 (alternate) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 44 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFH RYAMSWVRQAPGKGLEWVSAISGSGMNT YYADSVKGRFTISRDNSKNTLYLQMNSLR AEDTAVYYCARGGLYGSGSYLSDFDLWG RGTLVTVSS SEQ ID NO: 45 DNA encoding VH GAAGTGCAGCTGCTGGAATCTGGCGGCG GACTGGTGCAGCCTGGCGGCTCCCTGAG ACTGTCTTGCGCCGCCTCCGGCTTCACCT TCCACAGATACGCCATGTCCTGGGTCCGA CAGGCCCCTGGCAAGGGCCTGGAGTGGG TGTCCGCCATCTCCGGCTCCGGCATGAAC ACCTACTACGCCGACTCCGTGAAGGGCC GGTTCACCATCTCCCGGGGACAACTCCAA GAACACCCTGTACCTGCAGATGAACTCC CTGCGGGCCGAGGACACCGCCGTGTACT ACTGTGCCAGAGGCGGCCTGTACGGCTC CGGCTCCTACCTGTCCGACTTCGACCTGT GGGGCAGAGGCACCCTGGTCACCGTGTC CTCC SEQ ID NO: 46 Heavy chain 373.A EVQLLESGGGLVQPGGSLRLSCAASGFTFH RYAMSWVRQAPGKGLEWVSAISGSGMNT YYADSVKGRFTISRDNSKNTLYLQMNSLR

- 112 047335

AEDTAVYYCARGGLYGSGSYLSDFDLWG RGTLVTVSSASTKGPSVFPLAPCSRSTSEST AALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT CNVDHKPSNTKVDKRVESKYGPPCPPCPAP EFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNW YVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTL PPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSRLT VDKSRWQEGNVFSCSVMHEALHNHYTQK SLSLSLGX, where X represents K or is absent SEQ GO NO: 47 DNA encoding heavy chain 373.A GAAGTGCAGCTGCTGGAATCTGGCGGCG GACTGGTGCAGCCTGGCGGCTCCCTGAG ACTGTCTTGCGCCGCCTCCGGCTTCACCT TCCACAGATACGCCATGTCCTGGGTCCGA CAGGCCCCTGGCAAGGGCCTGGAGTGGG TGTCCGCCATCTCCGGCTCCGGCATGAAC ACCTACTACGCCGACTCCGTGAAGGGCC GGTTCACCATCTCCCGGGGACAACTCCAA GAACACCCTGTACCTGCAGATGAACTCC CTGCGGGCCGAGGACACCGCCGTGTACT ACTGTGCCAGAGGCGGCCTGTACGGCTC CGGCTCCTACCTGTCCGACTTCGACCTGT GGGGCAGAGGCACCCTGGTCACCGTGTC CTCCGCCTCCACAAAGGGCCCCTCCGTGT TCCCTCTGGCCCCTTGCTCCCGGTCCACC TCCGAGTCTACCGCCGCTCTGGGCTGCCT CGTGAAGGACTACTTCCCCGAGCCCGTG ACCGTGTCCTGGAACTCTGGCGCCCTGAC CTCCGGCGTGCACACCTTCCCTGCCGTGC TGCAGTCCTCCGGCCTGTACTCCCTGTCC AGCGTCGTGACCGTGCCCTCCTCCAGCCT

- 113 047335

GGGCACCAAGACCTACACCTGTAACGTG GACCACAAGCCCTCCAACACCAAAGTGG ACAAGCGGGTGGAATCTAAGTACGGCCC TCCCTGCCCTCCTTGCCCTGCCCCTGAGT TCCTGGGCGGACCTTCCGTGTTCCTGTTC CCTCCAAAGCCCAAGGACACCCTGATGA TCTCCCGGACCCCTGAAGTGACCTGCGTG GTGGTGGACGTGTCCCAGGAAGATCCCG AAGTCCAGTTCAATTGGTACGTGGACGG CGTGGAAGTGCACAACGCCAAGACCAAG CCCAGAGAGGAACAGTTCAACTCCACCT ACCGGGTGGTGTCCGTGCTGACCGTGCTG CACCAGGACTGGCTGAACGGCAAAGAGT ACAAGTGCAAAGTGTCCAACAAGGGCCT GCCCTCCAGCATCGAAAAGACCATCTCC AAGGCCAAGGGCCAGCCCCGCGAGCCCC AAGTGTACACCCTGCCTCCCAGCCAGGA AGAGATGACCAAGAATCAAGTGTCCCTG ACTTGTCTGGTCAAGGGCTTCTACCCCTC CGATATCGCCGTGGAGTGGGAGTCCAAC GGCCAGCCCGAGAACAACTACAAGACCA CCCCTCCCGTGCTGGACTCCGACGGCTCC TTCTTCCTGTACTCTCGGCTGACCGTGGA CAAGTCCCGGTGGCAGGAAGGCAACGTC TTCTCCTGCTCCGTGATGCACGAGGCCCT GCACAACCACTACACCCAGAAGTCCCTG TCCCTGTCTCTGGGC XiX ₂ X ₃ , где Xi представляет собой A, X ₂ представляет собой А, и Хз представляет собой G; or Xi is missing, X ₂ is missing and Xs is missing. SEQ GO NO: 114 Heavy chain 373.B EVQLLESGGGLVQPGGSLRLSCAASGFTFH RYAMSWVRQAPGKGLEWVSAISGSGMNT YYADSVKGRFTISRDNSKNTLYLQMNSLR AEDTAVYYCARGGLYGSGSYLSDFDLWG RGTLVTVSSASTKGPSVFPLAPCSRSTSEST

- 114 047335

AALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT CNVDHKPSNTKVDKRVESKYGPPCPPCPAP EFEGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTL PPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSRLT VDKSRWQEGNVFSCSVMHEALHNHYTQK SLSLSLGX, where X represents K or is absent SEQ ID NO: 48 (merged) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (merged) LCDR2 GASTRAT SEQ ID NO: 50 (combined) LCDR3 QQHNAFPYT SEQ ID NO: 48 (Kabat) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (Kabat) LCDR2 GASTRAT SEQ ID NO: 50 (Kabat) LCDR3 QQHNAFPYT SEQ ID NO: 51 (Chothia) LCDR1 SQSVGSN SEQ ID NO: 52 (Chothia) LCDR2 G.A.S. SEQ ID NO: 53 (Chothia) LCDR3 HNAFPY SEQ ID NO: 54 (IMGT) LCDR1 QSVGSN SEQ ID NO: 52 (IMGT) LCDR2 G.A.S. SEQ ID NO: 50 (IMGT) LCDR3 QQHNAFPYT SEQ ID NO: 48 (alternate) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (alternate) LCDR2 GASTRAT

- 115 047335

SEQ ID NO: 50 (alternate) LCDR3 QQHNAFPYT SEQ ID NO: 55 VL EIVLTQSPATLSVSPGERATLLSCRASQSVGS NLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQHN AFPYTFGGGTKVEIK SEQ ID NO: 56 DNA encoding VL GAGATCGTGCTGACACAGTCCCCTGCCA CCCTGTCTGTGTCTCCCGGCGAGAGAGCC ACCCTGAGCTGCAGAGCCTCCCAGTCCGT GGGCTCCAACCTGGCCTGGTATCAGCAG AAGCCCGGCCAGGCCCCTCGGCTGCTGA TCTACGGCGCCTCTACCAGAGCCACCGG CATCCCTGCCAGATTCTCCGGCTCTGGCT CCGGCACCGAGTTCACCCTGACCATCTCC AGCCTGCAGTCCGAGGACTTCGCCGTGT ACTACTGCCAGCAGCACAACGCCTTCCCT TACACCTTCGGCGGAGGCACCAAAGTGG AAATCAAG SEQ ID NO: 57 Light chain EIVLTQSPATLSVSPGERATLSCRASQSVGS NLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQHN AFPYTFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKV YACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 58 DNA encoding the light chain GAGATCGTGCTGACACAGTCCCCTGCCA CCCTGTCTGTGTCTCCCGGCGAGAGAGCC ACCCTGAGCTGCAGAGCCTCCCAGTCCGT GGGCTCCAACCTGGCCTGGTATCAGCAG AAGCCCGGCCAGGCCCCTCGGCTGCTGA TCTACGGCGCCTCTACCAGAGCCACCGG CATCCCTGCCAGATTCTCCGGCTCTGGCT CCGGCACCGAGTTCACCCTGACCATCTCC AGCCTGCAGTCCGAGGACTTCGCCGTGT

- 116 047335

ACTACTGCCAGCAGCACAACGCCTTCCCT TACACCTTCGGCGGAGGCACCAAAGTGG AAATCAAGCGTACGGTGGCCGCTCCCTC CGTGTTCATCTTCCCACCCTCCGACGAGC AGCTGAAGTCCGGCACCGCCTCCGTCGT GTGCCTGCTGAACAACTTCTACCCTCGCG AGGCCAAAGTGCAGTGGAAAGTGGACAA CGCCCTGCAGTCCGGCAACTCCCAGGAA TCCGTCACCGAGCAGGACTCCAAGGACA GCACCTACTCCCTGTCCTCCACCCCTGACC CTGTCCAAGGCCGACTACGAGAAGCACA AAGTGTACGCTGCGAAGTGACCCACCA GGGCCTGTCCAGCCCCGTGACCAAGTCCT TCAACCGGGGCGAGTGC 350 SEQ ID NO: 59 (merged) HCDR1 GGSIERYYWS SEQ ID NO: 60 (combined) HCDR2 YIYGRGSTNYNPSLKS SEQ ID NO: 3 (combined) HCDR3 ESQESPYNNWFDP SEQ ID NO: 61 (Kabat) HCDR1 RYYWS SEQ ID NO: 60 (Kabat) HCDR2 YIYGRGSTNYNPSLKS SEQ ID NO: 3 (Kabat) HCDR3 ESQESPYNNWFDP SEQ ID NO: 62 (Chothia) HCDR1 GGSIERY SEQ ID NO: 63 (Chothia) HCDR2 YGRGS SEQ ID NO: 3 (Chothia) HCDR3 ESQESPYNNWFDP SEQ ID NO: 64 (IMGT) HCDR1 GGSIERYY SEQ ID NO: 65 (IMGT) HCDR2 IYGRGST SEQ ID NO: 9 (IMGT) HCDR3 ARESQESPYNNWFDP SEQ ID NO: 197 HCDR1 GSIERYYWS

- 117 047335

(alternative) SEQ ID NO: 60 (alternate) HCDR2 YIYGRGSTNYNPSLKS SEQ GO NO: 9 (alternative) HCDR3 ARESQESPYNNWFDP SEQ ID NO: 66 VH QVQLQESGPGLVKPSETLSLTCTVSGGSIER YYWSWIRQPPGKGLEWIGYIYGRGSTNYN PSLKSRVTISVDTSKNQFSLKLSSVTAADTA VYYCARESQESPYNNWFDPWGQGTLVTVS S SEQ ID NO: 67 DNA encoding VH CAAGTGCAGCTGCAGGAATCTGGCCCTG GCCTGGTCAAGCCCTCCGAGACACTGTCC CTGACCTGCACCGTGTCCGGCGGCTCCAT CGAGCGGTACTACTGGTCCTGGATCCGG CAGCCTCCCGGCAAGGGCCTGGAATGGA TCGGCTACATCTACGGCAGAGGCTCCAC CAACTACAACCCCAGCCTGAAGTCCAGA GTGACCATCTCCGTGGACACCTCCAAGA ACCAGTTCTCCCTGAAGCTGTCCTCCGTG ACCGCCGCTGACACCGCCGTGTACTACTG CGCCAGAGAGTCCCAGGAATCCCCTTAC AACAATGGTTCGACCCCTGGGGCCAGG GCACCCTGGTCACCGTGTCCTCT SEQ ID NO: 68 Heavy chain 350.A GLYSLSSVVTVP SSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEM

- 118 047335

TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLG X where X is K or absent SEQ GO NO: 69 DNA encoding heavy chain 350.A CAAGTGCAGCTGCAGGAATCTGGCCCTG GCCTGGTCAAGCCCTCCGAGACACTGTCC CTGACCTGCACCGTGTCCGGCGGCTCCAT CGAGCGGTACTACTGGTCCTGGATCCGG CAGCCTCCCGGCAAGGGCCTGGAATGGA TCGGCTACATCTACGGCAGAGGCTCCAC CAACTACAACCCCAGCCTGAAGTCCAGA GTGACCATCTCCGTGGACACCTCCAAGA ACCAGTTCTCCCTGAAGCTGTCCTCCGTG ACCGCCGCTGACACCGCCGTGTACTACTG CGCCAGAGAGTCCCAGGAATCCCCTTAC AACAATGGTTCGACCCCTGGGGCCAGG GCACCCTGGTCACCGTGTCCTCTGCCTCC ACCAAGGGCCCCTCCGTGTTCCCTCTGGC CCCTTGCTCCCGGTCCACCTCCGAGTCTA CCGCCGCTCTGGGCTGCCTCGTGAAGGA CTACTTCCCCGAGCCCGTGACCGTGTCCT GGAACTCTGGCGCCCTGACCTCCGGCGT GCACACCTTCCCTGCCGTGCTGCAGTCCT CCGGCCTGTACTCCCTGTCCAGCGTCGTG ACCGTGCCCTCCTCCAGCCTGGGCACCAA GACCTACACCTGTAACGTGGACCACAAG CCCTCCAACACCAAAGTGGACAAGCGGG TGGAATCTAAGTACGGCCCTCCCTGCCCT CCTTGCCCTGCCCCTGAGTTCCCTGGGCGG ACCTTCCGTGTTCCTGTTCCCTCCAAAGC CCAAGGACACCCTGATGATCTCCCGGAC CCCTGAAGTGACCTGCGTGGTGGTGGAC GTGTCCCAGGAAGATCCCCGAAGTCCAGT TCAATTGGTACGTGGACGGCGTGGAAGT

- 119 047335

GCACAACGCCAAGACCAAGCCCAGAGAG GAACAGTTCAACTCCACCTACCGGGTGG TGTCCGTGCTGACCGTGCTGCACCAGGAC TGGCTGAACGGCAAAGAGTACAAGTGCA AAGTGTCCAACAAGGGCCTGCCCTCCAG CATCGAAAAGACCATCTCCAAGCCAAG GGCCAGCCCCGCGAGCCCCAAGTGTACA CCCTGCCTCCCAGCCAGGAAGAGATGAC CAAGAAT CAAGTGTCCCTGACTTGTCTGG TCAAGGGCTTCTACCCCTCCGATATCGCC GTGGAGTGGGAGTCCAACGGCCAGCCCG AGAACAACTACAAGACCACCCCTCCCGT GCTGGACTCCGACGGCTCCTTCTTCCTGT ACTCTCGGCTGACCGTGGACAAGTCCCG GTGGCAGGAAGGCAACGTCTTCTCCTGCT CCGTGATGCACGAGGCCCTGCACAACCA CTACACCCAGAAGTCCC TGTCCCTGTCTC TGGGC XiX ₂ X ₃ where Xi represents A, X2 represents A, and X3 represents G; or Xi is missing, Xs is missing and Xs is missing. SEQ GO NO: 115 Heavy chain 350.V GLYSLSSVVTVP TKNQVSLTC LVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRW

- 120 047335

QEGNVFSCSVMHEALHNHYTQKSLSLSLG X, where X represents K or is absent SEQ GO NO: 331 Heavy chain 350 Fab GLYSLSSVVTVP SSSLGTKTYTCNVDHKPS NTKVDKRVESKYGP SEQ ID NO: 14 (combined) LCDR1 RASQGISSWLA SEQ ID NO: 15 (combined) LCDR2 AASSLQS SEQ ID NO: 16 (combined) LCDR3 QQGNSFPRT SEQ ID NO: 14 (Kabat) LCDR1 RASQGISSWLA SEQ ID NO: 15 (Kabat) LCDR2 AASSLQS SEQ ID NO: 16 (Kabat) LCDR3 QQGNSFPRT SEQ ID NO: 17 (Chothia) LCDR1 SQGISSW SEQ ID NO: 18 (Chothia) LCDR2 A.A.S. SEQ ID NO: 19 (Chothia) LCDR3 GNSFPR SEQ ID NO: 20 (IMGT) LCDR1 QGISSW SEQ ID NO: 18 (IMGT) LCDR2 A.A.S. SEQ ID NO: 16 (IMGT) LCDR3 QQGNSFPRT SEQ ID NO: 14 (alternate) LCDR1 RASQGISSWLA SEQ ID NO: 15 (alternate) LCDR2 AASSLQS SEQ ID NO: 16 LCDR3 QQGNSFPRT

- 121 047335

(alternative) SEQ GO NO: 21 VL DIQMTQSPSSVSASVGDRVTITCRASQGISS WLAWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQG NSFPRTFGGGTKVEIK SEQ ID NO: 22 DNA encoding VL GACATCCAGATGACCCAGAGCCCCTCCT CCGTGTCCGCCTCCGTGGGCGACAGAGT GACCATCACCTGTCGGGCCTCCCAGGGC ATCTCCAGCTGGCTGGCCTGGTATCAGCA GAAGCCCGGCAAGGCCCCTAAGCTGCTG ATCTACGCCGCCTCCAGCCTGCAGTCCGG CGTGCCCTCCAGATTCTCCGGCTCTGGCT CCGGCACCGACTTCACCCTGACCATCAGC TCCCTGCAGCCCGAGGACTTCGCCACCTA CTACTGCCAGCAGGGCAACTCCTTTCCCTC GGACCTTCGGCGGAGGCACCAAAGTGGA AATCAAG SEQ ID NO: 23 Light chain SKADYE KHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 24 DNA encoding the light chain GACATCCAGATGACCCAGAGCCCCTCCT CCGTGTCCGCCTCCGTGGGCGACAGAGT GACCATCACCTGTCGGGCCTCCCAGGGC ATCTCCAGCTGGCTGGCCTGGTATCAGCA GAAGCCCGGCAAGGCCCCTAAGCTGCTG ATCTACGCCGCCTCCAGCCTGCAGTCCGG CGTGCCCTCCAGATTCTCCGGCTCTGGCT CCGGCACCGACTTCACCCTGACCATCAGC TCCCTGCAGCCCGAGGACTTCGCCACCTA CTACTGCCAGCAGGGCAACTCCTTTCCCTC

- 122 047335

GGACCTTCGGCGGAGGCACCAAAGTGGA AATCAAGCGTACGGTGGCCGCTCCCTCC GTGTTCATCTTCCCACCCTCCGACGAGCA GCTGAAGTCCGGCACCGCCTCCGTCGTGT GCCTGCTGAACAACTTCTACCCTCGCGAG GCCAAAGTGCAGTGGAAAGTGGACAACG CCCTGCAGTCCGGCAACTCCCAGGAATC CGTCACCGAGCAGGACTCCAAGGACAGC ACCTACTCCCTGTCCTCCACCCCTGACCCT GTCCAAGGCCGACTACGAGAAGCACAAA GTGTACGCTGCGAAGTGACCCACCAGG GCCTGTCCAGCCCCGTGACCAAGTCCTTC AACCGGGGCGAGTGC 374 SEQ ID NO: 70 (combined) HCDR1 GFTFSYNAMS SEQ ID NO: 71 (merged) HCDR2 SISGTGGSTYYADSVKG SEQ ID NO: 37 (merged) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 72 (Kabat) HCDR1 YNAMS SEQ ID NO: 71 (Kabat) HCDR2 SISGTGGSTYYADSVKG SEQ ID NO: 37 (Kabat) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 73 (Chothia) HCDR1 GFTFSYN SEQ ID NO: 74 (Chothia) HCDR2 SGTGGS SEQ ID NO: 37 (Chothia) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 75 (IMGT) HCDR1 GFTFSYNA SEQ ID NO: 76 (IMGT) HCDR2 ISGTGGST SEQ ID NO: 43 (IMGT) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 191 (alternate) HCDR1 FTFSYNAMS

- 123 047335

SEQ ID NO: 71 (alternate) HCDR2 SISGTGGSTYYADSVKG SEQ ID NO: 43 (alternate) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 77 VH EVQLLESGGGLVQPGGSLRLSCAASGTFFS YNAMSWVRQAPGKGLEWVSSISGTGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSGSYLSDFDLWGR GTLVTVSS SEQ ID NO: 78 DNA encoding VH GAAGTGCAGCTGCTGGAATCTGGCGGCG GACTGGTGCAGCCTGGCGGCTCCCTGAG ACTGTCTTGCGCCGCCTCCGGCTTCACCT TCTCCTACAACGCCATGTCCTGGGTCCGA CAGGCCCCTGGCAAGGGCCTGGAGTGGG TGTCCTCCATCTCCGGCACCGGCGGCTCC ACCTACTACGCCGACTCTGTGAAGGGCC GGTTCACCATCTCCCGGGGACAACTCCAA GAACACCCTGTACCTGCAGATGAACTCC CTGCGGGCCGAGGACACCGCCGTGTACT ACTGTGCCAGAGGCGGCCTGTACGGCTC CGGCTCCTACCTGTCCGACTTCGACCTGT GGGGCAGAGGCACCCTGGTCACCGTGTC CTCC SEQ ID NO: 79 Heavy chain 374.A EVQLLESGGGLVQPGGSLRLSCAASGTFFS YNAMSWVRQAPGKGLEWVSSISGTGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSGSYLSDFDLWGR GTLVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTC NVDHKPSNTKVDKRVESKYGPPCPPCPAPE FLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLP

- 124 047335

PSQEEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLGX where X represents K or is absent SEQ GO NO: 80 DNA encoding heavy chain 374.A A CCTGTACCTGCAGATGAACTCC CTGCGGGCCGAGGACACCGCCGTGTACT ACTGTGCCAGAGGCGGCCTGTACGGCTC CGGCTCCTACCTGTCCGACTTCGACCTGT GGGGCAGAGGCACCCTGGTCACCGTGTC CTCCGCCTCCACAAAGGGCCCCTCCGTGT TCCCTCTGGCCCCTTGCTCCCGGTCCACC TCCGAGTCTACCGCCGCTTGGGCTGCCT CGTGAAGGACTACT TCCCCGAGCCCGTG ACCGTGTCCTGGAACTCTGGCGCCCTGAC CTCCGGCGTGCACACCTTCCCTGCCGTGC TGCAGTCCTCCGGCCTGTACTCCCTGTCC AGCGTCGTGACCGTGCCCTCCTCCAGCCT GGGCACCAAGACCTACACCTGTAACGTG GACCACAAGCCCTCCAACACCAAAGTGG ACAAGCGGGTGGAATCTAAGTACGGCCC TCCCTGCCCTCCTTGCC CTGCCCCTGAGT TCCTGGGCGGACCTTCCGTGTTCCTGTTC CCTCCAAAGCCCAAGGACACCCTGATGA TCTCCCGGACCCCTGAAGTGACCTGCGTG GTGGTGGACGTGTCCCAGGAAGATCCCG AAGTCCAGTTCAATTGGTACGTGGACGG

- 125 047335

CGTGGAAGTGCACAACGCCAAGACCAAG CCCAGAGAGGAACAGTTCAACTCCACCT ACCGGGTGGTGTCCGTGCTGACCGTGCTG CACCAGGACTGGCTGAACGGCAAAGAGT ACAAGTGCAAAGTGTCCAACAAGGGCCT GCCCTCCAGCATCGAAAAGACCATCTCC AAGGCCAAGGGCCAGCCCCGCGAGCCCC AAGTGTACACCCTGCCTCCCAGCCAGGA AGAGATGA CCAAGAATCAAGTGTCCCTG ACTTGTCTGGTCAAGGGCTTCTACCCCTC CGATATCGCCGTGGAGTGGGAGTCCAAC GGCCAGCCCGAGAACAACTACAAGACCA CCCCTCCCGTGCTGGACTCCGACGGCTCC TTCTTCCTGTACTCTCGGCTGACCGTGGA CAAGTCCCGGTGGCAGGAAGGCAACGTC TTCTCCTGCTCCGTGATGCACGAGGCCCT GCACAACCACTACACC CAGAAGTCCCTG TCCCTGTCTCTGGGC XiX ₂ X ₃ where Xi is A, X ₂ is A, and X ₃ is G; or Xi is missing, X ₂ is missing and X ₃ is missing. SEQ GO NO: 116 Heavy chain 374.V EVQLLESGGGLVQPGGSLRLSCAASGTFFS YNAMSWVRQAPGKGLEWVSSISGTGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSGSYLSDFDLWGR GTLVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTC NVDHKPSNTKVDKRVESKYGPPCPPCPAPE FEGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVE WE SNGQPENNYKTTPPVLDSDGSFFLYSRLTV

- 126 047335

DKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLGX, where X represents K or is absent SEQ ID NO: 48 (merged) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (merged) LCDR2 GASTRAT SEQ ID NO: 50 (combined) LCDR3 QQHNAFPYT SEQ ID NO: 48 (Kabat) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (Kabat) LCDR2 GASTRAT SEQ ID NO: 50 (Kabat) LCDR3 QQHNAFPYT SEQ ID NO: 51 (Chothia) LCDR1 SQSVGSN SEQ ID NO: 52 (Chothia) LCDR2 G.A.S. SEQ ID NO: 53 (Chothia) LCDR3 HNAFPY SEQ ID NO: 54 (IMGT) LCDR1 QSVGSN SEQ ID NO: 52 (IMGT) LCDR2 G.A.S. SEQ ID NO: 50 (IMGT) LCDR3 QQHNAFPYT SEQ ID NO: 48 (alternate) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (alternate) LCDR2 GASTRAT SEQ ID NO: 50 (alternate) LCDR3 QQHNAFPYT SEQ ID NO: 55 VL EIVLTQSPATLSVSPGERATLLSCRASQSVGS NLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQHN AFPYTFGGGTKVEIK SEQ ID NO: 56 DNA encoding VL GAGATCGTGCTGACACAGTCCCCTGCCA CCCTGTCTGTGTCTCCCGGCGAGAGAGCC ACCCTGAGCTGCAGAGCCTCCCAGTCCGT

- 127 047335

GGGCTCCAACCTGGCCTGGTATCAGCAG AAGCCCGGCCAGGCCCCTCGGCTGCTGA TCTACGGCGCCTCTACCAGAGCCACCGG CATCCCTGCCAGATTCTCCGGCTCTGGCT CCGGCACCGAGTTCACCCTGACCATCTCC AGCCTGCAGTCCGAGGACTTCGCCGTGT ACTACTGCCAGCAGCACAACGCCTTCCCT TACACCTTCGGCGGAGGCACCAAAGTGG AAATCAAG SEQ GO NO: 57 Light chain EIVLTQSPATLSVSPGERATLSCRASQSVGS NLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQHN AFPYTFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKV YACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 58 DNA encoding the light chain GAGATCGTGCTGACACAGTCCCCTGCCA CCCTGTCTGTGTCTCCCGGCGAGAGAGCC ACCCTGAGCTGCAGAGCCTCCCAGTCCGT GGGCTCCAACCTGGCCTGGTATCAGCAG AAGCCCGGCCAGGCCCCTCGGCTGCTGA TCTACGGCGCCTCTACCAGAGCCACCGG CATCCCTGCCAGATTCTCCGGCTCTGGCT CCGGCACCGAGTTCACCCTGACCATCTCC AGCCTGCAGTCCGAGGACTTCGCCGTGT ACTACTGCCAGCAGCACAACGCCTTCCCT TACACCTTCGGCGGAGGCACCAAAGTGG AAATCAAGCGTACGGTGGCCGCTCCCTC CGTGTTCATCTTCCCACCCTCCGACGAGC AGCTGAAGTCCGGCACCGCCTCCGTCGT GTGCCTGCTGAACAACTTCTACCCTCGCG AGGCCAAAGTGCAGTGGAAAGTGGACAA CGCCCTGCAGTCCGGCAACTCCCAGGAA TCCGTCACCGAGCAGGACTCCAAGGACA

- 128 047335

GCACCTACTCCCTGTCCTCCACCCCTGACC CTGTCCAAGGCCGACTACGAGAAGCACA AAGTGTACGCTGCGAAGTGACCCACCA GGGCCTGTCCAGCCCCGTGACCAAGTCCT TCAACCGGGGCGAGTGC 379 SEQ ID NO: 81 (merged) HCDR1 GFTFSRYAMS SEQ ID NO: 71 (merged) HCDR2 SISGTGGSTYYADSVKG SEQ ID NO: 37 (merged) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 38 (Kabat) HCDR1 RYAMS SEQ ID NO: 71 (Kabat) HCDR2 SISGTGGSTYYADSVKG SEQ ID NO: 37 (Kabat) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 82 (Chothia) HCDR1 GFTFSRY SEQ ID NO: 74 (Chothia) HCDR2 SGTGGS SEQ ID NO: 37 (Chothia) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 83 (IMGT) HCDR1 GFTFSRYA SEQ ID NO: 76 (IMGT) HCDR2 ISGTGGST SEQ ID NO: 43 (IMGT) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 192 (alternate) HCDR1 FTFSRYAMS SEQ ID NO: 71 (alternate) HCDR2 SISGTGGSTYYADSVKG SEQ ID NO: 43 (alternate) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 84 VH EVQLLESGGGLVQPGGSLRLSCAASGTFFS RYAMSWVRQAPGKGLEWVSSISGTGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSGSYLSDFDLWGR

- 129 047335

GTLVTVSS SEQ GO NO: 85 DNA encoding VH GAAGTGCAGCTGCTGGAATCTGGCGGCG GACTGGTGCAGCCTGGCGGCTCCCTGAG ACTGTCTTGCGCCGCCTCCGGCTTCACCT TCTCCAGATACGCCATGTCCTGGGTCCGA CAGGCCCCTGGCAAGGGCCTGGAGTGGG TGTCCTCCATCTCCGGCACCGGCGGCTCC ACCTACTACGCCGACTCTGTGAAGGGCC GGTTCACCATCTCCCGGGGACAACTCCAA GAACACCCTGTACCTGCAGATGAACTCC CTGCGGGCCGAGGACACCGCCGTGTACT ACTGTGCCAGAGGCGGCCTGTACGGCTC CGGCTCCTACCTGTCCGACTTCGACCTGT GGGGCAGAGGCACCCTGGTCACCGTGTC STSS SEQ ID NO: 86 Heavy chain 379.A EVQLLESGGGLVQPGGSLRLSCAASGTFFS RYAMSWVRQAPGKGLEWVSSISGTGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSGSYLSDFDLWGR GTLVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTC NVDHKPSNTKVDKRVESKYGPPCPPCPAPE FLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDI AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLGX, where X represents K or is absent SEQ ID NO: 87 DNA encoding the heavy chain GAAGTGCAGCTGCTGGAATCTGGCGGCG GACTGGTGCAGCCTGGCGGCTCCCTGAG ACTGTCTTGCGCCGCCTCCGGCTTCACCT

- 130 047335

379.A TCTCCAGATACGCCATGTCCTGGGTCCGA CAGGCCCCTGGCAAGGGCCTGGAGTGGG TGTCCTCCATCTCCGGCACCGGCGGCTCC ACCTACTACGCCGACTCTGTGAAGGGCC GGTTCACCATCTCCCGGGACAACTCCAA GAACACCCTGTACCTGCAGATGAACTCC CTGCGGGCCGAGGACACCGCCGTGTACT ACTGTGCCAGAGGCGGCCTGTACGGCTC CGGCTCC TACCTGTCCGACTTCGACCTGT GGGGCAGAGGCACCCTGGTCACCGTGTC CTCCGCCTCCACAAAGGGCCCCTCCGTGT TCCCTCTGGCCCCTTGCTCCCGGTCCACC TCCGAGTCTACCGCCGCTCTGGGCTGCCT CGTGAAGGACTACTTCCCCGAGCCCGTG ACCGTGTCCTGGAACTCTGGCGCCCTGAC CTCCGGCGTGCACACCTTCCCTGCCGTGC GGCCTGTACTCCCTGTCC AGCGTCGTGACCGTGCCCTCCTCCAGCCT GGGCACCAAGACCTACACCTGTAACGTG GACCACAAGCCCTCCAACACCAAAGTGG ACAAGCGGGTGGAATCTAAGTACGGCCC TCCCTGCCCTCCTTGCCCTGCCCCTGAGT TCCTGGGCGGACCTTCCGTGTTCCTGTTC CCTCCAAAGCCCAAGGACACCCTGATGA TCTCCCGGACCC CTGAAGTGACCTGCGTG GTGGTGGACGTGTCCCAGGAAGATCCCG AAGTCCAGTTCAATTGGTACGTGGACGG CGTGGAAGTGCACAACGCCAAGACCAAG CCCAGAGAGGAACAGTTCAACTCCACCT ACCGGGTGGTGTCCGTGCTGACCGTGCTG CACCAGGACTGGCTGAACGGCAAAGAGT ACAAGTGCAAAGTGTCCAACAAGGGCCT GCCCTCCAGCATCGAAAAGAC CATCTCC AAGGCCAAGGGCCAGCCCCGCGAGCCCC AAGTGTACACCCTGCCTCCCAGCCAGGA

- 131 047335

AGAGATGACCAAGAATCAAGTGTCCCTG ACTTGTCTGGTCAAGGGCTTCTACCCCTC CGATATCGCCGTGGAGTGGGAGTCCAAC GGCCAGCCCGAGAACAACTACAAGACCA CCCCTCCCGTGCTGGACTCCGACGGCTCC TTCTTCCTGTACTCTCGGCTGACCGTGGA CAAGTCCCGGTGGCAGGAAGGCAACGTC TTCTCCTGCTCCGTGATGCACGAGGCCCT GCAC AACCACTACACCCAGAAGTCCCTG TCCCTGTCTCTGGGC XiX ₂ X ₃ where Xi represents A, X ₂ represents A, and X3 represents G; or Xi is missing, X ₂ is missing and Xs is missing. SEQ GO NO: 117 Heavy chain 379.B EVQLLESGGGLVQPGGSLRLSCAASGTFFS RYAMSWVRQAPGKGLEWVSSISGTGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSGSYLSDFDLWGR GTLVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTC NVDHKPSNTKVDKRVESKYGPPCPPCPAPE FEGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVE WE SNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLGX, where X represents K or is absent SEQ ID NO: 48 (merged) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (merged) LCDR2 GASTRAT SEQ ID NO: 50 LCDR3 QQHNAFPYT

- 132 047335

(merged) SEQ GO NO: 48 (Kabat) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (Kabat) LCDR2 GASTRAT SEQ ID NO: 50 (Kabat) LCDR3 QQHNAFPYT SEQ ID NO: 51 (Chothia) LCDR1 SQSVGSN SEQ ID NO: 52 (Chothia) LCDR2 G.A.S. SEQ ID NO: 53 (Chothia) LCDR3 HNAFPY SEQ ID NO: 54 (IMGT) LCDR1 QSVGSN SEQ ID NO: 52 (IMGT) LCDR2 G.A.S. SEQ ID NO: 50 (IMGT) LCDR3 QQHNAFPYT SEQ ID NO: 48 (alternate) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (alternate) LCDR2 GASTRAT SEQ ID NO: 50 (alternate) LCDR3 QQHNAFPYT SEQ ID NO: 55 VL EIVLTQSPATLSVSPGERATLLSCRASQSVGS NLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQHN AFPYTFGGGTKVEIK SEQ ID NO: 56 DNA encoding VL GAGATCGTGCTGACACAGTCCCCTGCCA CCCTGTCTGTGTCTCCCGGCGAGAGAGCC ACCCTGAGCTGCAGAGCCTCCCAGTCCGT GGGCTCCAACCTGGCCTGGTATCAGCAG AAGCCCGGCCAGGCCCCTCGGCTGCTGA TCTACGGCGCCTCTACCAGAGCCACCGG CATCCCTGCCAGATTCTCCGGCTCTGGCT CCGGCACCGAGTTCACCCTGACCATCTCC AGCCTGCAGTCCGAGGACTTCGCCGTGT ACTACTGCCAGCAGCACAACGCCTTCCCT TACACCTTCGGCGGAGGCACCAAAGTGG

- 133 047335

AAATCAAG SEQ GO NO: 57 Light chain EIVLTQSPATLSVSPGERATLSCRASQSVGS NLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQHN AFPYTFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKV YACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 58 DNA encoding the light chain GAGATCGTGCTGACACAGTCCCCTGCCA CCCTGTCTGTGTCTCCCGGCGAGAGAGCC ACCCTGAGCTGCAGAGCCTCCCAGTCCGT GGGCTCCAACCTGGCCTGGTATCAGCAG AAGCCCGGCCAGGCCCCTCGGCTGCTGA TCTACGGCGCCTCTACCAGAGCCACCGG CATCCCTGCCAGATTCTCCGGCTCTGGCT CCGGCACCGAGTTCACCCTGACCATCTCC AGCCTGCAGTCCGAGGACTTCGCCGTGT ACTACTGCCAGCAGCACAACGCCTTCCCT TACACCTTCGGCGGAGGCACCAAAGTGG AAATCAAGCGTACGGTGGCCGCTCCCTC CGTGTTCATCTTCCCACCCTCCGACGAGC AGCTGAAGTCCGGCACCGCCTCCGTCGT GTGCCTGCTGAACAACTTCTACCCTCGCG AGGCCAAAGTGCAGTGGAAAGTGGACAA CGCCCTGCAGTCCGGCAACTCCCAGGAA TCCGTCACCGAGCAGGACTCCAAGGACA GCACCTACTCCCTGTCCTCCACCCCTGACC CTGTCCAAGGCCGACTACGAGAAGCACA AAGTGTACGCTGCGAAGTGACCCACCA GGGCCTGTCCAGCCCCGTGACCAAGTCCT TCAACCGGGGCGAGTGC 376 SEQ ID NO: 135 (combined) HCDR1 GFTFRSYAMS

- 134 047335

SEQ GO NO: 136 (merged) HCDR2 AITGSGGLTYYADSVKG SEQ ID NO: 37 (merged) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 137 (Kabat) HCDR1 SYAMS SEQ ID NO: 136 (Kabat) HCDR2 AITGSGGLTYYADSVKG SEQ ID NO: 37 (Kabat) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 138 (Chothia) HCDR1 GFTFRSY SEQ ID NO: 139 (Chothia) HCDR2 TGSGGL SEQ ID NO: 37 (Chothia) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 140 (IMGT) HCDR1 GFTFRSYA SEQ ID NO: 141 (IMGT) HCDR2 ITGSGGLT SEQ ID NO: 43 (IMGT) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 193 (alternate) HCDR1 FTFRSYAMS SEQ ID NO: 136 (alternate) HCDR2 AITGSGGLTYYADSVKG SEQ ID NO: 43 (alternate) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 142 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFR SYAMSWVRQAPGKGLEWVSAITGSGGLTY YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSGSYLSDFDLWGR GTLVTVSS SEQ ID NO: 143 DNA encoding VH GAGGTGCAGCTGTTGGAGTCTGGGGGAG GCTTGGTACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCT

- 135 047335

TTCGTAGCTATGCCATGAGCTGGGTCCGC CAGGCTCCAGGGAAGGGGCTGGAGTGGG TCTCAGCTATTACGGGAAGTGGTGGTTTG ACATACTACGCAGACTCCGTGAAGGGCC GGTTCACCATCTCCAGAGACAATTCCAA GAACACGCTGTATCTGCAAATGAACAGC CTGAGAGCCGAGGACACGGCGGTGTACT ACTGCGCCAGAGGTGGATTGTACGGAAG CGGAAGCTACTTGAGTGACTTCGACCTAT GGGGGAGAGGTACCTTGGTCACCGTCTC CTCA SEQ ID NO: 48 (merged) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (merged) LCDR2 GASTRAT SEQ ID NO: 50 (combined) LCDR3 QQHNAFPYT SEQ ID NO: 48 (Kabat) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (Kabat) LCDR2 GASTRAT SEQ ID NO: 50 (Kabat) LCDR3 QQHNAFPYT SEQ ID NO: 51 (Chothia) LCDR1 SQSVGSN SEQ ID NO: 52 (Chothia) LCDR2 G.A.S. SEQ ID NO: 53 (Chothia) LCDR3 HNAFPY SEQ ID NO: 54 (IMGT) LCDR1 QSVGSN SEQ ID NO: 52 (IMGT) LCDR2 G.A.S. SEQ ID NO: 50 (IMGT) LCDR3 QQHNAFPYT SEQ ID NO: 48 (alternate) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (alternate) LCDR2 GASTRAT SEQ ID NO: 50 LCDR3 QQHNAFPYT

- 136 047335

(alternative) SEQ GO NO: 55 VL EIVLTQSPATLSVSPGERATLLSCRASQSVGS NLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQHN AFPYTFGGGTKVEIK SEQ ID NO: 144 DNA encoding VL GAAATAGTGTTGACGCAGTCTCCAGCCA CCCTGTCTGTGTCTCCAGGGGAAAGAGC CACCCTCTCCTGCAGGGCCAGTCAGAGT GTTGGCAGCAACTTAGCCTGGTACCAGC AGAAACCTGGCCAGGCTCCAGGCTCCT CATCTATGGTGCATCCACCAGGGCCACTG GTATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGAGTTCACTCTCACCATCA GCAGCCTGCAGTCTGAAGATTTTGCAGTT TATTACTGTCAGCAGCACAATGCCTTCCC TTACACTTTTGGCGGAGGGACCAAGGTT GAGATCAAA 377 SEQ ID NO: 145 (combined) HCDR1 GFTFKSYAMS SEQ ID NO: 146 (combined) HCDR2 AISGSGSYTYYADSVKG SEQ ID NO: 37 (merged) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 137 (Kabat) HCDR1 SYAMS SEQ ID NO: 146 (Kabat) HCDR2 AISGSGSYTYYADSVKG SEQ ID NO: 37 (Kabat) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 147 (Chothia) HCDR1 GFTFKSY SEQ ID NO: 148 (Chothia) HCDR2 SGSGSY SEQ ID NO: 37 HCDR3 GGLYGSGSYLSDFDL

- 137 047335

(Chothia) SEQ GO NO: 149 (IMGT) HCDR1 GFTFKSYA SEQ ID NO: 150 (IMGT) HCDR2 ISGSGSYT SEQ ID NO: 43 (IMGT) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 194 (alternate) HCDR1 FTFKSYAMS SEQ ID NO: 146 (alternate) HCDR2 AISGSGSYTYYADSVKG SEQ ID NO: 43 (alternate) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 151 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFK SYAMSWVRQAPGKGLEWVSAISGSGSYTY YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSGSYLSDFDLWGR GTLVTVSS SEQ ID NO: 152 DNA encoding VH GAGGTGCAGCTGTTGGAGTCTGGGGGAG GCTTGGTACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCT TTAAGAGCTATGCCATGAGTTGGGTCCGC CAGGCTCCAGGGAAGGGGCTGGAGTGGG TCTCAGCTATTAGTGGAAGTGGTTCGTAT ACATACTACGCAGACTCCGTGAAGGGCC GGTTCACCATCTCCAGAGACAATTCCAA GAACACGCTGTATCTGCAAATGAACAGC CTGAGAGCCGAGGACACGGCGGTGTACT ACTGCGCCAGAGGTGGATTGTACGGAAG CGGAAGCTACTTGAGTGACTTCGACCTAT GGGGGAGAGGTACCTTGGTCACCGTCTC CTCA SEQ ID NO: 48 (merged) LCDR1 RASQSVGSNLA SEQ ID NO: 49 LCDR2 GASTRAT

- 138 047335

(merged) SEQ ID NO: 50 (combined) LCDR3 QQHNAFPYT SEQ GO NO: 48 (Kabat) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (Kabat) LCDR2 GASTRAT SEQ ID NO: 50 (Kabat) LCDR3 QQHNAFPYT SEQ ID NO: 51 (Chothia) LCDR1 SQSVGSN SEQ ID NO: 52 (Chothia) LCDR2 G.A.S. SEQ ID NO: 53 (Chothia) LCDR3 HNAFPY SEQ ID NO: 54 (IMGT) LCDR1 QSVGSN SEQ ID NO: 52 (IMGT) LCDR2 G.A.S. SEQ ID NO: 50 (IMGT) LCDR3 QQHNAFPYT SEQ ID NO: 48 (alternate) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (alternate) LCDR2 GASTRAT SEQ ID NO: 50 (alternate) LCDR3 QQHNAFPYT SEQ ID NO: 55 VL EIVLTQSPATLSVSPGERATLLSCRASQSVGS NLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQHN AFPYTFGGGTKVEIK SEQ ID NO: 144 DNA encoding VL GAAATAGTGTTGACGCAGTCTCCAGCCA CCCTGTCTGTGTCTCCAGGGGAAAGAGC CACCCTCTCCTGCAGGGCCAGTCAGAGT GTTGGCAGCAACTTAGCCTGGTACCAGC AGAAACCTGGCCAGGCTCCAGGCTCCT CATCTATGGTGCATCCACCAGGGCCACTG GTATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGAGTTCACTCTCACCATCA GCAGCCTGCAGTCTGAAGATTTTGCAGTT

- 139 047335

TATTACTGTCAGCAGCACAATGCCTTCCC TTACACTTTTGGCGGAGGGACCAAGGTT GAGATCAAA 930 SEQ GO NO: 153 (merged) HCDR1 GFTFSSYAMS SEQ ID NO: 154 (merged) HCDR2 AISGSGGSTYYADSVKG SEQ ID NO: 37 (merged) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 137 (Kabat) HCDR1 SYAMS SEQ ID NO: 154 (Kabat) HCDR2 AISGSGGSTYYADSVKG SEQ ID NO: 37 (Kabat) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 155 (Chothia) HCDR1 GFTFSSY SEQ ID NO: 156 (Chothia) HCDR2 SGSGGS SEQ ID NO: 37 (Chothia) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 157 (IMGT) HCDR1 GFTFSSYA SEQ ID NO: 158 (IMGT) HCDR2 ISGSGGST SEQ ID NO: 43 (IMGT) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 195 (alternate) HCDR1 FTFSSYAMS SEQ ID NO: 154 (alternate) HCDR2 AISGSGGSTYYADSVKG SEQ ID NO: 43 (alternate) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 159 VH EVQLLESGGGLVQPGGSLRLSCAASGTFFS SYAMSWVRQAPGKGLEWVSAISGSGGSTY

- 140 047335

YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSSGSYLSDFDLWGR GTLVTVSS SEQ GO NO: 160 DNA encoding VH GAGGTGCAGCTGTTGGAGTCTGGGGGAG GCTTGGTACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCT TTAGCAGCTATGCCATGAGCTGGGTCCGC CAGGCTCCAGGGAAGGGGCTGGAGTGGG TCTCAGCTATTAGTGGTAGTGGTGGTAGC ACATACTACGCAGACTCCGTGAAGGGCC GGTTCACCATCTCCAGAGACAATTCCAA ACGCTGTATCTGCAAATGAACAGC CTGAGAGCCGAGGACACGGCGGTGTACT ACTGCGCCAGAGGTGGATTGTACGGAAG CGGAAGCTACTTGAGTGACTTCGACCTAT GGGGGAGAGGTACCTTGGTCACCGTCTC CTCA SEQ ID NO: 48 (merged) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (merged) LCDR2 GASTRAT SEQ ID NO: 50 (combined) LCDR3 QQHNAFPYT SEQ ID NO: 48 (Kabat) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (Kabat) LCDR2 GASTRAT SEQ ID NO: 50 (Kabat) LCDR3 QQHNAFPYT SEQ ID NO: 51 (Chothia) LCDR1 SQSVGSN SEQ ID NO: 52 (Chothia) LCDR2 G.A.S. SEQ ID NO: 53 (Chothia) LCDR3 HNAFPY SEQ ID NO: 54 (IMGT) LCDR1 QSVGSN SEQ ID NO: 52 (IMGT) LCDR2 G.A.S.

- 141 047335

SEQ GO NO: 50 (IMGT) LCDR3 QQHNAFPYT SEQ ID NO: 48 (alternate) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (alternate) LCDR2 GASTRAT SEQ ID NO: 50 (alternate) LCDR3 QQHNAFPYT SEQ ID NO: 55 VL EIVLTQSPATLSVSPGERATLLSCRASQSVGS NLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQHN AFPYTFGGGTKVEIK SEQ ID NO: 144 DNA encoding VL GAAATAGTGTTGACGCAGTCTCCAGCCA CCCTGTCTGTGTCTCCAGGGGAAAGAGC CACCCTCTCCTGCAGGGCCAGTCAGAGT GTTGGCAGCAACTTAGCCTGGTACCAGC AGAAACCTGGCCAGGCTCCAGGCTCCT CATCTATGGTGCATCCACCAGGGCCACTG GTATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGAGTTCACTCTCACCATCA GCAGCCTGCAGTCTGAAGATTTTGCAGTT TATTACTGTCAGCAGCACAATGCCTTCCC TTACACTTTTGGCGGAGGGACCAAGGTT GAGATCAAA 918 SEQ ID NO: 161 (merged) HCDR1 GGSISSYYWS SEQ ID NO: 162 (merged) HCDR2 YIYSSGSTNYNPSLKS SEQ ID NO: 3 (combined) HCDR3 ESQESPYNNWFDP SEQ ID NO: 163 (Kabat) HCDR1 SYYWS SEQ ID NO: 162 (Kabat) HCDR2 YIYSSGSTNYNPSLKS

- 142 047335

SEQ GO NO: 3 (Kabat) HCDR3 ESQESPYNNWFDP SEQ ID NO: 164 (Chothia) HCDR1 GGSISSY SEQ ID NO: 165 (Chothia) HCDR2 YSSGS SEQ ID NO: 3 (Chothia) HCDR3 ESQESPYNNWFDP SEQ ID NO: 166 (IMGT) HCDR1 GGSISSYY SEQ ID NO: 167 (IMGT) HCDR2 IYSSGST SEQ ID NO: 9 (IMGT) HCDR3 ARESQESPYNNWFDP SEQ ID NO: 200 (alternate) HCDR1 GSISSYYWS SEQ ID NO: 162 (alternate) HCDR2 YIYSSGSTNYNPSLKS SEQ ID NO: 9 (alternate) HCDR3 ARESQESPYNNWFDP SEQ ID NO: 168 VH QVQLQESGPGLVKPSETLSLTCTVSGGSISS YYWSWIRQPPGKGLEWIGYIYSSGSTNYNP SLKSRVTISVDTSKNQFSLKLSSVTAADTA VYYCARESQESPYNNWFDPWGQGTLVTVS S SEQ ID NO: 169 DNA encoding VH CAGGTGCAGCTGCAGGAGTCGGGCCCAG GACTGGTGAAGCCTTCGGAGACCCTGTC CCTCACCTGCACTGTCTCTGGTGGCTCCA TCAGTAGTTACTACTGGAGCTGGATCCGG CAGCCCCCAGGGAAGGGACTGGAGTGGA TTGGGTATATCTATAGTAGTGGGAGCACC AACTACAACCCCTCCCTCAAGAGTCGAG TCACCATATCAGTAGACACGTCCAAGAA CCAGTTCTCCCTGAAGCTGAGTTCTGTGA CCGCCGCAGACACGGCGGTGTACTACTG CGCCAGAGAATCTCAGGAGAGTCCATAC

- 143 047335

AACAATGGTTCGACCCATGGGGACAGG GTACATTGGTCACCGTCTCCTCA SEQ ID NO: 14 (combined) LCDR1 RASQGISSWLA SEQ ID NO: 15 (combined) LCDR2 AASSLQS SEQ ID NO: 16 (combined) LCDR3 QQGNSFPRT SEQ ID NO: 14 (Kabat) LCDR1 RASQGISSWLA SEQ ID NO: 15 (Kabat) LCDR2 AASSLQS SEQ ID NO: 16 (Kabat) LCDR3 QQGNSFPRT SEQ ID NO: 17 (Chothia) LCDR1 SQGISSW SEQ ID NO: 18 (Chothia) LCDR2 A.A.S. SEQ ID NO: 19 (Chothia) LCDR3 GNSFPR SEQ ID NO: 20 (IMGT) LCDR1 QGISSW SEQ ID NO: 18 (IMGT) LCDR2 A.A.S. SEQ ID NO: 16 (IMGT) LCDR3 QQGNSFPRT SEQ ID NO: 14 (alternate) LCDR1 RASQGISSWLA SEQ ID NO: 15 (alternate) LCDR2 AASSLQS SEQ ID NO: 16 (alternate) LCDR3 QQGNSFPRT SEQ ID NO: 21 VL DIQMTQSPSSVSASVGDRVTITCRASQGISS WLAWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQG NSFPRTFGGGTKVEIK SEQ ID NO: 170 DNA encoding VL GACATCCAGATGACCCAGTCTCCATCTTC CGTGTCTGCATCTGTAGGAGACAGAGTC ACCATCACTTGTCGGGCGAGTCAGGGTA TTAGCAGCTGGTTAGCCTGGTATCAGCAG

- 144 047335

AAACCAGGGAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCAGTTTGCAAAGTGGG GTCCCATCAAGGTTCAGCGGCAGTGGAT CTGGGACAGATTTCACTCTCACCATCAGC AGCCTGCAGCCTGAAGATTTTGCAACTTA TTACTGTCAGCAGGGAAACAGTTTCCCTA GGACTTTTGGCGGAGGGACCAAGGTTGA GATCAAA 363 SEQ ID NO: 81 (merged) HCDR1 GFTFSRYAMS SEQ ID NO: 201 (merged) HCDR2 AISGTGISTYYADSVKG SEQ ID NO: 37 (merged) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 38 (Kabat) HCDR1 RYAMS SEQ ID NO: 201 (Kabat) HCDR2 AISGTGISTYYADSVKG SEQ ID NO: 37 (Kabat) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 82 (Chothia) HCDR1 GFTFSRY SEQ ID NO: 202 (Chothia) HCDR2 SGTGIS SEQ ID NO: 37 (Chothia) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 83 (IMGT) HCDR1 GFTFSRYA SEQ ID NO: 203 (IMGT) HCDR2 ISGTGIST SEQ ID NO: 43 (IMGT) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 192 (alternate) HCDR1 FTFSRYAMS SEQ ID NO: 201 (alternate) HCDR2 AISGTGISTYYADSVKG SEQ ID NO: 43 HCDR3 ARGGLYGSSGSYLSDFDL

- 145 047335

(alternative) SEQ GO NO: 204 VH EVQLLESGGGLVQPGGSLRLSCAASGTFFS RYAMSWVRQAPGKGLEWVSAISGTGISTY YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSGSYLSDFDLWGR GTLVTVSS SEQ ID NO: 205 (combined) LCDR1 RASQSISSWLA SEQ ID NO: 206 (merged) LCDR2 DASSLES SEQ ID NO: 207 (merged) LCDR3 QQSNTFYT SEQ ID NO: 205 (Kabat) LCDR1 RASQSISSWLA SEQ ID NO: 206 (Kabat) LCDR2 DASSLES SEQ ID NO: 207 (Kabat) LCDR3 QQSNTFYT SEQ ID NO: 208 (Chothia) LCDR1 SQSISSW SEQ ID NO: 209 (Chothia) LCDR2 DAS SEQ ID NO: 228 (Chothia) LCDR3 SNTFY SEQ ID NO: 229 (IMGT) LCDR1 QSISSW SEQ ID NO: 209 (IMGT) LCDR2 DAS SEQ ID NO: 207 (IMGT) LCDR3 QQSNTFYT SEQ ID NO: 205 (alternate) LCDR1 RASQSISSWLA SEQ ID NO: 206 (alternate) LCDR2 DASSLES

- 146 047335

SEQ GO NO: 207 (alternative) LCDR3 QQSNTFYT SEQ ID NO: 230 VL DIQMTQSPSTLSASVGDRVTITCRASQSISS WLAWYQQKPGKAPKLLIYDASSLESGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQS NTFYTFGGGTKVEIK 366 SEQ ID NO: 81 (merged) HCDR1 GFTFSRYAMS SEQ ID NO: 231 (merged) HCDR2 AISGTGLSTYYADSVKG SEQ ID NO: 37 (merged) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 38 (Kabat) HCDR1 RYAMS SEQ ID NO: 231 (Kabat) HCDR2 AISGTGLSTYYADSVKG SEQ ID NO: 37 (Kabat) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 82 (Chothia) HCDR1 GFTFSRY SEQ ID NO: 232 (Chothia) HCDR2 SGTGLS SEQ ID NO: 37 (Chothia) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 83 (IMGT) HCDR1 GFTFSRYA SEQ ID NO: 233 (IMGT) HCDR2 ISGTGST SEQ ID NO: 43 (IMGT) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 192 (alternate) HCDR1 FTFSRYAMS SEQ ID NO: 231 (alternate) HCDR2 AISGTGLSTYYADSVKG SEQ ID NO: 43 (alternate) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 234 VH EVQLLESGGGLVQPGGSLRLSCAASGTFFS

- 147 047335

RYAMSWVRQAPGKGLEWVSAISGTGLSTY YADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARGGLYGSSGSYLSDFDLWGR GTLVTVSS SEQ GO NO: 205 (merged) LCDR1 RASQSISSWLA SEQ ID NO: 206 (merged) LCDR2 DASSLES SEQ ID NO: 207 (merged) LCDR3 QQSNTFYT SEQ ID NO: 205 (Kabat) LCDR1 RASQSISSWLA SEQ ID NO: 206 (Kabat) LCDR2 DASSLES SEQ ID NO: 207 (Kabat) LCDR3 QQSNTFYT SEQ ID NO: 208 (Chothia) LCDR1 SQSISSW SEQ ID NO: 209 (Chothia) LCDR2 DAS SEQ ID NO: 228 (Chothia) LCDR3 SNTFY SEQ ID NO: 229 (IMGT) LCDR1 QSISSW SEQ ID NO: 209 (IMGT) LCDR2 DAS SEQ ID NO: 207 (IMGT) LCDR3 QQSNTFYT SEQ ID NO: 205 (alternate) LCDR1 RASQSISSWLA SEQ ID NO: 206 (alternate) LCDR2 DASSLES SEQ ID NO: 207 (alternate) LCDR3 QQSNTFYT

- 148 047335

SEQ GO NO: 230 VL DIQMTQSPSTLSASVGDRVTITCRASQSISS WLAWYQQKPGKAPKLLIYDASSLESGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQS NTFYTFGGGTKVEIK 407 SEQ ID NO: 235 (combined) HCDR1 GYTFTYYWMH SEQ ID NO: 236 (combined) HCDR2 SINPNSGSTNYAQKFQG SEQ ID NO: 237 (merged) HCDR3 DTGGDKSPLTYYYYGMDV SEQ ID NO: 238 (Kabat) HCDR1 YYWMH SEQ ID NO: 236 (Kabat) HCDR2 SINPNSGSTNYAQKFQG SEQ ID NO: 237 (Kabat) HCDR3 DTGGDKSPLTYYYYGMDV SEQ ID NO: 239 (Chothia) HCDR1 GYTFTYY SEQ ID NO: 240 (Chothia) HCDR2 NPNSGS SEQ ID NO: 237 (Chothia) HCDR3 DTGGDKSPLTYYYYGMDV SEQ ID NO: 241 (IMGT) HCDR1 GYTFTYYW SEQ ID NO: 242 (IMGT) HCDR2 INPNSGST SEQ ID NO: 243 (IMGT) HCDR3 ARDTGGDKSPLTYYYYGMDV SEQ ID NO: 244 (alternate) HCDR1 YTFTYYWMH SEQ ID NO: 236 (alternate) HCDR2 SINPNSGSTNYAQKFQG SEQ ID NO: 243 HCDR3 ARDTGGDKSPLTYYYYGMDV

- 149 047335

(alternative) SEQ GO NO: 245 VH QVQLVQSGAEVKKPGASVKVSCKASGYTF TYYWMHWVRQAPGQGLEWMGSINPNSGS TNYAQKFQGRVTMTRDTSISTAYMELSRL RSDDTAVYYCARDTGGDKSPLTYYYYGM DVWGQGTTVTVSS SEQ ID NO: 246 (merged) LCDR1 RASQGISRWLA SEQ ID NO: 15 (combined) LCDR2 AASSLQS SEQ ID NO: 247 (merged) LCDR3 QQAIALPPFT SEQ ID NO: 246 (Kabat) LCDR1 RASQGISRWLA SEQ ID NO: 15 (Kabat) LCDR2 AASSLQS SEQ ID NO: 247 (Kabat) LCDR3 QQAIALPPFT SEQ ID NO: 248 (Chothia) LCDR1 SQGISRW SEQ ID NO: 18 (Chothia) LCDR2 A.A.S. SEQ ID NO: 249 (Chothia) LCDR3 AIALPPF SEQ ID NO: 250 (IMGT) LCDR1 QGISRW SEQ ID NO: 18 (IMGT) LCDR2 A.A.S. SEQ ID NO: 247 (IMGT) LCDR3 QQAIALPPFT SEQ ID NO: 246 (alternate) LCDR1 RASQGISRWLA SEQ ID NO: 15 (alternate) LCDR2 AASSLQS SEQ ID NO: 247 (alternate) LCDR3 QQAIALPPFT

- 150 047335

SEQ GO NO: 251 VL DIQMTQSPSSVSASVGDRVTITCRASQGISR WLAWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQA IALPPFTFGGGTKVEIK 893 SEQ ID NO: 252 (merged) HCDR1 GFTFSSYWMS SEQ ID NO: 253 (merged) HCDR2 NIKQDGSEKYYVDSVKG SEQ ID NO: 254 (merged) HCDR3 APEYYSTTTRLYYYYGMDV SEQ ID NO: 255 (Kabat) HCDR1 SYWMS SEQ ID NO: 253 (Kabat) HCDR2 NIKQDGSEKYYVDSVKG SEQ ID NO: 254 (Kabat) HCDR3 APEYYSTTTRLYYYYGMDV SEQ ID NO: 155 (Chothia) HCDR1 GFTFSSY SEQ ID NO: 256 (Chothia) HCDR2 KQDGSE SEQ ID NO: 254 (Chothia) HCDR3 APEYYSTTTRLYYYYGMDV SEQ ID NO: 257 (IMGT) HCDR1 GFTFSSYW SEQ ID NO: 258 (IMGT) HCDR2 IKQDGSEK SEQ ID NO: 259 (IMGT) HCDR3 ARAPEYYSTTTTRLYYYYGMDV SEQ ID NO: 260 (alternate) HCDR1 FTFSSYWMS SEQ ID NO: 253 (alternate) HCDR2 NIKQDGSEKYYVDSVKG SEQ ID NO: 259 HCDR3 ARAPEYYSTTTTRLYYYYGMDV

- 151 047335

(alternative) SEQ GO NO: 261 VH EVQLVESGGGLVQPGGSLRLSCAASGTFFS SYWMSWVRQAPGKGLEWVANIKQDGSEK YYVDSVKGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARAPEYYSTTTRLYYYYGM DVWGQGTTVTVSS SEQ ID NO: 262 (merged) LCDR1 KSSQSVLYSSNNNKNYLA SEQ ID NO: 263 (merged) LCDR2 WASTRES SEQ ID NO: 264 (merged) LCDR3 QQYDAHPFT SEQ ID NO: 262 (Kabat) LCDR1 KSSQSVLYSSNNNKNYLA SEQ ID NO: 263 (Kabat) LCDR2 WASTRES SEQ ID NO: 264 (Kabat) LCDR3 QQYDAHPFT SEQ ID NO: 265 (Chothia) LCDR1 SQSVLYSSNNNKNY SEQ ID NO: 266 (Chothia) LCDR2 W.A.S. SEQ ID NO: 267 (Chothia) LCDR3 YDAHPF SEQ ID NO: 268 (IMGT) LCDR1 QSVLYSSNNNKNY SEQ ID NO: 266 (IMGT) LCDR2 W.A.S. SEQ ID NO: 264 (IMGT) LCDR3 QQYDAHPFT SEQ ID NO: 262 (alternate) LCDR1 KSSQSVLYSSNNNKNYLA SEQ ID NO: 263 (alternate) LCDR2 WASTRES

- 152 047335

SEQ GO NO: 264 (alternative) LCDR3 QQYDAHPFT SEQ ID NO: 269 VL DIVMTQSPDSLAVSLGERATINCKSSQSVL YSSNNKNYLAWYQQKPGQPPKLLIYWAST RESGVPDRFSGSGSGTDFTLTISSLQAEDVA VYYCQQYDAHPFTFGGGTKVEIK 939 SEQ ID NO: 287 (merged) HCDR1 GGTFSSYAIS SEQ ID NO: 288 (merged) HCDR2 GIIPIFGTANYAQKFQG SEQ ID NO: 289 (merged) HCDR3 HYYDYWSGYYTNTGIY SEQ ID NO: 290 (Kabat) HCDR1 SYAIS SEQ ID NO: 288 (Kabat) HCDR2 GIIPIFGTANYAQKFQG SEQ ID NO: 289 (Kabat) HCDR3 HYYDYWSGYYTNTGIY SEQ ID NO: 291 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 292 (Chothia) HCDR2 IPIFGT SEQ ID NO: 289 (Chothia) HCDR3 HYYDYWSGYYTNTGIY SEQ ID NO: 293 (IMGT) HCDR1 GGTFSSYA SEQ ID NO: 294 (IMGT) HCDR2 IIPIFGTA SEQ ID NO: 295 (IMGT) HCDR3 ARHYYDYWSGYYTNTGIY SEQ ID NO: 296 (alternate) HCDR1 GTFSSYAIS SEQ ID NO: 288 HCDR2 GIIPIFGTANYAQKFQG

- 153 047335

(alternative) SEQ GO NO: 295 (alternative) HCDR3 ARHYYDYWSGYYTNTGIY SEQ GO NO: 297 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTF SSYAISWVRQAPGQGLEWMGGIIPIFGTAN YAQKFQGRVTITADESTSTAYMELSSSLRSE DTAVYYCARHYYDYWSGYYTNTGIYWGQ GTLVTVSS SEQ ID NO: 298 (merged) LCDR1 RASQSVSSNLA SEQ ID NO: 49 (merged) LCDR2 GASTRAT SEQ ID NO: 299 (merged) LCDR3 QQSGALPIT SEQ ID NO: 298 (Kabat) LCDR1 RASQSVSSNLA SEQ ID NO: 49 (Kabat) LCDR2 GASTRAT SEQ ID NO: 299 (Kabat) LCDR3 QQSGALPIT SEQ ID NO: 300 (Chothia) LCDR1 SQSVSSN SEQ ID NO: 52 (Chothia) LCDR2 G.A.S. SEQ ID NO: 301 (Chothia) LCDR3 SGALPI SEQ ID NO: 302 (IMGT) LCDR1 QSVSSN SEQ ID NO: 52 (IMGT) LCDR2 G.A.S. SEQ ID NO: 299 (IMGT) LCDR3 QQSGALPIT SEQ ID NO: 298 (alternate) LCDR1 RASQSVSSNLA SEQ ID NO: 49 (alternate) LCDR2 GASTRAT

- 154 047335

SEQ GO NO: 299 (alternative) LCDR3 QQSGALPIT SEQ ID NO: 303 VL EIVMTQSPATLSVSPGERATLLSCRASQSVSS NLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQSG ALPITFGGGTKVEIK 430 SEQ ID NO: 304 (merged) HCDR1 GGSFLRYYWS SEQ ID NO: 305 (combined) HCDR2 EIDHSGSTNYNPSLKS SEQ ID NO: 306 (combined) HCDR3 GQNYYGSGSADGFDP SEQ ID NO: 61 (Kabat) HCDR1 RYYWS SEQ ID NO: 305 (Kabat) HCDR2 EIDHSGSTNYNPSLKS SEQ ID NO: 306 (Kabat) HCDR3 GQNYYGSGSADGFDP SEQ ID NO: 307 (Chothia) HCDR1 GGSFLRY SEQ ID NO: 308 (Chothia) HCDR2 DHSGS SEQ ID NO: 306 (Chothia) HCDR3 GQNYYGSGSADGFDP SEQ ID NO: 309 (IMGT) HCDR1 GGSFLRYY SEQ ID NO: 310 (IMGT) HCDR2 IDHSGST SEQ ID NO: 311 (IMGT) HCDR3 ARGQNYYGSGSADGFDP SEQ ID NO: 312 (alternate) HCDR1 GSFLRYYWS SEQ ID NO: 305 (alternate) HCDR2 EIDHSGSTNYNPSLKS

- 155 047335

SEQ GO NO: 311 (alternative) HCDR3 ARGQNYYGSGSADGFDP SEQ ID NO: 313 VH QVQLQQWGAGLLKPSETLSLTCAVYGGSF LRYYWSWIRQPPGKGLEWIGEIDHSGSTNY NPSLKSRVTISVDTSKNQFSLKLSSVTAADT AVYYCARGQNYYGSGSADGFDPWGQGTL VTVSS SEQ ID NO: 14 (combined) LCDR1 RASQGISSWLA SEQ ID NO: 15 (combined) LCDR2 AASSLQS SEQ ID NO: 314 (merged) LCDR3 QQANSFPPT SEQ ID NO: 14 (Kabat) LCDR1 RASQGISSWLA SEQ ID NO: 15 (Kabat) LCDR2 AASSLQS SEQ ID NO: 314 (Kabat) LCDR3 QQANSFPPT SEQ ID NO: 17 (Chothia) LCDR1 SQGISSW SEQ ID NO: 18 (Chothia) LCDR2 A.A.S. SEQ ID NO: 315 (Chothia) LCDR3 ANSFPP SEQ ID NO: 20 (IMGT) LCDR1 QGISSW SEQ ID NO: 18 (IMGT) LCDR2 A.A.S. SEQ ID NO: 314 (IMGT) LCDR3 QQANSFPPT SEQ ID NO: 14 (alternate) LCDR1 RASQGISSWLA SEQ ID NO: 15 (alternate) LCDR2 AASSLQS SEQ ID NO: 314 (alternate) LCDR3 QQANSFPPT SEQ ID NO: 316 VL DIQMTQSPSSVSASVGDRVTITCRASQGISS

- 156 047335

WLAWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQA NSFPPTFGGGTKVEIK 398 SEQ GO NO: 317 (merged) HCDR1 GGSFSGYYWS SEQ ID NO: 318 (combined) HCDR2 EIDASGSTRYNPSLKS SEQ ID NO: 319 (merged) HCDR3 PLYDAYLDV SEQ ID NO: 320 (Kabat) HCDR1 GYYWS SEQ ID NO: 318 (Kabat) HCDR2 EIDASGSTRYNPSLKS SEQ ID NO: 319 (Kabat) HCDR3 PLYDAYLDV SEQ ID NO: 321 (Chothia) HCDR1 GGSFSGY SEQ ID NO: 322 (Chothia) HCDR2 DASGS SEQ ID NO: 319 (Chothia) HCDR3 PLYDAYLDV SEQ ID NO: 323 (IMGT) HCDR1 GGSFSGYY SEQ ID NO: 324 (IMGT) HCDR2 IDASGST SEQ ID NO: 325 (IMGT) HCDR3 ARPLYDAYLDV SEQ ID NO: 326 (alternate) HCDR1 GSFSGYYWS SEQ ID NO: 318 (alternate) HCDR2 EIDASGSTRYNPSLKS SEQ ID NO: 325 (alternate) HCDR3 ARPLYDAYLDV

- 157 047335

SEQ GO NO: 327 VH QVQLQQWGAGLLKPSETLSLTCAVYGGSF SGYYWSWIRQPPGKGLEWIGEIDASGSTRY NPSLKSRVTISVDTSKNQFSLKLSSVTAADT AVYYCARPLYDAYLDVWGQGTMVTVSS SEQ ID NO: 14 (combined) LCDR1 RASQGISSWLA SEQ ID NO: 15 (combined) LCDR2 AASSLQS SEQ ID NO: 328 (combined) LCDR3 QQAPIYPIT SEQ ID NO: 14 (Kabat) LCDR1 RASQGISSWLA SEQ ID NO: 15 (Kabat) LCDR2 AASSLQS SEQ ID NO: 328 (Kabat) LCDR3 QQAPIYPIT SEQ ID NO: 17 (Chothia) LCDR1 SQGISSW SEQ ID NO: 18 (Chothia) LCDR2 A.A.S. SEQ ID NO: 329 (Chothia) LCDR3 APIYPI SEQ ID NO: 20 (IMGT) LCDR1 QGISSW SEQ ID NO: 18 (IMGT) LCDR2 A.A.S. SEQ ID NO: 328 (IMGT) LCDR3 QQAPIYPIT SEQ ID NO: 14 (alternate) LCDR1 RASQGISSWLA SEQ ID NO: 15 (alternate) LCDR2 AASSLQS SEQ ID NO: 328 (alternate) LCDR3 QQAPIYPIT SEQ ID NO: 330 VL DIQMTQSPSSVSASVGDRVTITCRASQGISS WLAWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQA PIYPITFGGGTKVEIK

- 158 047335

table 2

Consensus CDR sequences for exemplary CD73 antibodies

Line 3 SEQ GO NO: 126 (merged) HCDR1 GFTFX1X2X3AMS, where Xi represents H, S, R or K; Xr represents R, Y or S; And Xs represents Y or N SEQ ID NO: 89 (merged) HCDR2 X1IX2GX3GX4X5TYYADSVKG, where X1 represents A or S; X2 represents S or T; Xs represents S or T; X4 is M, G or S; And X5 represents N, S, L or Y SEQ ID NO: 37 (merged) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 48 (merged) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (merged) LCDR2 GASTRAT SEQ ID NO: 50 (combined) LCDR3 QQHNAFPYT SEQ GO NO: 88 (Kabat) HCDR1 X1X2AMS, where Xi represents R, Y or S; And X2 represents Y or N SEQ GO NO: 89 (Kabat) HCDR2 X1IX2GX3GX4X5TYYADSVKG, where X1 represents A or S; X2 represents S or T; Xs represents S or T; X4 is M, G or S; And X5 represents N, S, L or Y SEQ ID NO: 37 (Kabat) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 48 (Kabat) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (Kabat) LCDR2 GASTRAT SEQ ID NO: 50 (Kabat) LCDR3 QQHNAFPYT

- 159 047335

SEQ GO NO: 122 (Chothia) HCDR1 GFTFX1X2X3, where Xi represents H, S, R or K; Xs represents R, Y or S; And Xs represents Y or N SEQ ID NO: 123 (Chothia) HCDR2 X1GX2GX3X4, where X1 represents S or T; X2 represents S or T; Xs represents M, G or S; And X4 represents N, S, L or Y SEQ ID NO: 37 (Chothia) HCDR3 GGLYGSGSYLSDFDL SEQ ID NO: 51 (Chothia) LCDR1 SQSVGSN SEQ ID NO: 52 (Chothia) LCDR2 G.A.S. SEQ ID NO: 53 (Chothia) LCDR3 HNAFPY SEQ ID NO: 128 (IMGT) HCDR1 GFTFX1X2X3A, where Xi represents H, S, R or K; Xr represents R, Y or S; And Xs represents Y or N SEQ ID NO: 129 (IMGT) HCDR2 IX1GX2GX3X4T, where X1 represents S or T; Xr represents S or T; Xs represents M, G or S; And X4 represents N, S, L or Y SEQ ID NO: 43 (IMGT) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 54 (IMGT) LCDR1 QSVGSN SEQ ID NO: 52 (IMGT) LCDR2 G.A.S. SEQ ID NO: 50 (IMGT) LCDR3 QQHNAFPYT SEQ ID NO: 189 (alternate) HCDR1 FTFX1X2X3AMS, where Xi represents H, S, R or K; Xr represents R, Y or S; And Xs represents Y or N

- 160 047335

SEQ ID NO: 89 (alternate) HCDR2 X1IX2GX3GX4X5TYYADSVKG, where Xi represents A or S; X2 represents S or T; Xs represents S or T; X4 is M, G or S; And X5 represents N, S, L or Y SEQ ID NO: 43 (alternate) HCDR3 ARGGLYGSSGSYLSDFDL SEQ ID NO: 48 (alternate) LCDR1 RASQSVGSNLA SEQ ID NO: 49 (alternate) LCDR2 GASTRAT SEQ ID NO: 50 (alternate) LCDR3 QQHNAFPYT Line 1 SEQ GO NO: 127 (merged) HCDR1 GGSIX1X2X3YWS, where X1 represents E or S; X2 represents R, G or S; And Xs represents Y or R SEQ ID NO: 91 (merged) HCDR2 YIYX1X2GSTX3YNPSLKS, where Xi represents G or S; X2 represents R, S or T; And Xs represents N or K SEQ ID NO: 3 (combined) HCDR3 ESQESPYNNWFDP SEQ ID NO: 14 (combined) LCDR1 RASQGISSWLA SEQ ID NO: 15 (combined) LCDR2 AASSLQS SEQ ID NO: 16 (combined) LCDR3 QQGNSFPRT SEQ ID NO: 90 (Kabat) HCDR1 X1X2YWS, where Xi represents R, G or S; And X2 represents Y or R

- 161 047335

SEQ GO NO: 91 (Kabat) HCDR2 YIYX1X2GSTX3YNPSLKS, where Xi represents G or S; X2 represents R, S or T; And Xs represents N or K SEQ ID NO: 3 (Kabat) HCDR3 ESQESPYNNWFDP SEQ ID NO: 14 (Kabat) LCDR1 RASQGISSWLA SEQ ID NO: 15 (Kabat) LCDR2 AASSLQS SEQ ID NO: 16 (Kabat) LCDR3 QQGNSFPRT SEQ ID NO: 124 (Chothia) HCDR1 GGSIX1X2X3, where Xi represents E or S; X2 represents R, G or S; And Xs represents Y or R SEQ ID NO: 125 (Chothia) HCDR2 YX1X2GS, where X1 represents G or S; And X2 represents R, S or T SEQ ID NO: 3 (Chothia) HCDR3 ESQESPYNNWFDP SEQ ID NO: 17 (Chothia) LCDR1 SQGISSW SEQ ID NO: 18 (Chothia) LCDR2 A.A.S. SEQ ID NO: 19 (Chothia) LCDR3 GNSFPR SEQ ID NO: 130 (IMGT) HCDR1 GGSIX1X2X3Y, where Xi represents E or S; Xg represents R, G or S; And Xs represents Y or R SEQ ID NO: 131 (IMGT) HCDR2 IYX1X2GST, where X1 represents G or S, and Xr represents R, S or T SEQ ID NO: 9 (IMGT) HCDR3 ARESQESPYNNWFDP SEQ ID NO: 20 (IMGT) LCDR1 QGISSW SEQ ID NO: 18 (IMGT) LCDR2 A.A.S. SEQ ID NO: 16 (IMGT) LCDR3 QQGNSFPRT

- 162 047335

SEQ GO NO: 196 (alternative) HCDR1 GSIXiX ₂ X3YWS, where X1 represents E or S; X ₂ represents R, G or S; and X3 represents Y or R SEQ ID NO: 91 (alternate) HCDR2 YIYX1X ₂ GSTX ₃ YNPSLKS where Xi represents G or S; X ₂ represents R, S or T; and X ₃ represents N or K SEQ ID NO: 9 (alternate) HCDR3 ARESQESPYNNWFDP SEQ ID NO: 14 (alternate) LCDR1 RASQGISSWLA SEQ ID NO: 15 (alternate) LCDR2 AASSLQS SEQ ID NO: 16 (alternate) LCDR3 QQGNSFPRT

Table 26

Corresponding anti-CD73 germline sequences

Antibody VH germinal type VL germinal type 918 VH4-59 VK1-12 350 VH4-59 VK1-12 356 VH4-59 VK1-12 358 VH4-59 VK1-12 930 VH3-23 VK3-15 373 VH3-23 VK3-15 374 VH3-23 VK3-15 376 VH3-23 VK3-15 377 VH3-23 VK3-15 379 VH3-23 VK3-15 363 VH3-23 VK1-05 366 VH3-23 VK1-05 407 VH1-02 VK1-12 893 VH3-07 VK4-01 939 VH1-69 VK3-15 430 VH4-34 VK1-12 398 VH4-34 VK1-12

- 163 047335

Table 3

Amino acid sequences of the constant region of the human IgG heavy chain and the human kappa light chain

SEQ ID NO Description Subsequence 92 IgG4 (S228P) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT CNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVL TVLHQDWLNGKEYKCK VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK 93 IgG4 (S228P), lacking C-terminal lysine ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT CNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVL TVLHQDWLNGKEYKCK VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LG 94 IgG4 (S228P/L235E) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT CNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCK VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK 95 IgG4 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW

- 164 047335

(S228P/L235E), without C-terminal lysine NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT CNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKGLPSSIEKTISKAKG QPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LG 119 Wild type IgGl ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK 120 wild IgGl like, no containing C-terminal lysine ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPG 96 Wild type IgGl ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK

- 165 047335

97 wild IgGl like, no containing C-terminal lysine ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG 98 IgGl (N297A) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVL TVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK 99 IgGl (N297A), without C-terminal lysine ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVL TVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG 100 IgGl (D265A/P329A) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYK CKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS

- 166 047335

LSLSPGK 101 IgGl (D265A/P329A), not containing C-terminal lysine ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYK CKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG 102 IgGl (L234A/L235A) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK 103 IgGl (L234A/L235A), not containing C-terminal lysine ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPG 104 Human kappa chain constant region RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC

Table 4

Exemplary CD73 sequences

SEQ ID NO Description Subsequence 105 human CD73 MCPRAARAPATLLLALGAVLWPAAGAWELTILHTN

- 167 047335

(Q6NZX3) DVHSRLEQTSEDSSKCVNASRCMGGVARLFTKVQQI RRAEPNVLLLDAGDQYQGTIWFTVYKGAEVAHFMN ALRYDAMALGNHEFDNGVEGLIEPLLKEAKFPILSA NIKAKGPLASQISGLYLPYKVLPVGDEVVGIVGYTSK ETPFLSNPGTNLVFEDEITALQPEVDKLKTLNVNKIIA LGHSGFEMDK LIAQKVRGVDVVVGGHSNTFLYTGN PPSKEVPAGKYPFIVTSDDGRKVPVVQAYAFGKYLG YLKIEFDERGNVISSHGNPILLNSSIPEDPSIKADINKW RIKLDNYSTQELGKTIVYLDGSSQSCRFRECNMGNLI CDAMINNNLRHADETFWNHVSMCILNGGGIRSPIDE RNNGTITWENLAAVLPFGGTFDLVQL KGSTLKKAFE HSVHRYGQSTGEFLQVGGIHVVYDLSRKPGDRVVKL DVLCTKCRVPSYDPLKMDEVYKVILPNFLANGGDGF QMIKDELLRHDSGDQDINVVSTYISKMKVIYPAVEG RIKFSTGSHCHGSFSLIFLSLWAVIFVLYQ 106 Human CD73 isoform (P21589-1) MCPRAARAPATLLLALGAVLWPAAGAWELTILHTN DVHSRLEQTSEDSSKCVNASRCMGGVARLFTKVQQI RRAEPNVLLLDAGDQYQGTIWFTVYKGAEVAHFMN ALRYDAMALGNHEFDNGVEGLIEPLLKEAKFPILSA NIKAKGPLASQISGLYLPYKVLPVGDEVVGIVGYTSK ETPFLSNPGTNLVFE DEITALQPEVDKLKTLNVNKIIA LGHSGFEMDKLIAQKVRGVDVVGGHSNTFLYTGN PPSKEVPAGKYPFIVTSDDGRKVPVVQAYAFGKYLG YLKIEFDERGNVISSHGNPILLNSSIPEDPSIKADINKW RIKLDNYSTQELGKTIVYLDGSSQSCRFRECNMGNLI CDAMINNNLRHTDEMFWNHVSMCIL NGGGIRSPIDE RNNGTITWENLAAVLPFGGTFDLVQLKGSTLKKAFE HSVHRYGQSTGEFLQVGGIHVVYDLSRKPGDRVVKL DVLCTKCRVPSYDPLKMDEVYKVILPNFLANGGDGF QMIKDELLRHDSGDQDINVVSTYISKMKVIYPAVEG RIKFSTGSHCHGSFSLIFLSLWAVIFVLYQ 107 Human CD73 isoform (P21589-2) MCPRAARAPATLLLALGAVLWPAAGAWELTILHTN DVHSRLEQTSEDSSKCVNASRCMGGVARLFTKVQQI RRAEPNVLLLDAGDQYQGTIWFTVYKGAEVAHFMN ALRYDAMALGNHEFDNGVEGLIEPLLKEAKFPILSA

- 168 047335

RIK LDNYSTQELGKTIVYLDGSSQSCRFRECNMGNLI CDAMINNNLRHTDEMFWNHVSMCILNGGGIRSProE RNNGIHVVYDLSRKPGDRVVKLDVLCTKCRVPSYDP LKMDEVYKVILPNFLANGGDGFQMIKDELLRHDSGD QDINVVSTYISKMKVIYPAVEGRIKFSTGSHCHGSFSL IFLSLWAVIFVLYQ 108 CD73 fragment (range of residues 158-172 from SEQ GO NO: 105) YLPYKVLPVGDEVVG 109 CD73 fragment (range of residues 206-215 from SEQ GO NO: 105) KLKTLNVNKI BY CD73 fragment (range of residues 368-387 from SEQ GO NO: 105) MINNNLRHADETFWNHVSMC 121 CD73 fragment (range of residues 368-387 from SEQ GO NO: 106) MINNNLRHTDEMFWNHVSMC 111 CD73 fragment (range of residues 87-104 from SEQ GO NO: 105) YQGTIWFTVYKGAEVAHF 118 CD73 fragment (range of residues 297-309 from SEQ GO NO: 105) RGNVISSHGNPIL

- 169 047335

134 CD73 fragment (range of residues 27-547 from SEQ GO NO: 105) WELTILHTNDVHSRLEQTSEDSSKCVNASRCMGGVA RLFTKVQQIRRAEPNVLLLDAGDQYQGTIWFTVYKG AEVAHFMNALRYDAMALGNHEFDNGVEGLIEPLLK EAKFPILSANIKAKGPLASQISGLYLPYKVLPVGDEV VGIVGYTSKETPFLSNPGTNLVFEDEITALQPEVDKL KTLNVNKIIALGH SGFEMDKLIAQKVRGVDVVVGGH SNTFLYTGNPPSKEVPAGKYPFIVTSDDGRKVPVVQA YAFGKYLGYLKIEFDERGNVISSHGNPILLNSSIPEDP SIKADINKWRIKLDNYSTQELGKTIVYLDGSSQSCRF RECNMGNLICDAMINNNLRHADETFWNHVSMCILN GGGIRSPIDERNGGTITWENLAAVLPF TFDLVQLK GSTLKKAFEHSVHRYGQSTGEFLQVGGIHVVYDLSR KPGDRVVKLDVLCTKCRVPSYDPLKMDEVYKVILPN FLANGGDGFQMIKDELLRHDSGDQDINVVSTYISKM KVIYPAVEGRIK 171 CD73 fragment (range of residues 27-547 from SEQ GO NO: 105), fused to the 6-H18 tag at the end (SEQ GO NO: 922) WELTILHTNDVHSRLEQTSEDSSKCVNASRCMGGVA RLFTKVQQIRRAEPNVLLLDAGDQYQGTIWFTVYKG AEVAHFMNALRYDAMALGNHEFDNGVEGLIEPLLK EAKFPILSANIKAKGPLASQISGLYLPYKVLPVGDEV VGIVGYTSKETPFLSNPGTNLVFEDEITALQPEVDKL KTLNVNKIIALGH SGFEMDKLIAQKVRGVDVVVGGH SNTFLYTGNPPSKEVPAGKYPFIVTSDDGRKVPVVQA YAFGKYLGYLKIEFDERGNVISSHGNPILLNSSIPEDP SIKADINKWRIKLDNYSTQELGKTIVYLDGSSQSCRF RECNMGNLICDAMINNNLRHADETFWNHVSMCILN GGGIRSPIDERNGGTITWENLAAVLPF TFDLVQLK GSTLKKAFEHSVHRYGQSTGEFLQVGGIHVVYDLSR KPGDRVVKLDVLCTKCRVPSYDPLKMDEVYKVILPN FLANGGDGFQMIKDELLRHDSGDQDINVVSTYISKM KVIYPAVEGRIKHHHHHH 332 CD73 fragment (residue range 27-547 from SEQ GO NO: 105) fused to the 6-H18 tag at C- MCPRAARAPATLLLALGAVLWPAAGAWELTILHTN DVHSRLEQTSEDSSKCVNASRCMGGVARLFTKVQQI RRAEPNVLLLDAGDQYQGTIWFTVYKGAEVAHFMN ALRYDAMALGNHEFDNGVEGLIEPLLKEAKFPILSA NIKAKGPLASQISGLYLPYKVLPVGDEVVGIVGYTSK

- 170 047335

end (SEQ Ш NO: 922), containing the signal peptide ETPFLSNPGTNLVFEDEITALQPEVDKLKTLNVNKIIA LGHSGFEMDKLIAQKVRGVDVVGGHSNTFLYTGN PPSKEVPAGKYPFIVTSDDGRKVPVVQAYAFGKYLG YLKIEFDERGNVISSHGNPILLNSSIPEDPSIKADINKW RIKLDNYSTQELGKTIVYLDGSSQSCRFRECNMGNLI CDAMINNNLRHA DETFWNHVSMCILNGGGIRSPIDE RNNGTITWENLAAVLPFGGTFDLVQLKGSTLKKAFE HSVHRYGQSTGEFLQVGGIHVVYDLSRKPGDRVVKL DVLCTKCRVPSYDPLKMDEVYKVILPNFLANGGDGF QMIKDELLRHDSGDQDINVVSTYISKMKVIYPAVEG RIKHHHHHH

In other embodiments, the above antibody molecules are capable of binding to human CD73 with a dissociation constant (KD) of less than about 1 x 10 M, 1 x 10 ^-5 M, 1 x ^{10 -6} M, 1 x 10 -7 M, 1 x 10 ^-8 M, 1 x 10 ^-9 M, which is, for example, measured using Biacore, Octet, flow cytometry or ELISA systems.

In some embodiments, the antibody molecule binds to CD73 of a mammal, such as a human or a cynomolgus monkey. For example, the antibody molecule binds to an epitope, such as a linear or conformational epitope (eg, an epitope described herein) on CD73. In certain aspects, it is advantageous to identify an antibody that binds with high affinity to homologs of the human and macaque cynomolgus protein of interest. This required cross-reactivity allows the same antibody (or two antibodies with the same CDRs or variable regions) to be tested in an animal model and then administered to human patients as a therapeutic agent.

In some embodiments, disclosed herein is an isolated antibody molecule that competes for binding to human CD73 with the aforementioned anti-CD73 antibody molecules.

In some embodiments, disclosed herein is an isolated antibody molecule that binds to the same epitope, substantially the same epitope, overlapping epitope, or substantially overlapping epitope as the aforementioned anti-CD73 antibody molecules.

In some embodiments, the antibody molecule binds to the N-terminal domain of human CD73. In some embodiments, the antibody molecule binds to the A-loop and/or B-loop of human CD73. In some embodiments, the antibody molecule, upon binding to human CD73, induces a conformational change in the C-loop of human CD73.

In some embodiments, the antibody molecule reduces the level of hydrogen-deuterium exchange in one or more regions of a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171) , upon binding, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387, and residues 87-104 of SEQ ID NO: 105, for example, when examining an antibody molecule in form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, such as the method used in FIG. 14 and 15. Representative data is shown in FIG. 14 and 15. In some embodiments, hydrogen-deuterium exchange is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the antibody molecule causes a reduction in the level of hydrogen-deuterium exchange in one or more regions of a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 106 upon binding, wherein one or more regions is selected from the group consisting of of residues 158-172, residues 206-215, residues 368387 and residues 87-104 of SEQ ID NO: 106, for example, when examining the antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry.

In some embodiments, the antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), results in a greater reduction in hydrogen-deuterium exchange residues 368-387 of SEQ ID NO: 105 than residues 297-309 of SEQ ID NO: 105, as measured, for example, by a method described herein, such as hydrogen-deuterium exchange mass spectrometry performed with exchange for 1 minute at pH 7.5 and room temperature, such as the method used in FIG. 14 and 15. Representative

- 171 047335 These data are shown in Fig. 14 and 15. In some embodiments, the reduction in hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 is at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold or 4-fold relative to the reduction in hydrogen -deuterium exchange at residues 297-309 from SEQ ID NO: 105.

In some embodiments, an anti-CD73 antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 106), results in a greater reduction in hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 106 than for residues 297-309 of SEQ ID NO: 106, which, for example, is measured using the method described herein, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7.5 and room temperature .

In some embodiments, the anti-CD73 antibody molecule, when bound to human CD73, causes a decrease in the level of hydrogen-deuterium exchange in the C-loop of human CD73 to a greater extent than in the A-loop, B-loop, or D-loop of human CD73, which, for example , is measured using the method described herein, for example, hydrogen-deuterium exchange mass spectrometry performed with exchange for 1 minute at pH 7.5 and room temperature, for example, using the method used in FIG. 14 and 15. Representative data is shown in FIG. 14 and 15. In some embodiments, the reduction in hydrogen-deuterium exchange in the C-loop of human CD73 is at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6 -fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold or 4-fold relative to the decrease in hydrogen-deuterium exchange in A -loop, B-loop or D-loop of human CD73.

In some embodiments, an anti-CD73 antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a reduction in the level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 to a greater extent than at residues 158-172, residues 206-215, or residues 297-309 of SEQ ID NO: 105, as measured, for example, by the method described in herein, for example, hydrogen-deuterium exchange mass spectrometry performed with exchange for 1 minute at pH 7.5 and room temperature, for example, the method used in FIG. 14 and 15. Representative data is shown in FIG. 14 and 15. In some embodiments, the reduction in hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 105 is at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5- multiple, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold or 4-fold relative to the reduction in hydrogen -deuterium exchange at residues 158-172, residues 206-215, or residues 297-309 from SEQ ID NO: 105.

In some embodiments, the anti-CD73 antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 106, reduces the level of hydrogen-deuterium exchange at residues 368-387 of SEQ ID NO: 106 to a greater extent, than residues 158-172, residues 206-215, or residues 297-309 of SEQ ID NO: 106, as measured, for example, by a method described herein, such as hydrogen-deuterium exchange mass spectrometry, carried out with exchange in for 1 minute at pH 7.5 and room temperature.

In some embodiments, the anti-CD73 antibody molecule, when bound to human CD73, causes a decrease in the level of hydrogen-deuterium exchange in the A-loop of human CD73 to a greater extent than in the B-loop, C-loop, or D-loop of human CD73, which, for example , is measured using the method described herein, for example, hydrogen-deuterium exchange mass spectrometry performed with exchange for 1 minute at pH 7.5 and room temperature, for example, using the method used in FIG. 14 and 15. Representative data is shown in FIG. 14 and 15. In some embodiments, the reduction in hydrogen-deuterium exchange in the A-loop of human CD73 is at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6 -fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold or 4-fold relative to the decrease in hydrogen-deuterium exchange in B -loop, C-loop or D-loop of human CD73.

In some embodiments, an anti-CD73 antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a reduction in the level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 105 to a greater extent than at residues 206-215, residues 368-387, or residues 297-309 of SEQ ID NO: 105, as measured, for example, by the method described in herein, for example, hydrogen-deuterium exchange mass spectrometry performed with exchange for 1 minute at pH 7.5 and room temperature, for example, the method used in FIG. 14 and 15. Representative data is shown in FIG. 14 and 15. In some embodiments, reducing hydrogen-deuterium exchange at residues 158-172

- 172 047335 from SEQ ID NO: 105 is at least 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 -fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold or 4-fold relative to the decrease in hydrogen-deuterium exchange at residues 206-215, residues 368-387 or residues 297-309 from SEQ ID NO: 105.

In some embodiments, an anti-CD73 antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), provides a reduction in the level of hydrogen-deuterium exchange at residues 158-172 of SEQ ID NO: 106 to a greater extent than at residues 206-215, residues 368-387, or residues 297-309 of SEQ ID NO: 106, as measured, for example, by the method described in herein, for example, hydrogen-deuterium exchange mass spectrometry performed with exchange for 1 minute at pH 7.5 and room temperature.

In some embodiments, an anti-CD73 antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), is capable of reducing hydrogen-deuterium exchange in one or more regions of human CD73, wherein the one or more regions is selected from the group consisting of residues 158-172, residues 206-215, residues 368-387, and residues 87-104 of SEQ ID NO: 105, wherein the region , characterized by the greatest decrease among one or more regions, is not residues 206-215 of SEQ ID NO: 105, which, for example, is measured using the method described herein, for example, hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7.5 and room temperature, for example the method used in FIG. 14 and 15. Representative data is shown in FIG. 14 and 15.

In some embodiments, the anti-CD73 antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 106, is capable of reducing hydrogen-deuterium exchange in one or more regions of human CD73, wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87-104 of SEQ ID NO: 106, wherein the region having the greatest decrease among one or more regions is not residues 206- 215 of SEQ ID NO: 106, which, for example, is measured using the method described herein, for example, hydrogen-deuterium exchange mass spectrometry carried out with an exchange for 1 minute at pH 7.5 and room temperature.

In some embodiments, an anti-CD73 antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), results in a decrease in the level of hydrogen deuterium exchange of more than, for example, 0.02, 0.03, 0.04, 0.05 or 0.06 Da per residue, for residues 368-387 of SEQ ID NO: 105, which, for example, is measured with using the method described herein, for example, hydrogen-deuterium exchange mass spectrometry performed with exchange for 1 minute at pH 7.5 and room temperature, for example, the method used in FIG. 14 and 15. Representative data is shown in FIG. 14 and 15.

In some embodiments, an anti-CD73 antibody molecule, when bound to a protein comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 (e.g., a protein consisting of the amino acid sequence of SEQ ID NO: 171), results in a decrease in the level of hydrogen deuterium exchange of less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, which, for example, is measured using the method described herein, for example, hydrogen-deuterium exchange mass spectrometry performed with exchange for 1 minute at pH 7.5 and room temperature, for example, the method used in FIG. 14 and 15. Representative data is shown in FIG. 14 and 15.

In some embodiments, an antibody molecule is provided that binds to a human CD73 dimer, wherein the dimer consists of a first CD73 monomer and a second CD73 monomer, wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first monomer CD73 and the second antigen binding domain binds to the second CD73 monomer, for example, when assayed using size exclusion chromatography, for example, when assayed using the method described herein, for example, the method used in FIG. 17A and 17B.

In some embodiments, disclosed herein is a composition comprising multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO. : 105 (for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein if each of the antibody molecules in the plurality contains the same first antigen binding domain and the same second antigen binding domain, at least 30 %, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the antibody molecules in the specified composition bind to the CD73 dimer to form

- 173 047335 complex, where each of these complexes consists of one antibody molecule and one CD73 dimer, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, when assayed using the method described herein, such as the method used in FIG. 17A, 17B, 18A and 18B. Representative data is shown in FIG. 17A, 17B, 18A and 18B.

In some embodiments, disclosed herein are multiple antibody molecules that bind to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105 ( for example, each monomer consists of the amino acid sequence of SEQ ID NO: 171), wherein, if each of the antibody molecules in the plurality contains the same first antigen binding domain and the same second antigen binding domain, not more than 20%, 25% 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the antibody molecules in said composition bind to the CD73 dimer to form a complex, wherein each of said complexes contains two or more antibody molecules and two or more CD73 dimers, for example, when measured using size exclusion chromatography, and the percentage is obtained by determining the number of antibody molecules in the complex relative to the total number of antibody molecules binding to CD73 (excluding unbound antibody molecules), for example, when study using the method described herein, for example, the method used in FIG. 17A, 17B, 18A and 18B. Representative data is shown in FIG. 17A, 17B, 18A and 18B.

In some embodiments, the anti-CD73 antibody molecule, upon binding to human CD73, does not result in oligomerization of human CD73.

In some embodiments, the antibody molecule preferably binds to CD73 in an open conformation, such as a catalytically inactive conformation, rather than to CD73 in a closed conformation, such as a catalytically active conformation, e.g., does not bind or binds to CD73 in a closed conformation, such as CD73 in a catalytically active conformation. active conformation, with lower affinity, e.g., with an affinity that is 50%, 60%, 70%, 80%, 90%, 95%, or 99% lower than when the antibody molecule binds to CD73 in an open conformation, e.g., catalytically inactive conformation.

In some embodiments, the anti-CD73 antibody molecule prevents or reduces the level of human CD73 from converting from a catalytically inactive open conformation to a catalytically active closed conformation. In some embodiments, the level of conversion of human CD73 from a catalytically inactive open conformation to a catalytically active closed conformation is reduced by at least 1.5-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold times, 70 times, 80 times, 90 times or 100 times the conversion rate in the absence of the antibody molecule.

In some embodiments, the anti-CD73 antibody molecule interacts, for example, directly or indirectly with at least one residue within residues 158-172 of SEQ ID NO: 105. In some embodiments, the anti-CD73 antibody molecule interacts, for example, directly or indirectly with at least at least one residue within residues 206-215 of SEQ ID NO: 105. In some embodiments, the anti-CD73 antibody molecule interacts, for example, directly or indirectly with at least one residue within residues 368-387 of SEQ ID NO: 105. B In some embodiments, the anti-CD73 antibody molecule interacts, e.g., directly or indirectly with at least one residue within residues 87-104 of SEQ ID NO: 105. In some embodiments, the anti-CD73 antibody molecule interacts, e.g., directly or indirectly with at least one residue within residues 368-387 of SEQ ID NO: 106.

In some embodiments, the anti-CD73 antibody molecule inhibits or reduces the enzymatic activity of CD73 (e.g., soluble human CD73 or membrane-bound human CD73), e.g., human CD73-mediated conversion of adenosine monophosphate (AMP) to adenosine, e.g., measured using the method described herein, for example by phosphate quantitation using the Malachite Green (MG) reaction or a modified Cell Titer Glo (CTG) assay, such as the method used in FIG. 2B, 3A, 3B, 3C, 4, 5, 6, 7A, 7B, 7C, 8A, 8B, 9A, 9B, 10, 11A, 11B, or 13. Representative data is shown in FIG. 2B, 3A, 3B, 3C, 4, 5, 6, 7A, 7B, 7C, 8A, 8B, 9A, 9B, 10, 11A, 11B, and 13. In some embodiments, the enzymatic activity of CD73 (e.g., soluble human CD73 or membrane-bound human CD73) is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 99%.

In some embodiments, the anti-CD73 antibody molecule provides an increase in the level of proliferation of anti-CD3 antibody/anti-CD28 antibody-stimulated T cells, e.g., CD4+ T cells, in the presence of adenosine monophosphate (AMP), as measured, for example, using a method described herein , for example, using a CellTrace Violet (CTV) cell proliferation assay, such as the method used in FIG. 12A or 12V. Representative data is shown in FIG. 12A

- 174 047335 and 12V. In some embodiments, the proliferation of T cells stimulated with anti-CD3 antibodies/anti-CD28 antibodies, e.g., CD4+ T cells, is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7 -fold, 8-fold, 9-fold or 10-fold.

In another aspect, the present invention provides an isolated nucleic acid encoding any of the above antibody molecules, vectors and host cells thereof. The nucleic acid molecule includes, but is not limited to, RNA, genomic DNA and cDNA.

In some embodiments, the isolated nucleic acid encodes an antibody heavy chain variable region, a light chain variable region, a heavy chain, and/or a light chain of any of the foregoing antibody molecules.

In some embodiments, the isolated nucleic acid encodes a heavy chain variable region, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 45, 78, 85, 143, 152, 160, 67, 32, 11, or 169, or a nucleotide sequence characterized by at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 45, 78, 85, 143, 152, 160, 67, 32, 11, or 169.

In some embodiments, the isolated nucleic acid encodes a heavy chain, wherein the nucleic acid comprises a nucleotide sequence of SEQ ID NO: 47, 80, 87, 69, 34, or 13, or a nucleotide sequence characterized by at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 47, 80, 87, 69, 34, or 13.

In some embodiments, the isolated nucleic acid encodes a light chain variable region, wherein the nucleic acid comprises a nucleotide sequence of SEQ ID NO: 56, 144, 22, or 170, or a nucleotide sequence characterized by at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 56, 144, 22 or 170.

In some embodiments, the isolated nucleic acid encodes a light chain, wherein the nucleic acid comprises a nucleotide sequence of SEQ ID NO: 58 or 24, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 58 or 24.

Pharmaceutical compositions and kits

In some aspects, the present invention provides compositions, for example, pharmaceutically acceptable compositions, that contain an anti-CD73 antibody molecule described herein formulated together with a pharmaceutically acceptable carrier. As used herein, the term pharmaceutically acceptable carrier includes any and all solvents, dispersion media, isotonic and absorption retarding agents, and the like that are physiologically compatible. The carrier may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (eg, by injection or infusion).

The compositions provided herein may be in various forms. These include, for example, liquid, semi-solid and solid dosage forms such as liquid solutions (eg solutions for injection or infusion), dispersions or suspensions, liposomes and suppositories. The appropriate form depends on the intended route of administration and therapeutic use. Typically suitable compositions are in the form of solutions for injection or infusion. One suitable route of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular). In some embodiments, the antibody molecule is administered via intravenous infusion or injection. In certain embodiments, the antibody is administered by intramuscular or subcutaneous injection.

The phrases parenteral administration and parenterally administered as used herein refer to modes of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal , transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

Therapeutic compositions generally must be sterile and stable under conditions of manufacture and storage. The composition may be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for high concentrations of the antibody. Sterile injection solutions can be prepared by incorporating the active compound (ie, antibody or portion of an antibody) in the required amount into an appropriate diluent with one or a combination of the above ingredients, if necessary, followed by sterilization by filtration. Typically, dispersions are prepared by incorporating the active compound into a sterile carrier medium that contains the basic dispersion medium and other required ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization, which result in a powder of the active ingredient and any additional

- 175 047335 of the desired ingredient from their solution, previously sterilized by filtration. Proper fluidity of the solution can be maintained, for example, by the use of a coating agent such as lecithin, by maintaining the required particle size in the case of a dispersion, and by the use of surfactants. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that slows absorption, for example, monostearate salts and gelatin.

The antibody molecule can be administered using a number of methods. Several methods are known in the art, and for many therapeutic applications, intravenous injection or infusion is a suitable route/mode of administration. In one embodiment, the antibody molecules can be administered by intravenous infusion at a rate greater than 20 mg/min, such as 20-40 mg/min. In one embodiment, the antibody molecules can be administered by intravenous infusion at a rate greater than or equal to 40 mg/minute to achieve a dose of from about 35 to 440 mg/m ² , from about 70 to 310 mg/m ² , or from about 110 to 130 mg/ ^m2 . In an embodiment, the antibody molecules can be administered by intravenous infusion at a rate of less than 10 mg/minute, such as 5 mg/minute or less, to achieve a dose of from about 1 to 100 mg/m ² , for example, from about 5 to 50 mg /m ² , from about 7 to 25 mg/m ² or about 10 mg/m ² . As will be appreciated by one skilled in the art, the route and/or method of administration will vary depending on the desired results. In certain embodiments, the active compound may be formulated with a carrier that will protect the compound from immediate release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Many methods for preparing such compositions are patented or well known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In certain embodiments, the antibody molecule can be administered orally, for example, using an inert diluent or digestible edible carrier. The antibody molecule (and other ingredients, if necessary) can also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or administered directly into the subject's diet. For oral therapeutic administration, the antibody molecule can be administered with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, tinctures, suspensions, syrups, wafers, etc. To administer the antibody molecule of the present invention by a route other than parenteral, It may be necessary to coat the compound or co-administer the compound with the material to prevent inactivation. Therapeutic compositions can also be administered using medical devices known in the art.

Dosage regimens are adjusted to provide the desired response (eg, therapeutic response). For example, a single bolus dose may be administered, multiple divided doses may be administered over time, or the dose may be proportionally decreased or increased according to the needs of the therapeutic situation. It is particularly advantageous to formulate compositions for parenteral use in a single dosage form for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to physically discrete units suitable as unitary dosages for subjects to be treated; each unit containing a predetermined amount of active compound calculated to obtain the desired therapeutic effect, in combination with the required pharmaceutical carrier. The parameters of the unit dosage forms are dictated by and directly depend on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art with respect to the formulation of such active compound for the treatment of sensitivity in individuals.

In some embodiments, the anti-CD73 antibody molecule disclosed herein is administered by injection (e.g., subcutaneously or intravenously) at a dose (e.g., fixed dose) of from about 60 mg to 2400 mg, such as from about 100 mg to 2400 mg, from from about 100 mg to 2200 mg, from about 100 mg to 2000 mg, from about 100 mg to 1800 mg, from about 100 mg to 1600 mg, from about 100 mg to 1400 mg, from about 100 mg to 1200 mg, from about 100 mg to 1000 mg, from about 100 mg to 800 mg, from about 100 mg to 600 mg, from about 100 mg to 400 mg, from about 100 mg to 200 mg or about 100 mg, about 180 mg or about 200 mg. The dosing schedule (eg, fixed dose schedule) may vary, for example, from once a week to once every 2, 3 or 4 weeks. In one embodiment, an anti-CD73 antibody molecule disclosed herein is administered at a dose of about 100 mg to 200 mg once per week, once every two weeks, or once every three weeks. In one embodiment, the anti-CD73 antibody molecule disclosed herein is administered at a dose of at least about 180 mg every two weeks.

- 176 047335

In some embodiments, an anti-CD73 antibody molecule disclosed herein is administered by injection (e.g., subcutaneously or intravenously) at a dose (e.g., fixed dose) of about 5 mg to 100 mg, about 100 mg to 500 mg, from about 500 mg to 1000 mg, from about 1000 mg to 1500 mg, from about 1500 mg to 2000 mg, from about 2000 mg to 2500 mg, from about 2500 mg to 3000 mg, from about 3000 mg to 3500 mg, or from about 3500 mg up to 4000 mg, for example once a week (QW), every two weeks (Q2W) or every four weeks (Q4W). In certain embodiments, the antibody molecule is administered, for example, intravenously, at a dose of about 6 mg, about 20 mg, about 60 mg, about 200 mg, about 600 mg, about 1200 mg, about 2400 mg, about 3000 mg, or about 3600 mg, for example QW, Q2W or Q4W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 60 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 200 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 600 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 1200 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 2400 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 3000 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 3600 mg Q2W.

In one embodiment, an anti-CD73 antibody molecule disclosed herein is administered, for example by infusion, over a period of 30 minutes, a period of 1 hour, or a period of no more than 2 hours.

An exemplary non-limiting range for a therapeutically or prophylactically effective amount of an antibody molecule is 0.1-30 mg/kg, more preferably 1-25 mg/kg. Dosages and therapeutic regimens for the anti-CD73 antibody molecule can be determined by one skilled in the art. In certain embodiments, the anti-CD73 antibody molecule is administered by injection (e.g., subcutaneously or intravenously) at a dose of from about 1 to 40 mg/kg, such as from 1 to 30 mg/kg, such as from about 5 to 25 mg/kg, from about 10 to 20 mg/kg, about 1 to 5 mg/kg, 1 to 10 mg/kg, 5 to 15 mg/kg, 10 to 20 mg/kg, 15 to 25 mg/kg, or about 3 mg/kg. The dosing schedule may vary from, for example, once a week to every 2, 3 or 4 weeks. In one embodiment, the anti-CD73 antibody molecule is administered at a dose of about 10 to 20 mg/kg every two weeks. The antibody molecule can be administered by intravenous infusion at a rate greater than 20 mg/min, for example 20-40 mg/min, for example equal to 40 mg/min. or more, achieving a dose of from about 35 to 440 mg/m ² , from about 70 to 310 mg/m 2 , or from about 110 to 130 mg/m ² . In embodiments, an infusion rate of approximately 110-130 mg/m ² achieves a level of approximately 3 mg/kg. In other embodiments, the antibody molecule can be administered by intravenous infusion at a rate of less than 10 mg/minute, such as 5 mg/minute. Or less, achieving a dose of from about 1 to 100 mg/m ² , for example, from about 5 to 50 mg/m ² , from about 7 to 25 mg/m ² or about 10 mg/m ² . In some embodiments, the antibody is administered over a period of approximately 30 minutes. It should be noted that dosage values may vary depending on the type and severity of the condition being alleviated. It should also be understood that for any particular subject, specific dosage regimens should be adjusted over time according to individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are illustrative only and are not intended to be limiting. volume or practical application of the claimed composition.

The pharmaceutical compositions of the present invention may contain a therapeutically effective amount or a prophylactically effective amount of an antibody molecule of the present invention. A therapeutically effective amount refers to an amount effective in doses and for periods of time necessary to achieve the desired therapeutic result. The therapeutically effective amount of the modified antibody or antibody fragment may vary according to factors such as the stage of the disease, the age, sex and weight of the individual, and the ability of the antibody and antibody portion to elicit the desired response in the individual. A therapeutically effective amount is also one in which the beneficial effects outweigh any toxic or detrimental effects of the antibody molecule. The therapeutically effective dose preferably provides at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80% inhibition of the measured parameter compared to subjects who were not treated. The parameter being measured could be, for example, the growth rate of a tumor or the growth rate of a pathogen. The ability of an antibody molecule to inhibit a measurable parameter can be assessed in an animal model system that provides the ability to predict efficacy when appropriate.

- 177 047335 developing human disease. Alternatively, this property of the composition can be assessed by examining the inhibitory ability of the compound, for example, inhibition in in vitro assays known to one skilled in the art.

A prophylactically effective amount refers to an amount effective in doses and for periods of time necessary to achieve the desired prophylactic result. In general, since the prophylactic dose is administered to subjects before the onset of the disease or at an earlier stage thereof, the prophylactically effective amount will be less than the therapeutically effective amount.

Also included within the scope of the present invention is a kit containing the antibody molecule described herein. The kit may contain one or more other items, including instructions for use; other reagents, for example, a tag, a therapeutic agent or an agent suitable for chelation or other combination, an antibody to the tag or therapeutic agent, or a radioprotective composition; devices or other materials for preparing the antibody molecule for administration; pharmaceutically acceptable carriers; and devices or other materials for administration to a subject.

Routes of application of anti-CD73 antibody molecules

The anti-CD73 antibody molecules disclosed herein have diagnostic as well as therapeutic and prophylactic properties in vitro and in vivo. For example, these molecules can be administered to cells in in vitro or ex vivo culture or to a subject, such as a human subject, for the treatment, prevention and/or diagnosis of various disorders, such as cancers and infectious disorders.

Accordingly, in one aspect, the present invention provides a method of modifying an immune response in a subject, comprising administering to the subject an antibody molecule described herein such that the immune response in the subject is modified. In one embodiment, the immune response is enhanced, stimulated, or upregulated. In one embodiment, the antibody molecules provide an enhancement of the immune response in a subject through blockade of CD73.

As used herein, the term subject is intended to include human and non-human animals. In one embodiment, the subject is a human subject, for example, a human patient having a disorder or condition characterized by abnormal functioning of CD73. The term non-human animals includes mammals and non-mammalian animals such as non-human primates. In one embodiment, the subject is a human. In one embodiment, the subject is a human patient in need of an enhanced immune response. In one embodiment, the subject suffers from an immune deficiency, for example, the subject is or has been treated with chemotherapy and/or radiation therapy. Alternatively or in combination, the subject suffers from or is at risk of immune deficiency as a result of infection. The methods and compositions described herein are suitable for the treatment of human patients having a disorder that can be treated by enhancing the T cell-mediated immune response. For example, the methods and compositions described herein can enhance a number of immune activities. In one embodiment, the subject has an increased number or activity of tumor-infiltrating T lymphocytes (TILs).

Routes of therapeutic use

Cancer

In one aspect, the present invention relates to treating a subject in vivo with an anti-CD73 antibody molecule thereby inhibiting or reducing the growth of cancerous tumors. Antibody to CD73 can be used alone to inhibit the growth of cancerous tumors. Alternatively, an anti-CD73 antibody may be used in combination with one or more of a standard treatment (eg, for cancers), another antibody molecule, an immunomodulator (eg, a co-stimulatory molecule activator or a coinhibitory molecule inhibitor); vaccines, for example, a therapeutic cancer vaccine; or other forms of cell therapy as described below.

Accordingly, in one embodiment, the present invention provides a method of inhibiting the growth of tumor cells in a subject, which comprises administering to the subject a therapeutically effective amount of an anti-CD73 antibody molecule disclosed herein.

In one embodiment, the methods are suitable for treating cancer in vivo. To achieve antigen-specific immune enhancement, the anti-CD73 antibody molecule can be administered together with the antigen of interest. When anti-CD73 antibodies are administered in combination with one or more agents, the combination may be administered in either order or simultaneously.

Types of Cancer

In another aspect, there is provided a method of treating a subject, for example, reducing the intensity or amelioration of a hyperproliferative condition or disorder (eg, cancer), such as a solid tumor, hematologic cancer, soft tissue tumor, or metastatic lesion in the subject.

- 178 047335

The method involves administering to a subject one or more anti-CD73 antibody molecules described herein, alone or in combination with other agents or therapeutic modalities.

As used herein, the term cancer is intended to include all types of malignancies or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues or organs, regardless of histopathological type or stage of invasiveness. Examples of malignant disorders include, but are not limited to, solid tumors, hematologic cancers, soft tissue tumors, and metastatic lesions. Examples of solid tumors include malignancies, such as forms of sarcoma and carcinoma (including forms of adenocarcinoma and squamous cell carcinoma), various organ systems, such as malignancies affecting the liver, lung, breast, lymphoid tissue, gastrointestinal tract (eg, colon intestine), genitourinary tract (eg, kidney cells, urothelium), prostate gland and pharynx. Forms of adenocarcinoma include malignancies such as most forms of colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung carcinoma, small intestinal cancer, and esophageal cancer. Forms of squamous cell carcinoma include cancers in areas such as the lung, esophagus, skin, head and neck, mouth, anus, and cervix. In one embodiment, the cancer is melanoma, for example, advanced melanoma. Metastatic lesions of the above-mentioned forms of cancer can also be treated or prevented using the methods and compositions of the present invention.

Exemplary cancers that can be inhibited using the antibody molecules disclosed herein include cancers typically responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment include melanoma (eg, metastatic malignant melanoma), kidney cancer (eg, clear cell carcinoma), prostate cancer (eg, hormone-refractory prostate adenocarcinoma), breast cancer, colon cancer, and lung cancer (eg, non-small cell lung cancer). Additionally, refractory or relapsed cancers can be treated with the antibody molecules described herein.

Examples of other types of cancer that may be treated include bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach and esophageal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Merkel cell cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer glands, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute forms of leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma , bladder cancer, multiple myeloma, myelodysplastic syndromes, kidney or ureteral cancer, renal pelvic carcinoma, central nervous system (CNS) neoplasia, primary CNS lymphoma, tumor angiogenesis, spinal cord tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmental cancers, including asbestos-related cancers (eg, mesothelioma), and combinations of these cancers.

In some embodiments, the therapies provided herein may be used to treat a patient who has (or is identified as having) cancer associated with an infection, such as a viral or bacterial infection. Exemplary cancers include cervical cancer, anal cancer, HPV-associated squamous cell carcinoma of the head and neck, HPV-associated esophageal papillomas, HHV6-associated lymphomas, EBV-associated lymphomas (including Burkitt's lymphoma), MALT lymphoma of the GI tract, other types of MALT lymphoma associated with infection, HCC and Kaposi's sarcoma.

In other embodiments, the cancer is a hematologic malignancy or cancer, including but not limited to leukemia or lymphoma. For example, an anti-CD73 antibody molecule may be used to treat cancers and malignancies, including, but not limited to, e.g., acute leukemia, including, but not limited to, e.g., B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL) ), acute lymphoid leukemia (ALL); one or more types of chronic leukemia, including without limitation, for example, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to, B-cell prolymphocytic leukemia, blast plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, villous cell leukemia, small or large cell follicular lymphoma, malignant lymphoproliferators active conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma,

- 179 047335 multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenström macroglobulinemia and preleukemia, which are a diverse set of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells, and etc. .

In one embodiment, the cancer is selected from lung cancer (e.g., non-small cell lung cancer (NSCLC) (e.g., NSCLC with squamous and/or non-squamous histology or adenocarcinoma NSCLC)), melanoma (e.g., advanced melanoma), kidney cancer (e.g., renal cell carcinoma, eg clear cell renal cell carcinoma), liver cancer, myeloma (eg multiple myeloma), prostate cancer, breast cancer (eg breast cancer that does not express one, two or all of the receptor estrogen, progesterone receptor or Her2/neu, e.g. triple negative breast cancer), colorectal cancer (microsatellite stable (MSS) colorectal cancer), ovarian cancer, pancreatic cancer, head and neck cancer (e.g. head and neck squamous cell carcinoma (HNSCC), anal cancer, gastric and esophageal cancer, thyroid cancer, cervical cancer, lymphoproliferative disease (eg, post-transplant lymphoproliferative disease) or hematologic malignancy, T-cell lymphoma, non-Hodgkin's lymphoma, or leukemia (eg, myeloid leukemia).

In one embodiment, the cancer is selected from lung cancer (eg, non-small cell lung cancer), pancreatic cancer (eg, pancreatic ductal adenocarcinoma), breast cancer (eg, triple negative breast cancer), melanoma, head and neck cancer (eg , squamous cell carcinoma of the head and neck), colorectal cancer (eg, microsatellite stability (MSS) colorectal cancer), ovarian cancer, or kidney cancer (eg, renal cell carcinoma).

In one embodiment, the cancer is selected from bladder cancer, leukemia, lymphoma, glioma, glioblastoma, ovarian cancer, thyroid cancer, esophageal cancer, prostate cancer, uterine/cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer , colon cancer, kidney cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, skin cancer, central nervous system neoplasm, myeloma, sarcoma and virus-associated cancer.

Combination of anti-CD73 antibody molecules

Anti-CD73 antibody molecules can be used in combination with other therapies. For example, a combination therapy may include a composition of the present invention co-formulated and/or administered together with one or more additional therapeutic agents, for example, one or more anticancer agents, cytotoxic or cytostatic agents, hormonal treatments, vaccines and/or other immunotherapies. In other embodiments, antibody molecules are administered in combination with other therapeutic treatments, including surgery, radiation, cryosurgery, and/or thermotherapy. Such combination therapies may advantageously use lower doses of the therapeutic agents administered, thereby avoiding the potential toxic effects or complications associated with the various monotherapies.

The term in combination with is not intended to indicate that the therapy or therapeutic agents must be administered at the same time and/or formulated for delivery together, although these delivery methods are within the scope described herein. The anti-CD73 antibody molecules can be administered simultaneously with, before or after one or more additional therapies or therapeutic agents. The anti-CD73 antibody molecule and the other agent or therapeutic protocol can be administered in any order. Typically, each agent will be administered at a dose and/or time schedule that is specified for that agent. It should also be understood that the additional therapeutic agent used in a given combination may be administered together in a single composition or administered separately in different compositions. In general, it is expected that additional therapeutic agents used in combination will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than the levels used individually.

Exemplary A2A Adenosine Receptor Antagonists

In certain embodiments, the anti-CD73 antibody molecules described herein are administered in combination with an A2A adenosine receptor (A2AR) antagonist. Exemplary A2AR antagonists include, for example, PBF509 (Palobiofarma/Novartis), CPI444/V81444 (Corvus/Genen tech), AZD4635/HTL-1071 (AstraZeneca/Heptares), vipadenant (Redox/Juno), GBV-2034 (Globav) (Globavir ), AB928 (Arcus Biosciences), theophylline, istradefylline (Kyowa Hakko Kogyo), tozadenant/SYN-115 (Acorda), KW-6356 (Kyowa Hakko Kogyo), ST-4206 (Leadiant Biosciences) and preladenant/SCH 420814 (Merck/ Schering).

In certain embodiments, the A2AR antagonist is PBF509. PBF509 and

- 180 047335 other A2AR antagonists are disclosed in US 8796284 and WO 2017/025918, incorporated herein by reference in their entirety. PBF509 refers to 5-bromo-2,6-di-(1H-pyrazol-1yl)pyrimidin-4-amine with the following structure:

In certain embodiments, the A2AR antagonist is CPI444/V81444. CPI-444 and other A2AR antagonists are disclosed in WO 2009/156737, which is incorporated herein by reference in its entirety. In certain embodiments, the A2AR antagonist is ^)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2yl)methyl)-3H [1,2,3]triazolo[4,5^]pyrimidin-5-amine. In certain embodiments, the A2AR antagonist is ^)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl) -3H[1,2,3]triazolo[4,5^]pyrimidin-5-amine or its racemate. In certain embodiments, the A2AR antagonist is 7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H [1,2,3]triazolo[4,5^]pyrimidin-5-amine. In certain embodiments, the A2AR antagonist has the following structure:

In certain embodiments, the A2AR antagonist is AZD4635/HTL1071. A2AR antagonists are disclosed in WO 2011/095625, which is incorporated herein by reference in its entirety. In certain embodiments, the A2AR antagonist is 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine. In certain embodiments, the A2AR antagonist has the following structure:

In certain embodiments, the A2AR antagonist is ST-4206 (Leadiant Biosciences). In certain embodiments, the A2AR antagonist is the A2AR antagonist described in US Pat. No. 9,331,997, incorporated herein by reference in its entirety. In certain embodiments, the A2AR antagonist has the following structure:

In certain embodiments, the A2AR antagonist is the A2AR antagonist described in US8114845, US9029393, US20170015758, or US20160129108, all of which are incorporated herein by reference in their entirety.

In certain embodiments, the A2AR antagonist is istradefylline (CAS registration number: 155270-99-8). Istradefylline is also known as KW-6002 or 8-[(E)-2(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6- dione Istradefylline is disclosed, for example, in LeWitt et al. (2008) Annals of Neurology 63 (3): 295-302).

In certain embodiments, the A2aR antagonist is tosadenant (Biotie). Tozadenant is also known as SYN115 or 4-hydroxy-N(4-methoxy-7-morpholin-4-yl-1,3-benzothiazole

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2-yl)-4-methylpiperidin-1-carboxamide. Tozadenant blocks the action of endogenous adenosine on the A2a receptor, which leads to increased action of dopamine on the D2 receptor and inhibition of the action of glutamate on the mGluR5 receptor. In some embodiments, the A2aR antagonist is preladenant (CAS Registry No.: 377727-87-2). Preladenant is also known as SCH 420814 or 2-(2-furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e] [1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

Preladenant was developed as a drug that acts as a potent and selective antagonist of the adenosine A2A receptor.

In certain embodiments, the A2aR antagonist is vipadenane. Vipadenane is also known as BIIB014, V2006 or 3-[(4-amino-3-methylphenyl)methyl]-7-(furan-2-yl)triazolo[4,5-d]pyrimidin-5-amine.

Other exemplary A2aR antagonists include, for example, ATL-444, MSX-3, SCH-58261, SCH-412,348, SCH-442,416, VER-6623, VER-6947, VER-7835, CGS-15943, or ZM-241,385.

In some embodiments, the A2aR antagonist is an A2aR pathway antagonist (e.g., CD-73 inhibitor, e.g., anti-CD73 antibody) is MEDI9447. MEDI9447 is a monoclonal antibody specific for CD73. Targeting extracellular adenosine production via CD73 may reduce the immunosuppressive effects of adenosine. MEDI9447 has been reported to have a number of activity parameters, such as inhibition of CD73 ectonucleotidase activity, attenuation of AMP-mediated lymphocyte suppression, and inhibition of syngeneic tumor growth. MEDI9447 can drive changes in both myeloid and lymphoid infiltrating leukocyte populations in the tumor microenvironment. These changes include, for example, increases in CD8 effector cells and activated macrophages and decreases in the proportions of myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes.

Exemplary PD-1 inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a PD-1 inhibitor. The PD-1 inhibitor may be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. In some embodiments, the PD-1 inhibitor is selected from PDR001 (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro ), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).

Exemplary anti-PD-1 antibody molecules

In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule described in US 2015/0210769, published July 30, 2015, entitled Antibody Molecules to PD-1 and Uses Thereof, incorporated by reference in its entirety.

In one embodiment, an anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all CDRs) of a heavy and light chain variable region comprising an amino acid sequence, shown in table. 5 (for example, from the variable region sequences of the heavy and light chains of BAP049-clone-E or BAP049-clone-B disclosed in Table 5), or encoded by the nucleotide sequence shown in table. 5. In some embodiments, CDRs are defined in accordance with the Kabat numbering scheme (eg, as set forth in Table 5). In some embodiments, the CDRs are defined in accordance with the Chothia numbering scheme (eg, as set forth in Table 5). In some embodiments, CDRs are defined in accordance with a combined Kabat and Chothia CDR numbering scheme (eg, as set forth in Table 5). In one embodiment, CDR1 VH according to the combined Kabat and Chothia CDR numbering scheme contains the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequence, shown in table. 5, or the encoded nucleotide sequence shown in table. 5.

In one embodiment, an anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 501, the amino acid sequence of VHCDR2 of SEQ ID NO: 502, and the amino acid sequence of VHCDR3 of SEQ ID NO: 503; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 510, the amino acid sequence of VLCDR2 of SEQ ID NO: 511 and the amino acid sequence of VLCDR3 of SEQ ID NO: 512, each of which is disclosed in table. 5.

In one embodiment, the antibody molecule contains a VH containing VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, VHCDR2 encoded by the nucleotide sequence

- 182 047335 sequence under SEQ ID NO: 525, and VHCDR3, encoded by the nucleotide sequence under SEQ ID NO: 526; and VL, comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 529, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 530, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 531, each of which is disclosed in table. 5.

In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% or greater sequence identity to SEQ ID NO: 506. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 520, or an amino acid sequence characterized by at least about 85%, 90%, 95%, or 99%, or greater sequence identity to SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence characterized by at least about 85%, 90%, 95% , or 99% or greater sequence identity to SEQ ID NO: 516. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 520 In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 516.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% or greater sequence identity to SEQ ID NO: 507 In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% or greater sequence identity to SEQ ID. NO: 521 or 517. In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 507, and a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517.

In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% or greater sequence identity with SEQ ID NO: 508. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence characterized by at least about 85%, 90%, 95%, or 99 % or greater sequence identity to SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence characterized by at least about 85%, 90% , 95%, or 99% or greater sequence identity to SEQ ID NO: 518. In one embodiment, an anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 518.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% or greater sequence identity to SEQ ID NO: 509. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% or greater sequence identity with SEQ ID NO: 523 or 519. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519.

The antibody molecules described herein can be produced using the vectors, host cells and methods described in US 2015/0210769, incorporated by reference in its entirety.

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Table 5

Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules

NS VAR049-CLONV SEQ GO NO: 501 (Kabat) HCDR1 TYWMH SEQ GO NO: 502 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 503 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 504 (Chothia) HCDR1 GYTFTY SEQ ID NO: 505 (Chothia) HCDR2 YPGTGG SEQ ID NO: 503 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 506 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDE KFKNRVTITADKSTSTAYMELSSLRSEDTAVYY CTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 507 DNA encoding VH GAGGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAGCCCGGCGGTCACTGAGAATTA GCTGTAAAGGTTCAGGCTACACCTTCACTAC CTACTGGATGCACTGGGTCCGCCAGGCTACC GGTCAAGGCCTCGAGTGGATGGGTAATATCT ACCCCGGCACCGGCGGCTCTAACTTCGACGA GAAGTTTAAGAATAGAGTGACTATCACCGCC GATAAGTCTACTAGCACCGC CTATATGGAAC TGTCTAGCCTGAGATCAGAGGACACCGCCGT CTACTACTGCACTAGGTGGACTACCGGCACA GGCGCCTACTGGGGTCAAGGCACTACCGTGA

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CCGTGTCTAGC SEQ GO NO: 508 Heavy chain EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDE KFKNRVTITADKSTSTAYMELSSLRSEDTAVYY CTRWTTGTGAYWGQGTTVTVSSASTKGPSVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTKTCNVDHK PSNTKVDKRVESKYGPPCPP CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNG QPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 509 DNA encoding the heavy chain GAGGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAGCCCGGCGGTCACTGAGAATTA GCTGTAAAGGTTCAGGCTACACCTTCACTAC CTACTGGATGCACTGGGTCCGCCAGGCTACC GGTCAAGGCCTCGAGTGGATGGGTAATATCT ACCCCGGCACCGGCGGCTCTAACTTCGACGA GAAGTTTAAGAATAGAGTGACTATCACCGCC GATAAGTCTACTAGCACCGC CTATATGGAAC TGTCTAGCCTGAGATCAGAGGACACCGCCGT CTACTACTGCACTAGGTGGACTACCGGCACA GGCGCCTACTGGGGTCAAGGCACTACCGTGA CCGTGTCTAGCGCTAGCACTAAGGGCCCGTC CGTGTTCCCCCTGGCACCTTGTAGCCGGAGC ACTAGCGAATCCACCGCTGCCCTCGGCTGCC TGGTCAAGGATTACTTCCCGGAGCCCGTGAC CGTCCT GGAACAGCGGAGCCCTGACCTCC GGAGTGCACACCTTCCCCGCTGTGCTGCAGA GCTCCGGGCTGTACTCGCTGTCGTCGGTGGT CACGGTGCCTTCATCTAGCCTGGGTACCAAG ACCTACACTTGCAACGTGGACCACAAGCCTT CCAACACTAAGGTGGACAAGCGCGTCGAATC GAAGTACGGCCCACCGTGCCCGCCTTGTCCC GCGCCGGAGTTCCTCGGCGGTC CCTCGGTCT TTCTGTTCCCACCGAAGCCCAAGGACACTTT GATGATTTCCCGCACCCCTGAAGTGACATGC GTGGTCGTGGACGTGTCACAGGAAGATCCGG AGGTGCAGTTCAATTGGTACGTGGATGGCGT CGAGGTGCACAACGCCAAAACCAAGCCGAG GGAGGAGCAGTTCAACTCCACTTACCGCGTC GTGTCCGTGCTGACGGTGCTGCATCAGGACT

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GGCTGAACGGGAAGGAGTACAAGTGCAAAG TGTCCAACAAGGGACTTCCTAGCTCAATCGA AAAGACCATCTCGAAAGCCAAGGGACAGCC CCGGGAACCCCAAGTGTATACCCTGCCACCG AGCCAGGAAGAAATGACTAAGAACCAAGTC TCATTGACTTGCCTTGTGAAGGGCTTCTACCC ATCGGATATCGCCGTGGAATGGGAGTCCAAC GGCCAGCCGGAAAACAACTACAAG ACCACC CCTCCGGTGCTGGACTCAGACGGATCCTTCTT CCTCTACTCGCGGCTGACCGTGGATAAGAC AGATGGCAGGAGGGAAATGTGTTCAGCTGTT CTGTGATGCATGAAGCCCTGCACAACCACTA CACTCAGAAGTCCCTGTCCCTCTCCCTGGGA LC VAR049-clone-B SEQ GO NO: 510 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 511 (Kabat) LCDR2 WASTRES SEQ ID NO: 512 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 513 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 514 (Chothia) LCDR2 W.A.S. SEQ ID NO: 515 (Chothia) LCDR3 DYSYPY SEQ ID NO: 516 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGN QKNFLTWYQQKPGKAPKLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSY PYTFGQGTKVEIK SEQ ID NO: 517 DNA encoding VL GAGATCGTCCTGACTCAGTCACCCGCTACCC TGAGCCTGAGCCCTGGCGAGCGGGCTACACT GAGCTGTAAATCTAGTCAGTCACTGCTGGAT AGCGGTAATCAGAAGAACTTCCTGACCTGGT ATCAGCAGAAGCCCGGTAAAGCCCCTAAGCT GCTGATCTACTGGGCCTCTACTAGAGAATCA GGCGTGCCCTCTAGGTTTAGCGGTAGCGGTA GTGGCACCGACTTC ACCTTCACTATCTCTAGC CTGCAGCCCGAGGATATCGCTACCTACTACT GTCAGAACGACTATAGCTACCCCTACACCTT CGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 518 Light chain EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGN QKNFLTWYQQKPGKAPKLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSY PYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSG

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TASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC SEQ GO NO: 519 DNA encoding the light chain GAGATCGTCCTGACTCAGTCACCCGCTACCC TGAGCCTGAGCCCTGGCGAGCGGGCTACACT GAGCTGTAAATCTAGTCAGTCACTGCTGGAT AGCGGTAATCAGAAGAACTTCCTGACCTGGT ATCAGCAGAAGCCCGGTAAAGCCCCTAAGCT GCTGATCTACTGGGCCTCTACTAGAGAATCA GGCGTGCCCTCTAGGTTTAGCGGTAGCGGTA GTGGCACCGACTTC ACCTTCACTATCTCTAGC CTGCAGCCCGAGGATATCGCTACCTACTACT GTCAGAACGACTATAGCTACCCCTACACCTT CGGTCAAGGCACTAAGGTCGAGATTAAGCGT ACGGTGGCCGCTCCCAGCGTGTTCATCTTCCC CCCCAGCGACGAGCAGCTGAAGAGCGGCAC CGCCAGCGTGGTGTGCCTGCTGAACAACTTC TACCCCCGGGAGGCCAAGGTGCAGTGGAAG CGCCCTGCAGAGCGGCAACAGC CAGGAGAGCGTCACCGAGCAGGACAGCAAG GACTCCACCTACAGCCTGAGCAGCACCCTGA CCCTGAGCAAGGCCGACTACGAGAAGCATA AGGTGTACGCCTGCGAGGTGACCCACCAGGG CCTGTCCAGCCCCGTGACCAAGAGCTTCAAC AGGGGCGAGTGC NS VAR049-CLONE- E SEQ ID NO: 501 (Kabat) HCDR1 TYWMH SEQ ID NO: 502 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 503 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 504 (Chothia) HCDR1 GYTFTY SEQ ID NO: 505 (Chothia) HCDR2 YPGTGG SEQ ID NO: 503 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 506 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDE KFKNRVTITADKSTSTAYMELSSLRSEDTAVYY CTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 507 DNA encoding GAGGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAGCCCGGCGAGTCACTGAGAATTA

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VH GCTGTAAAGGTTCAGGCTACACCTTCACTAC CTACTGGATGCACTGGGTCCGCCAGGCTACC GGTCAAGGCCTCGAGTGGATGGGTAATATCT ACCCCGGCACCGGCGGCTCTAACTTCGACGA GAAGTTTAAGAATAGAGTGACTATCACCGCC GATAAGTCTACTAGCACCGCCTATATGGAAC TGTCTAGCCTGAGATCAGAGGACACCGCCGT CTACTACTGCACTAGGTGG ACTACCGGCACA GGCGCCTACTGGGGTCAAGGCACTACCGTGA CCGTGTCTAGC SEQ GO NO: 508 Heavy chain EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDE KFKNRVTITADKSTSTAYMELSSLRSEDTAVYY CTRWTTGTGAYWGQGTTVTVSSASTKGPSVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTKTCNVDHK PSNTKVDKRVESKYGPPCPP CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNG QPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 509 DNA encoding the heavy chain GAGGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAGCCCGGCGGTCACTGAGAATTA GCTGTAAAGGTTCAGGCTACACCTTCACTAC CTACTGGATGCACTGGGTCCGCCAGGCTACC GGTCAAGGCCTCGAGTGGATGGGTAATATCT ACCCCGGCACCGGCGGCTCTAACTTCGACGA GAAGTTTAAGAATAGAGTGACTATCACCGCC GATAAGTCTACTAGCACCGC CTATATGGAAC TGTCTAGCCTGAGATCAGAGGACACCGCCGT CTACTACTGCACTAGGTGGACTACCGGCACA GGCGCCTACTGGGGTCAAGGCACTACCGTGA CCGTGTCTAGCGCTAGCACTAAGGGCCCGTC CGTGTTCCCCCTGGCACCTTGTAGCCGGAGC ACTAGCGAATCCACCGCTGCCCTCGGCTGCC TGGTCAAGGATTACTTCCCGGAGCCCGTGAC CGTCCT GGAACAGCGGAGCCCTGACCTCC GGAGTGCACACCTTCCCCGCTGTGCTGCAGA GCTCCGGGCTGTACTCGCTGTCGTCGGTGGT CACGGTGCCTTCATCTAGCCTGGGTACCAAG ACCTACACTTGCAACGTGGACCACAAGCCTT CCAACACTAAGGTGGACAAGCGCGTCGAATC

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GAAGTACGGCCCACCGTGCCCGCCTTGTCCC GCGCCGGAGTTCCTCGGCGGTCCCTCGGTCT TTCTGTTCCCACCGAAGCCCAAGGACACTTT GATGATTTCCCGCACCCCTGAAGTGACATGC GTGGTCGTGGACGTGTCACAGGAAGATCCGG AGGTGCAGTTCAATTGGTACGTGGATGGCGT CGAGGTGCACAACGCCAAAACCAAGCCGAG GGAGGAGCAGTTCA ACTCCACTTACCGCGTC GTGTCCGTGCTGAACGTGCTGCATCAGGACT GGCTGAACGGGAAGGAGTACAAGTGCAAAG TGTCCAACAAGGGACTTCCTAGCTCAATCGA AAAGACCATCTCGAAAGCCAAGGGACAGCC CCGGGAACCCCAAGTGTATACCCTGCCACCG AGCCAGGAAGAAATGACTAAGAACCAAGTC TCATTGACTTGCCTTGTGAAGGGCTTCTACCC ATCGGATATC GCCGTGGAATGGGAGTCCAAC GGCCAGCCGGAAAACAACTACAAGACCACC CCTCCGGTGCTGGACTCAGACGGATCCTTCTT CCTCTACTCGCGGCTGACCGTGGATAAGAGC AGATGGCAGGAGGGAAATGTGTTCAGCTGTT CTGTGATGCATGAAGCCCTGCACAACCACTA CACTCAGAAGTCCCTGTCCCTCTCCCTGGGA LC VAR049-clone-E SEQ GO NO: 510 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 511 (Kabat) LCDR2 WASTRES SEQ ID NO: 512 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 513 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 514 (Chothia) LCDR2 W.A.S. SEQ ID NO: 515 (Chothia) LCDR3 DYSYPY SEQ ID NO: 520 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGN QKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 521 DNA encoding VL GAGATCGTCCTGACTCAGTCACCCGCTACCC TGAGCCTGAGCCCTGGCGAGCGGGCTACACT GAGCTGTAAATCTAGTCAGTCACTGCTGGAT AGCGGTAATCAGAAGAACTTCCTGACCTGGT ATCAGCAGAAGCCCGGTCAAGCCCCTAGACT GCTGATCTACTGGGCCTCTACTAGAGAATCA

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GGCGTGCCCTCTAGGTTTAGCGGTAGCGGTA GTGGCACCGACTTCACCTTCACTATCTCTAGC CTGGAAGCCGAGGACGCCGCTACCTACTACT GTCAGAACGACTATAGCTACCCCTACACCTT CGGTCAAGGCACTAAGGTCGAGATTAAG SEQ GO NO: 522 Light chain EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGN QKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYE KHKV YACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 523 DNA encoding the light chain GAGATCGTCCTGACTCAGTCACCCGCTACCC TGAGCCTGAGCCCTGGCGAGCGGGCTACACT GAGCTGTAAATCTAGTCAGTCACTGCTGGAT AGCGGTAATCAGAAGAACTTCCTGACCTGGT ATCAGCAGAAGCCCGGTCAAGCCCCTAGACT GCTGATCTACTGGGCCTCTACTAGAGAATCA GGCGTGCCCTCTAGGTTTAGCGGTAGCGGTA GTGGCACCGACTTCAC CTTCACTATCTCTAGC CTGGAAGCCGAGGACGCCGCTACCTACTACT GTCAGAACGACTATAGCTACCCCTACACCTT CGGTCAAGGCACTAAGGTCGAGATTAAGCGT ACGGTGGCCGCTCCCAGCGTGTTCATCTTCCC CCCCAGCGACGAGCAGCTGAAGAGCGGCAC CGCCAGCGTGGTGTGCCTGCTGAACAACTTC TACCCCCGGGAGGCCAAGGTGCAGTGGAAG CCCTGCAGAGCGGCAACAGC CAGGAGAGCGTCACCGAGCAGGACAGCAAG GACTCCACCTACAGCCTGAGCAGCACCCTGA CCCTGAGCAAGGCCGACTACGAGAAGCATA AGGTGTACGCTGCGAGGTGACCCACCAGGG CCTGTCCAGCCCCGTGACCAAGAGCTTCAAC AGGGGCGAGTGC NS VAR049-cloneB SEQ ID NO: 524 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 525 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACT TCGACGAGAAGTTTAAGAAT SEQ ID NO: 526 (Kabat) HCDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 527 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 528 HCDR2 TACCCCGGCACCGGCGGC

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(Chothia) SEQ GO NO: 526 (Chothia) HCDR3 TGGACTACCGGCACAGGCGCCTAC LC VAR049-clone-B SEQ ID NO: 529 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTA ATCAGAAGAACTTCCTGACC SEQ ID NO: 530 (Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 531 (Kabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 532 (Chothia) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGA AGAACTTC SEQ ID NO: 533 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 534 (Chothia) LCDR3 GACTATAGCTACCCCTAC NS VAR049-CLONE- E SEQ ID NO: 524 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 525 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACT TCGACGAGAAGTTTAAGAAT SEQ ID NO: 526 (Kabat) HCDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 527 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 528 (Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 526 (Chothia) HCDR3 TGGACTACCGGCACAGGCGCCTAC LC VAR049-clone-E SEQ ID NO: 529 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTA ATCAGAAGAACTTCCTGACC SEQ ID NO: 530 (Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 531 (Kabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 532 (Chothia) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGA AGAACTTC SEQ ID NO: 533 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 534 (Chothia) LCDR3 GACTATAGCTACCCCTAC

Other exemplary PD-1 inhibitors

In one embodiment, the anti-PD-1 antibody molecule is nivolumab (BristolMyers Squibb), also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®. Nivolumab (clone 5C4) and other anti-PD-1 antibodies are disclosed in US 8008449 and WO 2006/121168, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule contains one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a nivolumab heavy chain or light chain sequence, for example, those disclosed in table. 6.

In one embodiment, the anti-PD-1 antibody molecule is pembrolizumab (Merck & Co), also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA®. Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US 8354509 and WO 2009/114335, incorporated by reference in their entirety

- 191 047335 completeness. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a pembrolizumab heavy chain or light chain sequence, for example, those disclosed in Table 1. 6.

In one embodiment, the anti-PD-1 antibody molecule is pidilizumab (CureTech), also known as CT-011. Pidilizumab and other anti-PD-1 antibodies are disclosed in Rosenblatt, J. et al. (2011) J Immunotherapy 34(5): 409-18, US 7695715, US 7332582 and US 8686119, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a pidilizumab heavy chain or light chain sequence, such as those disclosed in Table 1. 6.

In one embodiment, the anti-PD-1 antibody molecule is MED10680 (Medimmune), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9205148 and WO 2012/145493, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a MEDI0680 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is REGN2810 (Regeneron). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a REGN2810 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence PF-06801591.

In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 or BGB-108 (Beigene). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a BGB-A317 or BGB-108 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an INCSFIR1210 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tesaro), also known as ANB011. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a TSR-042 heavy chain or light chain sequence.

Additional known anti-PD-1 antibodies include those described, for example, in WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119 , US 8735553, US 7488802, US 8927697, US 8993731 and US 9102727, incorporated by reference in their entirety.

In one embodiment, an anti-PD-1 antibody is an antibody that competes for and/or binds to the same epitope on PD-1 as one of the anti-PD-1 antibodies described herein.

In one embodiment, a PD-1 inhibitor is a peptide that inhibits a signaling pathway involving PD-1, for example, as described in US Pat. No. 8,907,053, incorporated by reference in its entirety. In one embodiment, the PD-1 inhibitor is an immunoadhesin (eg, an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (eg, an Fc region of an immunoglobulin sequence)). In one embodiment, the PD-1 inhibitor is AMP-224 (B7-DCIg (Amplimmune), for example, disclosed in WO 2010/027827 and WO 2011/066342, incorporated by reference in their entirety).

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Table 6

Amino acid sequences of other exemplary anti-PD-1 antibody molecules

Nivolumab SEQ ID NO: 535 Heavy chain QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVR QAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSK NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTK DHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNW YVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS QEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEA LHNHYTQKSLSLSLGK SEQ ID NO: 536 Light chain EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKP GQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPE DFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEV THQGLSSPVTKSFNRGEC Pembrolyse mab SEQ ID NO: 537 Heavy chain QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWV RQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSS TTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDI AVEWESNGQ PENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSC SVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 538 Light chain EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWY QQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTIS SLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYA CEVTHQGLSSPVTKSFNRGEC Pidilizuma 6 SEQ ID NO: 539 Heavy chain QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVR QAPGQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSV NTAYLQITSLTAEDTGMYFCVRVGYDALDYWGQGTLV

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TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 540 Light chain EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPG KAPKLWIYRTSNLASGVPSRFSGSGSGTSYCLTINSLQPE DFATYYCQQRSSFPLTFGGGTKLEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVT HQGLSSPVTKSFNRGEC

Exemplary PD-L1 inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a PD-L1 inhibitor. The PD-L1 inhibitor may be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. In some embodiments, the PD-L1 inhibitor is selected from FAZ053 (Novartis), atezolizumab (Genentech/Roche), avelumab (Merck Serono and Pfizer), durvalumab (MedImmune/AstraZeneca), or BMS-936559 (Bristol-Myers Squibb).

Exemplary Anti-PD-L1 Antibody Molecules

In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule disclosed in US 2016/0108123, published April 21, 2016, entitled Antibody Molecules to PDL1 and Uses Thereof, incorporated by reference in its entirety.

In one embodiment, an anti-PD-L1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all CDRs) of a heavy and light chain variable region comprising an amino acid sequence, shown in table. 7 (for example, from the variable region sequences of the heavy and light chains of BAP058-clone O or BAP058-clone N, disclosed in Table 7), or encoded by the nucleotide sequence shown in table. 7. In some embodiments, CDRs are defined in accordance with the Kabat numbering scheme (eg, as set forth in Table 7). In some embodiments, the CDRs are defined in accordance with the Chothia numbering scheme (eg, as set forth in Table 7). In some embodiments, CDRs are defined in accordance with a combined Kabat and Chothia CDR numbering scheme (eg, as set forth in Table 7). In one embodiment, CDR1 VH according to the combined Kabat and Chothia CDR numbering scheme contains the amino acid sequence GYTFTSYWMY (SEQ ID NO: 647). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequence, shown in table. 7, or the encoded nucleotide sequence shown in table. 7.

In one embodiment, an anti-PD-L1 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 601, the amino acid sequence of VHCDR2 of SEQ ID NO: 602, and the amino acid sequence of VHCDR3 of SEQ ID NO: 603; and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 of SEQ ID NO: 609, the amino acid sequence of VLCDR2 of SEQ ID NO: 610 and the amino acid sequence of VLCDR3 of SEQ ID NO: 611, each of which is disclosed in table. 7.

In one embodiment, an anti-PD-L1 antibody molecule comprises a VH comprising VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 628, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 629, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 630 ; and VL, comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 633, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 634, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 635, each of which is disclosed in table. 7.

In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 606, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity

- 194 047335 features with SEQ ID NO: 606. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 616, or an amino acid sequence characterized by at least about 85%, 90%, 95 %, or 99% or greater sequence identity to SEQ ID NO: 616. In one embodiment, the anti-PD-L1 antibody molecule contains a VH containing the amino acid sequence of SEQ ID NO: 620, or an amino acid sequence characterized by at least about 85% , 90%, 95%, or 99% sequence identity to SEQ ID NO: 620. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 624, or an amino acid sequence characterized by at least approximately 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 624. In one embodiment, an anti-PD-L1 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 606, and a VL containing the amino acid sequence the sequence of SEQ ID NO: 616. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 620 and a VL comprising the amino acid sequence of SEQ ID NO: 624.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 607, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 607. In one in an embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 617, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 617. In one embodiment the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 621, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 621. In one embodiment, the antibody molecule contains a VL encoded by the nucleotide sequence of SEQ ID NO: 625, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 625. In one embodiment, the antibody molecule contains a VH , encoded by the nucleotide sequence of SEQ ID NO: 607, and VL, encoded by the nucleotide sequence of SEQ ID NO: 617. In one embodiment, the antibody molecule comprises VH, encoded by the nucleotide sequence of SEQ ID NO: 621, and VL, encoded by the nucleotide sequence of SEQ ID NO: 625.

In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 608, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 608. In one embodiment, the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 618, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% identity sequences with SEQ ID NO: 618. In one embodiment, the anti-PD-L1 antibody molecule contains a heavy chain containing the amino acid sequence of SEQ ID NO: 622, or an amino acid sequence characterized by at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 622. In one embodiment, the anti-PD-L1 antibody molecule contains a light chain comprising the amino acid sequence of SEQ ID NO: 626, or an amino acid sequence characterized by at least about 85%, 90% , 95%, or 99% sequence identity to ID NO: 626. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 608 and a light chain comprising the amino acid sequence of SEQ ID NO: : 618. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 622 and a light chain comprising the amino acid sequence of SEQ ID NO: 626.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 615, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 615. B In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 619, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 619. In one in an embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 623, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 623. In one embodiment An antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 627, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 627. In one embodiment the antibody molecule contains a heavy chain encoded by the nucleotide

- 195 047335 by the tide sequence of SEQ ID NO: 615, and a light chain encoded by the nucleotide sequence of SEQ ID NO: 619. In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 623, and a light chain, encoded by the nucleotide sequence under SEQ ID NO: 627.

The antibody molecules described herein can be produced using the vectors, host cells and methods described in US 2016/0108123, incorporated by reference in its entirety.

Table 7

Amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules

NS VAR058-CLONE ABOUT SEQ ID NO: 601 (Kabat) HCDR1 SYWMY SEQ ID NO: 602 (Kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 603 HCDR3 DYRKGLYAMDY

- 196 047335

(Kabat) SEQ ID NO: 604 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 605 (Chothia) HCDR2 DPNSGS SEQ ID NO: 603 (Chothia) HCDR3 DYRKGLYAMDY SEQ ID NO: 606 VH EVQLVQSGAEVKKPGATVKISCKVSGYTFTS YWMYWVRQARGQRLEWIGRIDPNSGSTKYN EKFKNRFTISRDNSKNTLYLQMNSLRAEDTA VYYCARDYRKGLYAMDYWGQGTTVTVSS SEQ ID NO: 607 DNA encoding VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAACCCGGCGCTACCGTGAAGATT AGCTGTAAAGTCTCAGGCTACACCTTCACT AGCTACTGGATGTACTGGGTCCGACAGGCT AGAGGGCAAAGACTGGAGTGGATCGGTAG AATCGACCCTAATAGCGGCTCTACTAAGTA TAACGAGAAGTTTAAGAATAGGTTCACTAT TAGTAGGGATAACTCTAAGAACAC CCTGTA CCTGCAGATGAATAGCCTGAGAGCCGAGGA CACCGCCGTCTACTACTGCGCTAGAGACTA TAGAAAGGGCCTGTACGCTATGGACTACTG GGGTCAAGGCACTACCGTGACCGTGTCTTC A SEQ ID NO: 608 Heavy chain EVQLVQSGAEVKKPGATVKISCKVSGYTFTS YWMYWVRQARGQRLEWIGRIDPNSGSTKYN EKFKNRFTISRDNSKNTLYLQMNSLRAEDTA VYYCARDYRKGLYAMDYWGQGTTVTVSSAS TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS SSSLGTKTYTCNVDHKPSNTKVDKRV ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTL MISRPTPEVTCVVVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE

- 197 047335

PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQ KSLSLSLG SEQ GO NO: 615 DNA encoding the heavy chain GAAGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAACCCGGCGCTACCGTGAAGATT AGCTGTAAAGTCTCAGGCTACACCTTCACT AGCTACTGGATGTACTGGGTCCGACAGGCT AGAGGGCAAAGACTGGAGTGGATCGGTAG AATCGACCCTAATAGCGGCTCTACTAAGTA TAACGAGAAGTTTAAGAATAGGTTCACTAT TAGTAGGGATAACTCTAAGAACAC CCTGTA CCTGCAGATGAATAGCCTGAGAGCCGAGGA CACCGCCGTCTACTACTGCGCTAGAGACTA TAGAAAGGGCCTGTACGCTATGGACTACTG GGGTCAAGGCACTACCGTGACCGTGTCTTC AGCTAGCACTAAGGGCCCGTCCGTGTTCCC CCTGGCACCTTGTAGCCGGAGCACTAGCGA ATCCACCGCTGCCCTCGGCTGCCTGGTCAA GGATTACTTCCCGGAGCCCGTGACCGTG TC CTGGAACAGCGGAGCCCTGACCTCCGGAGT GCACACCTTCCCCGCTGTGCTGCAGAGCTCC GGGCTGTACTCGCTGTCGTCGGTGGTCACG GTGCCTTCATCTAGCCTGGGTACCAAGACCT ACACTTGCAACGTGGACCACAAGCCTTCCA ACACTAAGGTGGACAAGCGCGTCGAATCGA AGTACGGCCCACCGTGCCCGCCTTGTCCCG CGCCGGAGTTCCTCGGC GGTCCCTCGGTCTT TCTGTTCCCACCGAAGCCCAAGGACACTTT GATGATTTCCCGCACCCCTGAAGTGACATG CGTGGTCGTGGACGTGTCACAGGAAGATCC GGAGGTGCAGTTCAATTGGTACGTGGATGG CGTCGAGGTGCACAACGCCAAAACCAAGCC GAGGGAGGAGCAGTTCAACTCCACTTACCG CGTCGTGTCCGTGCTGACGGTGCTGCATCA

- 198 047335

AC AAGACCACCCCTCCGGTGCTGGACTCAG ACGGATCCTTCTTCCTCTACTCGCGGCTGAC CGTGGATAAGAGCAGATGGCAGGAGGGAA ATGTGTTCAGCTGTTCTGTGATGCATGAAGC CCTGCACAACCACTACACTCAGAAGTCCCT GTCCCCTCCCTGGGA LC VAR058-clone O SEQ ID NO: 609 (Kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 610 (Kabat) LCDR2 WASTRHT SEQ ID NO: 611(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 612 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 613 (Chothia) LCDR2 W.A.S. SEQ ID NO: 614 (Chothia) LCDR3 YNSYPL SEQ ID NO: 616 VL AIQLTQSPSSLSASVGDRVTITCKASQDVGTA VAWYLQKPGQSPQLLIYWASTRHTGVPSRFS GSGSGTDFTFTISSLEAEDAATYYCQQYNSYP LTFGQGTKVEIK SEQ ID NO: 617 DNA encoding VL GCTATTCAGCTGACTCAGTCACCTAGTAGCC TGAGCGCTAGTGTGGGCGATAGAGTGACTA TCACCTGTAAAGCCTCTCAGGACGTGGGCA

- 199 047335

CCGCCGTGGCCTGGTATCTGCAGAAGCCTG GTCAATCACCTCAGCTGCTGATCTACTGGGC CTCTACTAGACACACCGGCGTGCCCTCTAG GTTTAGCGGTAGCGGTAGTGGCACCGACTT CACCTTCACTATCTCTTCACTGGAAGCCGAG GACGCCGCTACCTACTACTGTCAGCAGTAT AATAGCTACCCCCTGACCTTTCGGTCAAGGC ACTAAGGTCGAGATTAAG SEQ GO NO: 618 Light chain AIQLTQSPSSLSASVGDRVTITCKASQDVGTA VAWYLQKPGQSPQLLIYWASTRHTGVPSRFS GSGSGTDFTFTISSLEAEDAATYYCQQYNSYP LTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEK HK VYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 619 DNA encoding the light chain GCTATTCAGCTGACTCAGTCACCTAGTAGCC TGAGCGCTAGTGTGGGCGATAGAGTGACTA TCACCTGTAAAGCCTCTCAGGACGTGGGCA CCGCCGTGGCCTGGTATCTGCAGAAGCCTG GTCAATCACCTCAGCTGCTGATCTACTGGGC CTCTACTAGACACACCGGCGTGCCCTCTAG GTTTAGCGGTAGCGGTAGTGGCACCGACTT CACCTTCACTATCTCTTCACTGGAA GCCGAG GACGCCGCTACCTACTACTGTCAGCAGTAT AATAGCTACCCCCTGACCTTCGGTCAAGGC ACTAAGGTCGAGATTAAGCGTACGGTGGCC GCTCCCAGCGTGTTCATCTTCCCCCCCAGCG ACGAGCAGCTGAAGAGCGGCACCGCCAGC GTGGTGTGCCTGCTGAACAACTTCTACCCCCC GGGAGGCCAAGGTGCAGTGGAAGGTGGAC AACGCCCTGCAGAGC GGCAACAGCCAGGA GAGCGTCACCGAGCAGGACAGCAAGGACTC CACCTACAGCCTGAGCAGCACCCTGACCCT GAGCAAGGCCGACTACGAGAAGCATAAGG TGTACGCCTGCGAGGTGACCCACCAGGGCC

- 200 047335

TGTCCAGCCCCGTGACCAAGAGCTTCAACA GGGGCGAGTGC NS VAR058-CLONE N SEQ ID NO: 601 (Kabat) HCDR1 SYWMY SEQ ID NO: 602 (Kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 603 (Kabat) HCDR3 DYRKGLYAMDY SEQ ID NO: 604 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 605 (Chothia) HCDR2 DPNSGS SEQ ID NO: 603 (Chothia) HCDR3 DYRKGLYAMDY SEQ ID NO: 620 VH EVQLVQSGAEVKKPGATVKISCKVSGYTFTS YWMYWVRQATGQGLEWMGRIDPNSGSTKY NEKFKNRVTITADKSTSTAYMELSSLRSEDTA VYYCARDYRKGLYAMDYWGQGTTVTVSS SEQ ID NO: 621 DNA encoding VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAACCCGGCGCTACCGTGAAGATTT AGCTGTAAAGTCTCAGGCTACACCTTCACT AGCTACTGGATGTACTGGGTCCGACAGGCT ACCGGTCAAGGCCTGGAGTGGATGGGTAGA ATCGACCCTAATAGCGGCTCTACTAAGTAT AACGAGAAGTTTAAGAATAGAGTGACTATC ACCGCCGATAAGTCTACTAGCACCGCCTAT ATGGAACTGTCTAGCCTGAGATCAGAGGAC ACCGCCGTCTACTACTGCGCTAGAGACTAT AGAAAGGGCCTGTACGCTATGGACTACTGG GGTCAAGGCACTACCGTGACCGTGTCTTCA SEQ ID NO: 622 Heavy chain EVQLVQSGAEVKKPGATVKISCKVSGYTFTS YWMYWVRQATGQGLEWMGRIDPNSGSTKY

- 201 047335

NEW ISRTPEVTCVVVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALH NHYTQ KSLSLSLG SEQ GO NO: 623 DNA encoding the heavy chain GAAGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAACCCGGCGCTACCGTGAAGATT AGCTGTAAAGTCTCAGGCTACACCTTCACT AGCTACTGGATGTACTGGGTCCGACAGGCT ACCGGTCAAGGCCTGGAGTGGATGGGTAGA ATCGACCCTAATAGCGGCTCTACTAAGTAT AACGAGAAGTTTAAGAATAGAGTGACTATC ACCGCCGATAAGTCTACTAGCACCGC CTAT ATGGAACTGTCTAGCCTGAGATCAGAGGAC ACCGCCGTCTACTACTGCGCTAGAGACTAT AGAAAGGGCCTGTACGCTATGGACTACTGG GGTCAAGGCACTACCGTGACCGTGTCTTCA GCTAGCACTAAGGGCCCGTCCGTGTTCCCC CTGGCACCTTGTAGCCGGAGCACTAGCGAA TCCACCGCTGCCCTCGGCTGCCTGGTCAAG GATTACTTCCCGGAGCCCGTGACCGTG TCCT GGAACAGCGGAGCCCTGACCTCCGGAGTGC ACACCTTCCCCGCTGTGCTGCAGAGCTCCG GGCTGTACTCGCTGTCGTCGGTGGTCACGGT GCCTTCATCTAGCCTGGGTACCAAGACCTA CACTTGCAACGTGGACCACAAGCCTTCCAA CACTAAGGTGGACAAGCGCGTCGAATCGAA

- 202 047335

GTACGGCCCACCGTGCCCGCCTTGTCCCGC GCCGGAGTTCCTCGGCGGTCCCTCGGTCTTT CTGTTCCCACCGAAGCCCAAGGACACTTTG ATGATTTCCCGCACCCCTGAAGTGACATGC GTGGTCGTGGACGTGTCACAGGAAGATCCG GAGGTGCAGTTCAATTGGTACGTGGATGGC GTCGAGGTGCACAACGCCAAAACCAAGCCG AGGGAGGAGCAGTTCAACTCC ACTTACCGC GTCGTGTCCGTGCTGACGGTGCTGCATCAG GACTGGCTGAACGGGAAGGAGTACAAGTGC AAAGTGTCCAACAAGGGACTTCCTAGCTCA ATCGAAAAGACCATCTCGAAAGCCAAGGGA CAGCCCCGGGAACCCCAAGTGTATACCCTG CCACCGAGCCAGGAAGAAATGACTAAGAA CCAAGTCTCATTGACTTGCCTTGTGAAGGGC TTCTACCCATCGGATATCGCCGTG GAATGG GAGTCCAACGGCCAGCCGGAAAACAACTAC AAGACCACCCCTCCGGTGCTGGACTCAGAC GGATCCTTCTTCCTACTCGCGGCTGACCG TGGATAAGAGCAGATGGCAGGAGGGAAAT GTGTTCAGCTGTTCTGTGATGCATGAAGCCC TGCACAACCACTACACTCAGAAGTCCCTGT CCCCTCCCTGGGA LC VAR058-clone N SEQ ID NO: 609 (Kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 610 (Kabat) LCDR2 WASTRHT SEQ ID NO: 611(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 612 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 613 (Chothia) LCDR2 W.A.S.

- 203 047335

SEQ ID NO: 614 (Chothia) LCDR3 YNSYPL SEQ ID NO: 624 VL DVVMTQSPLSLPVTLGQPASISCKASQDVGTA VAWYQQKPGQAPRLLIYWASTRHTGVPSRFS GSGSGTEFTLTISSLQPDDFATYYCQQYNSYP LTFGQGTKVEIK SEQ ID NO: 625 DNA encoding VL GACGTCGTGATGACTCAGTCACCCCTGAGC CTGCCCGTGACCCTGGGGCAGCCCGCCTCT ATTAGCTGTAAAGCCTCTCAGGACGTGGGC ACCGCCGTGGCCTGGTATCAGCAGAAGCCA GGGCAAGCCCCTAGACTGCTGATCTACTGG GCCTCTACTAGACACACCGGCGTGCCCTCT AGGTTTAGCGGTAGCGGTAGTGGCACCGAG TTCACCCTGACTATCTCTTCACTGC AGCCCG ACGACTTCGCTACCTACTACTGTCAGCAGTA TAATAGCTACCCCCTGACCTTTCGGTCAAGG CACTAAGGTCGAGATTAAG SEQ ID NO: 626 Light chain DVVMTQSPLSLPVTLGQPASISCKASQDVGTA VAWYQQKPGQAPRLLIYWASTRHTGVPSRFS GSGSGTEFTLTISSLQPDDFATYYCQQYNSYP LTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYE KHK VYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 627 DNA encoding the light chain GACGTCGTGATGACTCAGTCACCCCTGAGC CTGCCCGTGACCCTGGGGCAGCCCGCCTCT ATTAGCTGTAAAGCCTCTCAGGACGTGGGC ACCGCCGTGGCCTGGTATCAGCAGAAGCCA GGGCAAGCCCCTAGACTGCTGATCTACTGG GCCTCTACTAGACACACCGGCGTGCCCTCT AGGTTTAGCGGTAGCGGTAGTGGCACCGAG TTCACCCTGACTATCTCTTCACTGC AGCCCG ACGACTTCGCTACCTACTACTGTCAGCAGTA TAATAGCTACCCCCTGACCTTTCGGTCAAGG CACTAAGGTCGAGATTAAGCGTACGGTGGC

- 204 047335

CGCTCCCAGCGTGTTCATCTTCCCCCCCAGC GACGAGCAGCTGAAGAGCGGCACCGCCAG CGTGGTGTGCCTGCTGAACAACTTCTACCCC CGGGAGGCCAAGGTGCAGTGGAAGGTGGA CAACGCCCTGCAGAGCGGCAACAGCCAGGA GAGCGTCACCGAGCAGGACAGCAAGGACTC CACCTACAGCCTGAGCAGCACCCTGACCCT GAGCAAGGCCGACTACGAGAAGCATAA GG TGTACGCTGCGAGGTGACCCACCAGGGCC TGTCCAGCCCCGTGACCAAGAGCTTCAACA GGGGCGAGTGC NS VAR058-CLONE ABOUT SEQ ID NO: 628 (Kabat) HCDR1 agctactggatgtac SEQ ID NO: 629 (Kabat) HCDR2 agaatcgaccctaatagcggctctactaagtataacgagaagtttaagaa t SEQ ID NO: 630 (Kabat) HCDR3 gactatagaaagggcctgtacgctatggactac SEQ ID NO: 631 (Chothia) HCDR1 ggctacaccttcactagctac SEQ ID NO: 632 (Chothia) HCDR2 gaccctaatagcggctct SEQ ID NO: 630 (Chothia) HCDR3 gactatagaaagggcctgtacgctatggactac LC VAR058-clone O SEQ ID NO: 633 (Kabat) LCDR1 aaagcctctcaggacgtgggcaccgccgtggcc SEQ ID NO: 634 (Kabat) LCDR2 tggggcctctactagacacacc SEQ ID NO: 635 (Kabat) LCDR3 cagcagtataatagctaccccctgacc SEQ ID NO: 636 (Chothia) LCDR1 tctcaggacgtgggcaccgcc

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SEQ ID NO: 637 (Chothia) LCDR2 tggggcctct SEQ ID NO: 638 (Chothia) LCDR3 tataatagctaccccctg NS VAR058-clone N SEQ ID NO: 628 (Kabat) HCDR1 agctactggatgtac SEQ ID NO: 629 (Kabat) HCDR2 agaatcgaccctaatagcggctctactaagtataacgagaagtttaagaa t SEQ ID NO: 630 (Kabat) HCDR3 gactatagaaagggcctgtacgctatggactac SEQ ID NO: 631 (Chothia) HCDR1 ggctacaccttcactagctac SEQ ID NO: 632 (Chothia) HCDR2 gaccctaatagcggctct SEQ ID NO: 630 (Chothia) HCDR3 gactatagaaagggcctgtacgctatggactac LC VAR058-clone N SEQ ID NO: 633 (Kabat) LCDR1 aaagcctctcaggacgtgggcaccgccgtggcc SEQ ID NO: 634 (Kabat) LCDR2 tggggcctctactagacacacc SEQ ID NO: 635 (Kabat) LCDR3 cagcagtataatagctaccccctgacc SEQ ID NO: 636 (Chothia) LCDR1 tctcaggacgtgggcaccgcc SEQ ID NO: 637 (Chothia) LCDR2 tggggcctct SEQ ID NO: 638 (Chothia) LCDR3 tataatagctaccccctg

Other exemplary PD-L1 inhibitors

In one embodiment, the anti-PD-1 antibody molecule is atezolizumab (Genentech/Roche), also known as MPDL3280A, RG7446, RO5541267, YW243.55.S70, or TECENTRIQ™. Atezolizumab and other anti-PD-L1 antibodies are disclosed in US 8,217,149, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an atezolizumab heavy chain or light chain sequence, for example, those disclosed in Table. 8.

In one embodiment, the anti-PD-L1 antibody molecule is avelumab (Merck Serono and Pfizer), also known as MSB0010718C. Avelumab and other anti-PD-L1 antibodies are disclosed in WO 2013/079174, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an avelumab heavy chain or light chain sequence, for example, those disclosed in Table. 8.

In one embodiment, the anti-PD-L1 antibody molecule is durvalumab

- 206 047335 (Medlmmune/AstraZeneca), also known as MEDI4736. Durvalumab and other anti-PD-L1 antibodies are disclosed in US 8,779,108, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a durvalumab heavy chain or light chain sequence, for example, those disclosed in Table 1. 8.

In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (Bristol-Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-L1 antibodies are disclosed in US 7943743 and WO 2015/081158, incorporated by reference in their entirety. In one embodiment, the anti-PD-L1 antibody molecule contains one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence BMS936559, for example, disclosed in table. 8.

Additional known anti-PD-L1 antibodies include those described, for example, in WO 2015/181342, WO 2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO 2013/07917 4, WO 2012/145493, WO 2015/112805, WO 2015/109124, WO 2015/195163, US 8168179, US 8552154, US 8460927 and US 9175082, incorporated by reference in their entirety.

In one embodiment, an anti-PD-L1 antibody is an antibody that competes for and/or binds to the same epitope on PD-L1 as one of the anti-PD-L1 antibodies described herein.

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Table 8

Amino acid sequences of other exemplary anti-PD-L1 antibody molecules

Atesolisum ab SEQ ID NO: 639 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQ APGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNT AYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK SEQ ID NO: 640 Light chain DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQK PGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTH QGLSSPVTKSFNRGEC Avelumab SEQ ID NO: 641 Heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQ APGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT Q TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK SEQ ID NO: 642 Light chain QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQ HPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTV TLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPV KAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ VTHEGSTVEKTVAPTECS Durvalumab SEQ ID NO: 643 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGTFFSRYWMSWVR QAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKN SLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGT

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LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP EFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQ DWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK SEQ ID NO: 644 Light chain EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQK PGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPE DFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTH QGLSSPVTKSFNRGEC BMS-936559 SEQ ID NO: 645 VH QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQ APGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTSTA YMELSSLRSEDTAVYFCARKFHFVSSGSPFGMDVWGQGTT VTVSS SEQ ID NO: 646 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKP GQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPED FAVYYCQQRSNWPTFGQGTKVEIK

Exemplary LAG-3 Inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a LAG-3 inhibitor known in the art. The LAG-3 inhibitor may be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. In some embodiments, the LAG-3 inhibitor is selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), TSR-033 (Tesaro), MK-4280 (Merck & Co), or REGN3767 (Regeneron).

Exemplary anti-LAG-3 antibody molecules

In one embodiment, the LAG-3 inhibitor is an anti-LAG3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule disclosed in US 2015/0259420, published September 17, 2015, entitled Antibody Molecules to LAG-3 and Uses Thereof, incorporated by reference in its entirety.

In one embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all CDRs) of a heavy and light chain variable region comprising an amino acid sequence, shown in table. 9 (for example, from the variable region sequences of the heavy and light chains of BAP050 clone I or BAP050 clone J disclosed in Table 9), or encoded by the nucleotide sequence shown in table. 9. In some embodiments, CDRs are defined in accordance with the Kabat numbering scheme (eg, as set forth in Table 9). In some embodiments, the CDRs are defined in accordance with the Chothia numbering scheme (eg, as set forth in Table 5). In some embodiments, CDRs are defined in accordance with a combined Kabat and Chothia CDR numbering scheme (eg, as set forth in Table 9). In one embodiment, CDR1 VH according to the combined Kabat and Chothia CDR numbering scheme contains the amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequence, shown in table. 9, or the encoded nucleotide sequence shown in table. 9.

In one embodiment, an anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 701, the amino acid sequence of VHCDR2 of SEQ ID NO: 702, and the amino acid sequence of VHCDR3 of SEQ ID NO: 703; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 710, the amino acid sequence of VLCDR2 of SEQ ID NO: 711 and the amino acid sequence of VLCDR3 of SEQ ID NO: 712, each of which is disclosed in table. 9.

In one embodiment, the anti-LAG-3 antibody molecule contains a VH containing

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VHCDR1, encoded by the nucleotide sequence of SEQ ID NO: 736 or 737, VHCDR2, encoded by the nucleotide sequence of SEQ ID NO: 738 or 739, and VHCDR3, encoded by the nucleotide sequence of SEQ ID NO: 740 or 741; and VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751, each of which is disclosed in table. 9. In one embodiment, an anti-LAG-3 antibody molecule comprises a VH comprising VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 758 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 759 or 739, and VHCDR3 encoded by the nucleotide sequence under SEQ ID NO: 760 or 741; and VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751, each of which is disclosed in table. 9.

In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 706, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: : 706. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 718, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 718. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 724, or an amino acid sequence characterized by at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 724. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 730, or an amino acid sequence characterized by at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 730. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 706 and a VL comprising the amino acid sequence of SEQ ID NO: 718. In one In an embodiment, the anti-LAG-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 724, and a VL containing the amino acid sequence of SEQ ID NO: 730.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 707 or 708. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 725 or 726. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 731 or 732. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708, and a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule contains VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726, and VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732.

In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 709, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 709. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 721, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% identity sequences with SEQ ID NO: 721. In one embodiment, the anti-LAG-3 antibody molecule contains a heavy chain containing the amino acid sequence of SEQ ID NO: 727, or an amino acid sequence characterized by at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 727. In one embodiment, the anti-LAG-3 antibody molecule contains a light chain comprising the amino acid sequence of SEQ ID NO: 733, or an amino acid sequence characterized by at least about 85%, 90% , 95%, or 99% identical follower

- 210 047335 features with SEQ ID NO: 733. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 709 and a light chain comprising the amino acid sequence of SEQ ID NO: 721. B In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 727 and a light chain comprising the amino acid sequence of SEQ ID NO: 733.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 716 or 717. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 728 or 729. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735, or a nucleotide sequence characterized by at least about 85%, 90%, 95%, or 99 % sequence identity to SEQ ID NO: 734 or 735. In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717, and a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729, and a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735.

The antibody molecules described herein can be produced using the vectors, host cells and methods described in US 2015/0259420, incorporated by reference in its entirety.

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Table 9

Amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules

NS VAR050-clone I SEQ ID NO: 701 (Kabat) HCDR1 NYGMN SEQ ID NO: 702 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 703 (Kabat) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 704 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 705 (Chothia) HCDR2 NTDTGE SEQ ID NO: 703 (Chothia) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO:706 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGM NWVRQARGQRLEWIGWINTDTGEPTYADDFKGRF VFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYY YGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 707 DNA encoding VH CAAGTGCAGCTGGTGCAGTCGGGAGCCGAAGTG AAGAGCCTGGAGCCTCGGTGAAGGTGTCGTGC AAGGCATCCGGATTCACCCTCACCAATTACGGGA TGAACTGGGTCAGACAGGCCCGGGGTCAACGGC TGGAGTGGATCGGATGGATTAACACCGACACCG GGGAGCCTACCTACGCGGACGATTTCAAGGGAC GGTTCGTGTTCTCCCTCGACACCTCCGTGTCCA C CGCCTACCTCCAAATCTCCTCACTGAAAGCGGAG GACACCGCCGTGTACTATTGCGCGAGGAACCCG CCCTACTACTACGGAACCAACAACGCCGAAGCC ATGGACTACTGGGGCCAGGGCACCACTGTGACT GTGTCCAGC SEQ ID NO: 708 DNA, encode CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTG AAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGC

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shaya VH C TTACTACTACGGCACCAACAACGCCGAGGCCAT GGACTATTGGGGCCAGGCACCACCGTGACCGT GTCCTCT SEQ GO NO: 709 Heavy chain QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGM NWVRQARGQRLEWIGWINTDTGEPTYADDFKGRF VFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYY YGTNNAEAMDYWGQGTTVTVSSASTKGPSVFPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSS SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQF NWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ GO NO: 716 DNA encoding the heavy chain CAAGTGCAGCTGGTGCAGTCGGGAGCCGAAGTG AAGAGCCTGGAGCCTCGGTGAAGGTGTCGTGC AAGGCATCCGGATTCACCCTCACCAATTACGGGA TGAACTGGGTCAGACAGGCCCGGGGTCAACGGC TGGAGTGGATCGGATGGATTAACACCGACACCG GGGAGCCTACCTACGCGGACGATTTCAAGGGAC GGTTCGTGTTCTCCCTCGACACCTCCGTGTCCA c CCGGAGCCCGTGACCGTGTCCTGGAACA GCGGAGCCCTGACCTCCGGAGTGCACACCTTCCC CGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTG TCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGG GTACCAAGACCTACACTTGCAACGTGGACCACA AGCCTTCCAACACTAAGGTGGACAAGCGCGTCG AATCGAAGTACGGCCCACCGTGCCCGCCTTGTCC CCGGAGTTCCTCGGCGGTCCCTCGGTCTTT

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CTGTTCCCACCGAAGCCCAAGGACACTTTGATGA TTTCCCGCACCCCTGAAGTGACATGCGTGGTCGT GGACGTGTCACAGGAAGATCCGGAGGTGCAGTT CAATTGGTACGTGGATGGCGTCGAGGTGCACAA CGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAA CTCCACTTACCGCGTCGTGTCCGTGCTGACGTG CTGCATCAGGACTGGCTGAACGGGAAG GAGTAC AAGTGCAAAGTGTCCAACAAGGGACTTCCTAGC TCAATCGAAAAGACCATCTCGAAAGCCAAGGGA CAGCCCCGGGAACCCCAAGTGTATACCCTGCCAC CGAGCCAGGAAGAAATGACTAAGAACCAAGTCT CATTGACTTGCCTTGTGAAGGGCTTCTACCCATC GGATATCGCCGTGGAATGGGAGTCCAACGGCCA GCCGGAAAACAACTACAAGACCACCCCTCC GGT GCTGGACTCAGACGGATCCTTCTTCCTCTACTCG CGGCTGACCGTGGATAAGAGCAGATGGCAGGAG GGAAATGTGTTCAGCTGTTCTGTGATGCATGAAG CCCTGCACAACCACTACACTCAGAAGTCCCTGTC CCTCTCCCTGGGA SEQ GO NO: 717 DNA encoding the heavy chain CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTG AAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGC AAGGCCTCTGGCTTCACCCTGACCAACTACGGCA TGAACTGGGTGCGACAGGCCAGGGGCCAGCGGC TGGAATGGATCGGCTGGATCAACACCGACACCG GCGAGCCTACCTACGCCGACGACTTCAAGGGCA GATTCGTGTTCTCCCTGGACACCTCCGTGTCCAC CGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAG GATACCGCCGTGTACTACTGCCCCGGAACCCCC CTTACTACTACGGCACCAACAACGCCGAGGCCAT GGACTATTGGGGCCAGGGCACCACCGTGACCGT GTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTC CCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAG AGCACAGCCGCCCTGGGCTGCCTGGTGAAGGAC TACTTCCC CGAGCCCGTGACCGTGTCCTGGAACA GCGGAGCCCTGACCAGCGGCGTGCACACCTTCCC CGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCT GAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCT GGGCACCAAGACCTACACCTGTAACGTGGACCA CAAGCCCAGCAACACCAAGGTGGACAAGAGGGT GGAGACAAGTACGCCCACCCTGCCCCCCCTG CGAGTTCCTGGGCGGACCCAGCGTG TTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGA TGATCAGCAGAACCCCCGAGGTGACCTGTGTGGT GGTGGACGTGTCCCAGGAGGACCCCGAGGTCCA GTTCAACTGGTACGTGGACGGCGTGGAGGTGCA

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CAACGCCAAGACCAAGCCCAGAGGAGCAGTT TAACAGCACCTACCGGGTGGTGTCCGTGCTGACC GTGCTGCACCAGGACTGGCTGAACGGCAAAGAG TACAAGTGTAAGGTCTCCAACAAGGGCCTGCCA AGCAGCATCGAAAAGACCATCAGCAAGGCCAAG GGCCAGCCTAGAGAGCCCCAGGTCTACACCCTG CCACCCAGCCAAGAGGAGATGACCAAGAACCAG GTG CTG AGCCTGTCCCTGGGGC LC VAR050-clone I SEQ ID NO: 710 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 711 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 712 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 713 (Chothia) LCDR1 SQDISNY SEQ ID NO: 714 (Chothia) LCDR2 YTS SEQ ID NO: 715 (Chothia) LCDR3 YYNLPW SEQ ID NO: 718 VL DIQMTQSPSSSLSASVGDRVTITCSSSQDISNYLNWY LQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTL TISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 719 DNA encoding VL GATATTCAGATGACTCAGTCACCTAGTAGCCTGA GCGCTAGTGTGGGCGATAGAGTGACTATCACCTG TAGCTCTAGTCAGGATATCTCTAACTACCTGAAC TGGTATCTGCAGAAGCCCGGTCAATCACCTCAGC TGCTGATCTACTACACTAGCACCCTGCACCTGGG CGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGC ACCGAGTTCACCCTGACTATCTCTAGCCTGCAGC CC GACGACTTCGCTACCTACTACTGTCAGCAGTA CTATAACCTGCCCTGGACCTTCGGTCAAGGCACT AAGGTCGAGATTAAG SEQ ID NO: 720 DNA encoding VL GACATCCAGATGACCCAGTCCCCCTCCAGCCTGT CTGCTTCCGTGGGCGACAGAGTGACCATCACCTG TTCCTCCAGCCAGGACATCTCCAACTACCTGAAC TGGTATCTGCAGAAGCCCGGCCAGTCCCCTCAGC

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TGCTGATCTACTACACCTCCACCCTGCACCTGGG CGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGC ACCGAGTTTACCCTGACCATCAGCTCCCTGCAGC CCGACGACTTCGCCACCTACTACTGCCAGCAGTA CTACAACCTGCCCTGGACCTTCGGCCAGGGCACC AAGGTGGAAATCAAG SEQ GO NO: 721 Light chain TLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 722 DNA encoding the light chain GATATTCAGATGACTCAGTCACCTAGTAGCCTGA GCGCTAGTGTGGGCGATAGAGTGACTATCACCTG TAGCTCTAGTCAGGATATCTCTAACTACCTGAAC TGGTATCTGCAGAAGCCCGGTCAATCACCTCAGC TGCTGATCTACTACACTAGCACCCTGCACCTGGG CGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGC ACCGAGTTCACCCTGACTATCTCTAGCCTGCAGC CC GACGACTTCGCTACCTACTACTGTCAGCAGTA CTATAACCTGCCCTGGACCTTCGGTCAAGGCACT AAGGTCGAGATTAAGCGTACGGTGGCCGCTCCC AGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGC TGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGC TGAACAACTTCTACCCCCGGGAGGCCAAGGTGC AGTGGAAGGTGGACAACGCCCTGCAGAGC CA ACAGCCAGGAGAGCGTCACCGAGCAGGACAGCA AGGACTCCACCTACAGCCTGAGCAGCACCCTGA CCCTGAGCAAGGCCGACTACGAGAAGCATAAGG TGTACGCCTGCGAGGTGACCCACCAGGGCCTGTC CAGCCCCGTGACCAAGAGCTTCAACAGGGGCGA GTGC SEQ ID NO: 723 DNA encoding the light chain GACATCCAGATGACCCAGTCCCCCTCCAGCCTGT CTGCTTCCGTGGGCGACAGAGTGACCATCACCTG TTCCTCCAGCCAGGACATCTCCAACTACCTGAAC TGGTATCTGCAGAAGCCCGGCCAGTCCCCTCAGC TGCTGATCTACTACACCTCCACCCTGCACCTGGG CGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGC ACCGAGTTTACCCTGACCATCAGCTCCCTGCAGC CCGACGACTTCGCCACCTACTACTGCCAGCAGTA CTACAACCTGCCCTGGACCTTCGGCCAGGGCACC AAGGTGGAAATCAAGCGTACGGTGGCCGCTCCC AGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGC TGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCT GAACAACTTCTACCCCAGGGAGGCCAAGGTGCA

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GTGGAAGGTGGACAACGCCCTGCAGAGCGGCAA CAGCCAGGAGAGCGTCACCGAGCAGGACAGCAA GGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCACAAGGTG TACGCCTGTGAGGTGACCCACCAGGGCCTGTCCA GCCCCGTGACCAAGAGCTTCAACAGGGGCGAGT GC NS VAR050-clone J SEQ ID NO: 701 (Kabat) HCDR1 NYGMN SEQ ID NO: 702 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 703 (Kabat) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 704 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 705 (Chothia) HCDR2 NTDTGE SEQ ID NO: 703 (Chothia) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 724 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGM NWVRQAPGQGLEWMGWINTDTGEPTYADDFKGR FVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYY YGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 725 DNA encoding VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTG AAGAAACCCGGCCTAGTGTGAAAGTCAGCTGT AAAGCTAGTGGCTTCACCCTGACTAACTACGGGA TGAACTGGGTCCGCCAGGCCCCAGGTCAAGGCC TCGAGTGGATGGGCTGGATTAACACCGACACCG GCGAGCCTACCTACGCCGACGACTTTAAGGGCA GATTCGTGTTTAGCCTGGACACTAGTGTGTCTAC CGCCTACCTGCAGATCTCTAGCCTGAAGGCCGAG GACACCGCCGTCTACTACTGCGCTAGAAACCCCC CCTACTACTACGGCACTAACAACGCCGAGGCTAT GGACTACTGGGGTCAAGGCACTACCGTGACCGT GTCTAGC SEQ ID NO: 726 DNA encoding VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTG AAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGC AAGGCCTCTGGCTTCACCCTGACCAACTACGGCA TGAACTGGGTGCGACAGGCCCCTGGACAGGGCC TGGAATGGATGGGCTGGATCAACACCGACACCG GCGAGCCTACCTACGCCGACGACTTCAAGGGCA GATTCGTGTTCTCCCTGGACACCTCCGTGTCCAC CGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAG GATACCGCCGTGTACTACTGCGCCCGGAACCCCC

- 217 047335

CTTACTACTACGGCACCAACAACGCCGAGGCCAT GGACTATTGGGGCCAGGCACCACCGTGACCGT GTCCTCT SEQ GO NO: 727 Heavy chain QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGM NWVRQAPGQGLEWMGWINTDTGEPTYADDFKGR FVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYY YGTNNAEAMDYWGQGTTVTVSSASTKGPSVFPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSS SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQF NWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 728 DNA encoding the heavy chain CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTG AAGAAACCCGGCCTAGTGTGAAAGTCAGCTGT AAAGCTAGTGGCTTCACCCTGACTAACTACGGGA TGAACTGGGTCCGCCAGGCCCCAGGTCAAGGCC TCGAGTGGATGGGCTGGATTAACACCGACACCG GCGAGCCTACCTACGCCGACGACTTTAAGGGCA GATTCGTGTTTAGCCTGGACACTAGTGTGTCTAC CGCCTACCTGCAGATCTCTAGCCTGAAGGCCGAG GACACCGCCGTCTACTACTGCGCTAGAAACCCCC CCTACTACTACGGCACTAACAACGCCGAGGCTAT GGACTACTGGGGTCAAGGCACTACCGTGACCGT GTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTC CCCCTGGCACCTTGTAGCCGGAGCACTAGCGAAT CCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTA CT TCCCGGAGCCCGTGACCGTGTCCTGGAACAGC GGAGCCCTGACCTCCGGAGTGCACACCTTCCCCG CTGCTGCAGAGCTCCGGGCTGTACTCGCTGTC GTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGT ACCAAGACCTACACTTGCAACGTGGACCACAAG CCTTCCAACACTAAGGTGGACAAGCGCGTCGAA TCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCG CGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCT GTTCCCACCGAAGCCCAAGGACACTTTGATGATT TCCCGCACCCCTGAAGTGACATGCGTGGTCGTGG ACGTGTCACAGGAAGATCCGGAGGTGCAGTTCA ATTGGTACGTGGATGGCGTCGAGGTGCACAACG CCAAAACCAAGCCGAGGGAGGAGCAGTTCAACT CCACTTACCGCGTCGTGTCCGTGCTGACGTG CT GCATCAGGACTGGCTGAACGGGAAGGAGTACAA

- 218 047335

GTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCA ATCGAAAAGACCATCTCGAAAGCCAAGGGACAG CCCCGGGAACCCCAAGTGTATACCCTGCCACCGA GCCAGGAAGAAATGACTAAGAACCAAGTCTCAT TGACTTGCCTTGTGAAGGGCTTCTACCCATCGGA TATCGCCGTGGAATGGGAGTCCAACGGCCAGCC GGAAAACAACTACAAGACCACCCCTCCGGTGCT GGACTCAGACG GATCCTTCTTCCTCTACTCCGGG CTGACCGTGGATAAGAGCAGATGGCAGGAGGGA AATGTGTTCAGCTGTTCTGTGATGCATGAAGCCC TGCACAACCACTACACTCAGAAGTCCCTGTCCCT CTCCCTGGGA SEQ GO NO: 729 DNA encoding the heavy chain CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTG AAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGC AAGGCCTCTGGCTTCACCCTGACCAACTACGGCA TGAACTGGGTGCGACAGGCCCCTGGACAGGGCC TGGAATGGATGGGCTGGATCAACACCGACACCG GCGAGCCTACCTACGCCGACGACTTCAAGGGCA GATTCGTGTTCTCCCTGGACACCTCCGTGTCCAC CGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAG GATACCGCCGTGTACTACTGCCCCGGAACCCCC CTTACTACTACGGCACCAACAACGCCGAGGCCAT GGACTATTGGGGCCAGGGCACCACCGTGACCGT GTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTC CCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAG AGCACAGCCGCCCTGGGCTGCCTGGTGAAGGAC TACTTCCC CGAGCCCGTGACCGTGTCCTGGAACA GCGGAGCCCTGACCAGCGGCGTGCACACCTTCCC CGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCT GAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCT GGGCACCAAGACCTACACCTGTAACGTGGACCA CAAGCCCAGCAACACCAAGGTGGACAAGAGGGT GGAGACAAGTACGCCCACCCTGCCCCCCCTG CGAGTTCCTGGGCGGACCCAGCGTG TTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGA TGATCAGCAGAACCCCCGAGGTGACCTGTGTGGT GGTGGACGTGTCCCAGGAGGACCCCGAGGTCCA GTTCAACTGGTACGTGGACGGCGTGGAGGTGCA CAACGCCAAGACCAAGCCCAGAGAGGAGCAGTT TAACAGCACCTACCGGGTGGTGTCCGTGCTGACC ACCAGGACTGGCTGAACGGCAAAGAG TACAAGTGTAAGGTCTCCAACAAGGGCCTGCCA AGCAGCATCGAAAAGACCATCAGCAAGGCCAAG GGCCAGCCTAGAGAGCCCCAGGTCTACACCCTG CCACCCAGCCAAGAGGAGATGACCAAGAACCAG

- 219 047335

GTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACC CAAGCGACATCGCCGTGGAGTGGGAGAGCAACG GCCAGCCCGAGAACAACTACAAGACCACCCCCC CAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTA CAGCAGGCTGACCGTGGACAAGTCCAGATGGCA GGAGGGCAACGTCTTTAGCTGCTCCGTGATGCAC GAGGCCCTGCACAACCACTACACCCAGAAGA GC CTGAGCCTGTCCCTGGGGC LC VAR050-clone J SEQ ID NO: 710 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 711 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 712 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 713 (Chothia) LCDR1 SQDISNY SEQ ID NO: 714 (Chothia) LCDR2 YTS SEQ ID NO: 715 (Chothia) LCDR3 YYNLPW SEQ ID NO: 730 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWY QQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFT LTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 731 DNA encoding VL GATATTCAGATGACTCAGTCACCTAGTAGCCTGA GCGCTAGTGTGGGCGATAGAGTGACTATCACCTG TAGCTCTAGTCAGGATATCTCTAACTACCTGAAC TGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAG CTGCTGATCTACTACACTAGCACCCTGCACCTGG GAATCCCCCCTAGGTTTAGCGGTAGCGGCTACGG CACGACTTCACCCTGACTATTAACAATATCGAG TC AGAGGACGCCGCCTACTACTTCTGTCAGCAGT ACTATAACCTGCCCTGGACCTTCGGTCAAGGCAC TAAGGTCGAGATTAAG SEQ ID NO: 732 DNA encoding VL GACATCCAGATGACCCAGTCCCCCTCCAGCCTGT CTGCTTCCGTGGGCGACAGAGTGACCATCACCTG TTCCTCCAGCCAGGACATCTCCAACTACCTGAAC TGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAG CTGCTGATCTACTACACCTCCACCCTGCACCTGG GCATCCCCCCTAGATTCTCCGGCTCTGGCTACGG CACCGACTTCACCCTGACCATCAACAACATCGAG TC CGAGGACGCCGCCTACTACTTCTGCCAGCAGT ACTACAACCTGCCCTGGACCTTCGGCCAGGGCAC CAAGGTGGAAATCAAG SEQ ID NO: 733 Lightweight DIQMTQSPSSLSSASVGDRVTITCSSSQDISNYLNWY

- 220 047335

chain EU SEQ GO NO: 734 DNA encoding the light chain GATATTCAGATGACTCAGTCACCTAGTAGCCTGA GCGCTAGTGTGGGCGATAGAGTGACTATCACCTG TAGCTCTAGTCAGGATATCTCTAACTACCTGAAC TGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAG CTGCTGATCTACTACACTAGCACCCTGCACCTGG GAATCCCCCCTAGGTTTAGCGGTAGCGGCTACGG CACGACTTCACCCTGACTATTAACAATATCGAG TC AGAGGACGCCGCCTACTTCTGTCAGCAGT ACTATAACCTGCCCTGGACCTTCGGTCAAGGCAC TAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCC AGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGC TGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGC TGAACAACTTCTACCCCCGGGAGGCCAAGGTGC AGTGGAAGGTGGACAACGCCCTGCAGAGC CA ACAGCCAGGAGAGCGTCACCGAGCAGGACAGCA AGGACTCCACCTACAGCCTGAGCAGCACCCTGA CCCTGAGCAAGGCCGACTACGAGAAGCATAAGG TGTACGCCTGCGAGGTGACCCACCAGGGCCTGTC CAGCCCCGTGACCAAGAGCTTCAACAGGGGCGA GTGC SEQ ID NO: 735 DNA encoding the light chain GACATCCAGATGACCCAGTCCCCCTCCAGCCTGT CTGCTTCCGTGGGCGACAGAGTGACCATCACCTG TTCCTCCAGCCAGGACATCTCCAACTACCTGAAC TGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAG CTGCTGATCTACTACACCTCCACCCTGCACCTGG GCATCCCCCCTAGATTCTCCGGCTCTGGCTACGG CACCGACTTCACCCTGACCATCAACAACATCGAG TC CGAGGACGCCGCCTACTACTTCTGCCAGCAGT ACTACAACCTGCCCTGGACCTTCGGCCAGGGCAC CAAGGTGGAAATCAAGCGTACGGTGGCCGCTCC CAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAG CTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTG CTGAACAACTTCTACCCCAGGGAGGCCAAGGTG CAGTGGAAGGTGGACAACGCCCTGCAGAGCGGC CCAGGAGACGTCACCGAGCAGGACAGC AAGGACTCCACCTACAGCCTGAGCAGCACCCTG ACCCTGAGCAAGGCCGACTACGAGAAGCACAAG GTGTACGCCTGTGAGGTGACCCACCAGGGCCTGT CCAGCCCCGTGACCAAGAGCTTCAACAGGGGCG

- 221 047335

AGTGC NS VAR050-clone I SEQ ID NO: 736 (Kabat) HCDR1 AATTACGGGATGAAC SEQ ID NO: 737 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 738 (Kabat) HCDR2 TGGATTAACACCGACACCGGGGAGCCTACCTAC GCGGACGATTTCAAGGGA SEQ ID NO: 739 (Kabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTAC GCCGACGACTTCAAGGGC SEQ ID NO: 740 (Kabat) HCDR3 AACCCGCCCTACTACGGAACCAACAACGCC GAAGCCATGGACTAC SEQ ID NO: 741 (Kabat) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCG AGGCCATGGACTAT SEQ ID NO: 742 (Chothia) HCDR1 GGATTCACCCTCACCAATTAC SEQ ID NO: 743 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 744 (Chothia) HCDR2 AACACCGACACCGGGGAG SEQ ID NO: 745 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 740 (Chothia) HCDR3 AACCCGCCCTACTACGGAACCAACAACGCC GAAGCCATGGACTAC SEQ ID NO: 741 (Chothia) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCG AGGCCATGGACTAT LC VAR050-clone I SEQ ID NO: 746 (Kabat) LCDR1 AGCTCTAGTCAGGATATCTCTAACTACCTGAAC SEQ ID NO: 747 (Kabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 748 (Kabat) LCDR2 TACACTAGCACCCTGCACCTG SEQ ID NO: 749 (Kabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 750 (Kabat) LCDR3 CAGCAGTACTATAACCTGCCCTGGACC SEQ ID NO: 751 (Kabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 752 (Chothia) LCDR1 AGTCAGGATATCTCTAACTAC SEQ ID NO: 753 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 754 LCDR2 TACACTAGC

- 222 047335

(Chothia) SEQ ID NO: 755 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 756 (Chothia) LCDR3 TACTATAACCTGCCCTGG SEQ ID NO: 757 (Chothia) LCDR3 TACTACAACCTGCCCTGG NS VAR050-clone J SEQ ID NO: 758 (Kabat) HCDR1 AACTACGGGATGAAC SEQ ID NO: 737 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 759 (Kabat) HCDR2 TGGATTAACACCGACACCGGCGAGCCTACCTAC GCCGACGACTTTAAGGGC SEQ ID NO: 739 (Kabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTAC GCCGACGACTTCAAGGGC SEQ ID NO: 760 (Kabat) HCDR3 AACCCCCCCTACTACTACGGCACTAACAACGCCG AGGCTATGGACTAC SEQ ID NO: 741 (Kabat) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCG AGGCCATGGACTAT SEQ ID NO: 761 (Chothia) HCDR1 GGCTTCACCCTGACTAACTAC SEQ ID NO: 743 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 744 (Chothia) HCDR2 AACACCGACACCGGGGAG SEQ ID NO: 745 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 760 (Chothia) HCDR3 AACCCCCCCTACTACTACGGCACTAACAACGCCG AGGCTATGGACTAC SEQ ID NO: 741 (Chothia) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCG AGGCCATGGACTAT LC VAR050-clone J SEQ ID NO: 746 (Kabat) LCDR1 AGCTCTAGTCAGGATATCTCTAACTACCTGAAC SEQ ID NO: 747 (Kabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 748 (Kabat) LCDR2 TACACTAGCACCCTGCACCTG SEQ ID NO: 749 (Kabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 750 (Kabat) LCDR3 CAGCAGTACTATAACCTGCCCTGGACC SEQ ID NO: 751 LCDR3 CAGCAGTACTACAACCTGCCCTGGACC

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(Kabat) SEQ ID NO: 752 (Chothia) LCDR1 AGTCAGGATATCTCTAACTAC SEQ ID NO: 753 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 754 (Chothia) LCDR2 TACACTAGC SEQ ID NO: 755 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 756 (Chothia) LCDR3 TACTATAACCTGCCCTGG SEQ ID NO: 757 (Chothia) LCDR3 TACTACAACCTGCCCTGG

Other exemplary LAG-3 inhibitors

In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and US 9505839, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule contains one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence BMS986016, for example, disclosed in table. 10.

In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a TSR-O33 heavy chain or light chain sequence.

In one embodiment, the anti-LAG-3 antibody molecule is MK-4280 (Merck & Co). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a MK-4280 heavy chain or light chain sequence.

In one embodiment, the anti-LAG-3 antibody molecule is REGN3767 (Regeneron). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a REGN3767 heavy chain or light chain sequence.

In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008/132601 and US 9244059, incorporated by reference in their entirety. In one embodiment, an anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an IMP731 heavy chain or light chain sequence, for example, those disclosed in Table 1. 10. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence GSK2831781.

In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an IMP761 heavy chain or light chain sequence.

Additional known anti-LAG-3 antibodies include those described, for example, in WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9244059, US 95 05839 , incorporated by reference in their entirety.

In one embodiment, an anti-LAG-3 antibody is an antibody that competes for and/or binds to the same epitope on LAG-3 as one of the anti-LAG-3 antibodies described herein.

In one embodiment, the anti-LAG-3 antibody inhibitor is a soluble LAG-3 protein, for example, IMP321 (Prima BioMed), for example, disclosed in WO 2009/044273, incorporated by reference in its entirety.

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Table 10

Amino acid sequences of other exemplary anti-LAG-3 antibody molecules

BMS-986016 SEQ ID NO: 762 Heavy chain QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIR QPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQF SLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTL VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQ FNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTL PPSQEEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMH EALHNHYTQKSLSLSLGK SEQ ID NO: 763 Light chain EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKP GQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPE DFAVYYCQQRSNWPLTFGQGTNLEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC IMP731 SEQ ID NO: 764 Heavy chain QVQLKESGPGLVAPSQSLSITCTVSGFSLTAYGVNWVRQ PPGKGLEWLGMIWDDGSTDYNSALKSRLSISKDNSKSQV FLKMNSLQTDDTARYYCAREGDVAFDYWGQGTTLTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ T YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK SEQ ID NO: 765 Light chain DIVMTQSPSSLAVSVGQKVTMSCKSSQSLLNGSNQKNYL AWYQQKPGQSPKLLVYFASTRDSGVPDRFIGSGSGTDFT LTISSVQAEDLADYFCLQHFGTPPTFGGGTKLEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHK VYACEVTHQGLSSPVTKSFNRGEC

Exemplary TIM-3 Inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a TIM-3 inhibitor. The TIM-3 inhibitor may be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. In some embodiments, the TIM-3 inhibitor is selected from MGB453 (Novartis), TSR-022 (Tesaro), or LY3321367 (Eli Lilly).

Exemplary anti-TIM-3 antibody molecules

In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule disclosed in US 2015/0218274 published August 6, 2015 entitled Antibody Molecules to TIM-3 and Uses Thereof, incorporated by reference in its entirety.

In one embodiment, an anti-TIM-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all CDRs) of a heavy and light chain variable region comprising an amino acid sequence, shown in table. 11 (for example, from the heavy and light chain variable region sequences ABTIM3-hum11 or ABTIM3-hum03 disclosed in Table 11), or encoded by the nucleotide sequence shown in Table. 11. In some embodiments, CDRs are defined in

- 225 047335 in accordance with the Kabat numbering scheme (for example, as set out in Table 11). In some embodiments, the CDRs are defined in accordance with the Chothia numbering scheme (eg, as set forth in Table 11). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequence, shown in table. 11, or the encoded nucleotide sequence shown in table. eleven.

In one embodiment, an anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 801, the amino acid sequence of VHCDR2 of SEQ ID NO: 802, and the amino acid sequence of VHCDR3 of SEQ ID NO: 803; and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 of SEQ ID NO: 810, the amino acid sequence of VLCDR2 of SEQ ID NO: 811 and the amino acid sequence of VLCDR3 of SEQ ID NO: 812, each of which is disclosed in table. 11. In one embodiment, an anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 801, the amino acid sequence of VHCDR2 of SEQ ID NO: 820, and the amino acid sequence of VHCDR3 of SEQ ID NO: 803; and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 of SEQ ID NO: 810, the amino acid sequence of VLCDR2 of SEQ ID NO: 811 and the amino acid sequence of VLCDR3 of SEQ ID NO: 812, each of which is disclosed in table. eleven.

In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 806, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: : 806. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 816, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 816. In one embodiment, the anti-TIM3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 822, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 822. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 826, or an amino acid sequence characterized by at least about 85%, 90%, 95%, or 99 % sequence identity to SEQ ID NO: 826. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 806 and a VL comprising the amino acid sequence of SEQ ID NO: 816. In one embodiment an anti-TLM-3 antibody molecule contains a VH containing the amino acid sequence of SEQ ID NO: 822, and a VL containing the amino acid sequence of SEQ ID NO: 826.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 807, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 807. B In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 817, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 817. In one embodiment An antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 823, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 823. In one embodiment, the molecule The antibody comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 827, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 827. In one embodiment, the antibody molecule contains VH, encoded by the nucleotide sequence of SEQ ID NO: 807, and VL, encoded by the nucleotide sequence of SEQ ID NO: 817. In one embodiment, the antibody molecule contains VH, encoded by the nucleotide sequence of SEQ ID NO: 823, and VL, encoded by the nucleotide sequence under SEQ ID NO: 827.

In one embodiment, the anti-TLM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 808, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 808. In one embodiment, the anti-TLM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 818, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% identity sequences with SEQ ID NO: 818. In one embodiment, the anti-TLM-3 antibody molecule comprises a heavy chain containing the amino acid sequence

- 226 047335 under SEQ ID NO: 824, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 824. In one embodiment, an anti-TLM-3 antibody molecule contains a light chain containing the amino acid sequence of SEQ ID NO: 828, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity with ID NO: 828. In one embodiment, the antibody molecule to TIM-3 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 808 and a light chain comprising the amino acid sequence of SEQ ID NO: 818. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 824, and a light chain containing the amino acid sequence of SEQ ID NO: 828.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 809, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 809. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 819, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 819. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 825, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 825. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 829, or a nucleotide sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 829. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 809 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 819. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 825, and the light chain encoded by the nucleotide sequence of SEQ ID NO: 829.

The antibody molecules described herein can be produced using the vectors, host cells and methods described in US 2015/0218274, incorporated by reference in its entirety.

Table 11

Amino acid and nucleotide sequences of exemplary anti-TIM-3 antibody molecules

ABTIM3-humll SEQ ID NO: 801 (Kabat) HCDR1 SYNMH SEQ ID NO: 802 (Kabat) HCDR2 DIYPGNGDTSYNQKFKG SEQ ID NO: 803 HCDR3 VGGAFMDY

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(Kabat) SEQ ID NO: 804 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 805 (Chothia) HCDR2 YPGNGD SEQ ID NO: 803 (Chothia) HCDR3 VGGAFMDY SEQ ID NO: 806 VH QVQLVQSGAEVKKPGSSVKVSCKASGYTFTS YNMHWVRQAPGQGLEWMGDIYPGNGDTSY NQKFKGRVTITADKSTSTVYMELSSLRSEDTA VYYCARVGGAFMDYWGQGTTVTVSS SEQ ID NO: 807 DNA encoding VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAACCCGGCTCTAGCGTGAAAGTT TCTTGTAAAGCTAGTGGCTACACCTTCACTA GCTATAATATGCACTGGGTTCGCCAGGCCC CAGGGCAAGGCCTCGAGTGGATGGGCGATA TCTACCCCGGGAACGGCGACACTAGTTATA ATCAGAAGTTTAAGGGTAGAGTCACTATCA CCGCCGATAAGTCTACTAGCACCGTCTATA T GGAACTGAGTTCCCTGAGGTCTGAGGACAC CGCCGTCTACTACTGCGCTAGAGTGGGCGG AGCCTTCCCTATGGACTACTGGGGTCAAGG CACTACCGTGACCGTGTCTAGC SEQ ID NO: 808 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGYTFTS YNMHWVRQAPGQGLEWMGDIYPGNGDTSY NQKFKGRVTITADKSTSTVYMELSSLRSEDTA VYYCARVGGAFPMDYWGQGTTVTVSSASTK GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGT KTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKGLPSSIEKTISKAKGQPREP

- 228 047335

QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLG SEQ GO NO: 809 DNA encoding the heavy chain CAGGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAACCCGGCTCTAGCGTGAAAGTT TCTTGTAAAGCTAGTGGCTACACCTTCACTA GCTATAATATGCACTGGGTTCGCCAGGCCC CAGGGCAAGGCCTCGAGTGGATGGGCGATA TCTACCCCGGGAACGGCGACACTAGTTATA ATCAGAAGTTTAAGGGTAGAGTCACTATCA CCGCCGATAAGTCTACTAGCACCGTCTATAT GGAACTGAGTTCCCTGAGGTCTGAGGACAC CGCCGTCTACTACTGCGCTAGAGTGGGCGG AGCCTTCCCTATGGACTACTGGGGTCAAGG CACTACCGTGACCGTGTCTAGCGCTAGCAC TAAGGGCCCGTCCGTGTTCCCCCTGGCACCT TGTAGCCGGAGCACTAGCGAATCCACCGCT GCCCTCGGCTGCCTGGTCAAGGATTACTTCC CGGAGCCCGTGACCGTGTCCTGGAACAGCG GAGCCCTGACCTCCGGAGTGCACACCTTCC CCGCTGTGCTGCAGAGCTCCGGGCTGTACT CGCTGTCGTCGGTGGTCACGGTGCCTTCATC TAGCCTGGGTACCAAGACCTACACTTGCAA CGTGGACCACAAGCCTTCCAACACTAAGGT GGACAAGCGCGTCGAATCGAAGTACGGCCC ACCGTGCCCGCCTTGTCCCGCGCCGGAGTTC CTCGGCGGTCCCTCGGTCTTTCTGTTCCCAC CGAAGCCCAAGGACACTTTGATGATTTCCC GCACCCCTGAAGTGACATGCGTGGTCGTGG ACGTGTCACAGGAAGATCCGGAGGTGCAGT TCAATTGGTACGTGGATGGCGTCGAGGTGC ACAACGCCAAAACCAAGCCGAGGGAGGAG CAGTTCAACTCCACTTACCGCGTCGTGTCCG TGCTGACGGTGCTGCATCAGGACTGGCTGA

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ACGGGAAGGAGTACAAGTGCAAAGTGTCCA ACAAGGGACTTCCTAGCTCAATCGAAAAGA CCATCTCGAAAGCCAAGGGACAGCCCCGGG AACCCCAAGTGTATACCCTGCCACCGAGCC AGGAAGAAATGACTAAGAACCAAGTCTCAT TGACTTGCCTTGTGAAGGGCTTCTACCCATC GGATATCGCCGTGGAATGGGAGTCCAACGG CCAGCCGGAAAACAACTACAAGACCA CCCC TCCGGTGCTGGACTCAGACGGATCCTTCTTC CTCTACTCGCGGCTGACCGTGGATAAGAC AGATGGCAGGAGGGAAATGTGTTCAGCTGT TCTGTGATGCATGAAGCCCTGCACAACCAC TACACTCAGAAGTCCCTGTCCCTCTCCCTGG GA SEQ ID NO: 810 (Kabat) LCDR1 RASES VEYYGTSLMQ SEQ ID NO: 811 (Kabat) LCDR2 AASNVES SEQ ID NO: 812 (Kabat) LCDR3 QQSRKDPST SEQ ID NO: 813 (Chothia) LCDR1 SESVEYYGTSL SEQ ID NO: 814 (Chothia) LCDR2 A.A.S. SEQ ID NO: 815 (Chothia) LCDR3 SRKDPS SEQ ID NO: 816 VL AIQLTQSPSSLSSASVGDRVTITCRASESVEYYG TSLMQWYQQKPGKAPKLLIYAASNVESGVPS RFSGSGSGTDFTLTISSLQPEDFATYFCQQSRK DPSTFGGGTKVEIK SEQ ID NO: 817 DNA encoding VL GCTATTCAGCTGACTCAGTCACCTAGTAGCC TGAGCGCTAGTGTGGGCGATAGAGTGACTA TCACCTGTAGAGCTAGTGAATCAGTCGAGT ACTACGGCACTAGCCTGATGCAGTGGTATC

- 230 047335

AGCAGAAGCCCGGGAAAGCCCCTAAGCTGC TGATCTACGCCGCCTCTAACGTGGAATCAG GCGTGCCCTCTAGGTTTAGCGGTAGCGGTA GTGGCACCGACTTCACCCTGACTATCTCTAG CCTGCAGCCCGAGGACTTCGCTACCTACTTC TGTCAGCAGTCTAGGAAGGACCCTAGCACC TTCGGCGGAGGCACTAAGGTCGAGATTAAG SEQ GO NO: 818 Light chain AIQLTQSPSSLSASVGDRVTITCRASESVEYYG TSLMQWYQQKPGKAPKLLIYAASNVESGVPS RFSGSGSGTDFTLTISSLQPEDFATYFCQQSRK DPSTFGGGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYE K HKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 819 DNA encoding the light chain GCTATTCAGCTGACTCAGTCACCTAGTAGCC TGAGCGCTAGTGTGGGCGATAGAGTGACTA TCACCTGTAGAGCTAGTGAATCAGTCGAGT ACTACGGCACTAGCCTGATGCAGTGGTATC AGCAGAAGCCCGGGAAAGCCCCTAAGCTGC TGATCTACGCCGCCTCTAACGTGGAATCAG GCGTGCCCTCTAGGTTTAGCGGTAGCGGTA GTGGCACCGACTTCACCCTG ACTATCTCTAG CCTGCAGCCCGAGGACTTCGCTACCTACTTC TGTCAGCAGTCTAGGAAGGACCCTAGCACC TTCGGCGGAGGCACTAAGGTCGAGATTAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCT TCCCCCCCAGCGACGAGCAGCTGAAGAGCG GCACCGCCAGCGTGGTGTGCCTGCTGAACA ACTTCTACCCCCGGGAGGCCAAGGTGCAGT GGAAGGTG GACAACGCCCTGCAGAGCGGC AACAGCCAGGAGAGCGTCACCGAGCAGGA CAGCAAGGACTCCACCTACAGCCTGAGCAG CACCCTGACCCTGAGCAAGGCCGACTACGA GAAGCATAAGGTGTACGCCTGCGAGGTGAC CCACCAGGGCCTGTCCAGCCCCGTGACCAA

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GAGCTTCAACAGGGGCGAGTGC ABTIM3-humO3 SEQ ID NO: 801 (Kabat) HCDR1 SYNMH SEQ ID NO: 820 (Kabat) HCDR2 DIYPGQGDTSYNQKFKG SEQ ID NO: 803 (Kabat) HCDR3 VGGAFMDY SEQ ID NO: 804 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 821 (Chothia) HCDR2 YPGQGD SEQ ID NO: 803 (Chothia) HCDR3 VGGAFMDY SEQ ID NO: 822 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTS YNMHWVRQAPGQGLEWIGDIYPGQGDTSYN QKFKGRATMTADKSTSTVYMELSSLRSEDTA VYYCARVGGAFPMDYWGQGTLVTVSS SEQ ID NO: 823 DNA encoding VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAACCCGGCCTAGTGTGAAAGTT AGCTGTAAAGCTAGTGGCTATACTTTCACTT CTTATAATATGCACTGGGTCCGCCAGGCCC CAGGTCAAGGCCTCGAGTGGATCGGCGATA TCTACCCCGGTCAAGGCGACACTTCCTATA ATCAGAAGTTTAAGGGTAGAGCTACTATGA CCGCCGATAAGTCTACTTCTACCGTCTATA T GGAACTGAGTTCCCTGAGGTCTGAGGACAC CGCCGTCTACTACTGCGCTAGAGTGGGCGG AGCCTTCCCAATGGACTACTGGGGTCAAGG CACCCTGGTCACCGTGTCTAGC SEQ ID NO: 824 Heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTS YNMHWVRQAPGQGLEWIGDIYPGQGDTSYN QKFKGRATMTADKSTSTVYMELSSLRSEDTA VYYCARVGGAFPMDYWGQGTLVTVSSASTK

- 232 047335

GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQ DWL NGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLG SEQ GO NO: 825 DNA encoding the heavy chain CAGGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAACCCGGCCTAGTGTGAAAGTT AGCTGTAAAGCTAGTGGCTATACTTTCACTT CTTATAATATGCACTGGGTCCGCCAGGCCC CAGGTCAAGGCCTCGAGTGGATCGGCGATA TCTACCCCGGTCAAGGCGACACTTCCTATA ATCAGAAGTTTAAGGGTAGAGCTACTATGA CCGCCGATAAGTCTACTTCTACCGTCTATA t GCGG AGCCCTGACCTCCGGAGTGCACACCTTCCC CGCTGTGCTGCAGAGCTCCGGGCTGTACTC GCTGTCGTCGGTGGTCACGGTGCCTTCATCT AGCCTGGGTACCAAGACCTACACTTGCAAC GTGGACCACAAGCCTTCCAACACTAAGGTG GACAAGCGCGTCGAATCGAAGTACGGCCCA CCGTGCCCGCCTTGTCCCGCGCCGGAGTTCC TCGGCGGTCCCTCGG TCTTTCTGTTCCCACC

- 233 047335

GAAGCCCAAGGACACTTTGATGATTTCCCG CACCCCTGAAGTGACATGCGTGGTCGTGGA CGTGTCACAGGAAGATCCGGAGGTGCAGTT CAATTGGTACGTGGATGGCGTCGAGGTGCA CAACGCCAAAACCAAGCCGAGGGAGGAGC AGTTCAACTCCACTTACCGCGTCGTGTCCGT GCTGACGGTGCTGCATCAGGACTGGCTGAA CGGGAAGGAGTACAAGTGC AAAGTGTCCAA CAAGGGACTTCCTAGCTCAATCGAAAAGAC CATCTCGAAAGCCAAGGGACAGCCCCGGGA ACCCCAAGTGTATACCCTGCCACCGAGCCA GGAAGAAATGACTAAGAACCAAGTCTCATT GACTTGCCTTGTGAAGGGCTTCTACCCATCG GATATCGCCGTGGAATGGGAGTCCAACGGC CAGCCGGAAAACAACTACAAGACCACCCCT CCGGTGCTGGACTCAGACGGATCCTTC TTCC TCTACTCGCGGCTGACCGTGGATAAGAGCA GATGGCAGGAGGGAAATGTGTTCAGCTGTT CTGTGATGCATGAAGCCCTGCACAACCACT ACACTCAGAAGTCCCTGTCCCTCTCCCTGGG A SEQ ID NO: 810 (Kabat) LCDR1 RASES VEYYGTSLMQ SEQ ID NO: 811 (Kabat) LCDR2 AASNVES SEQ ID NO: 812 (Kabat) LCDR3 QQSRKDPST SEQ ID NO: 813 (Chothia) LCDR1 SESVEYYGTSL SEQ ID NO: 814 (Chothia) LCDR2 A.A.S. SEQ ID NO: 815 (Chothia) LCDR3 SRKDPS SEQ ID NO: 826 VL DIVLTQSPDSLAVSLGERATINCRASESVEYY

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GTSLMQWYQQKPGQPPKLLIYAASNVESGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQS RKDPSTFGGGTKVEIK SEQ ID NO: 827 DNA encoding VL GATATCGTCCTGACTCAGTCACCCGATAGC CTGGCCGTCAGCCTGGGCGAGCGGGCTACT ATTAACTGTAGAGCTAGTGAATCAGTCGAG TACTACGGCACTAGCCTGATGCAGTGGTAT CAGCAGAAGCCCGGTCAACCCCCTAAGCTG CTGATCTACGCCGCCTCTAACGTGGAATCA GGCGTGCCCGATAGGTTTAGCGGTAGCGGT AGTGGCACCGACTTCACCCTGACTAT TAGT AGCCTGCAGGCCGAGGACGTGGCCGTCTAC TACTGTCAGCAGTCTAGGAAGGACCCTAGC ACCTTCGGCGGAGGCACTAAGGTCGAGATT AAG SEQ ID NO: 828 Light chain DIVLTQSPDSLAVSLGERATINCRASESVEYY GTSLMQWYQQKPGQPPKLLIYAASNVESGVP DRFSGSGSGTDFTLTISSLQAEDVAVYYCQQS RKDPSTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EK HKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 829 DNA encoding the light chain GATATCGTCCTGACTCAGTCACCCGATAGC CTGGCCGTCAGCCTGGGCGAGCGGGCTACT ATTAACTGTAGAGCTAGTGAATCAGTCGAG TACTACGGCACTAGCCTGATGCAGTGGTAT CAGCAGAAGCCCGGTCAACCCCCTAAGCTG CTGATCTACGCCGCCTCTAACGTGGAATCA GGCGTGCCCGATAGGTTTAGCGGTAGCGGT AGTGGCACCGACTTCACCCTGACTAT TAGT AGCCTGCAGGCCGAGGACGTGGCCGTCTAC TACTGTCAGCAGTCTAGGAAGGACCCTAGC ACCTTCGGCGGAGGCACTAAGGTCGAGATT AAGCGTACGGTGGCCGCTCCCAGCGTGTTC ATCTTCCCCCCCAGCGACGAGCAGCTGAAG

- 235 047335

AGCGGCACCGCCAGCGTGGTGTGCCTGCTG AACAACTTCTACCCCCGGGAGGCCAAGGTG CAGTGGAAGGTGGACAACGCCCTGCAGAGC GGCAACAGCCAGGAGCGTCACCGAGCA GGACAGCAAGGACTCCACCTACAGCCTGAG CAGCACCCTGACCCTGAGCAAGGCCGACTA CGAGAAGCATAAGGTGTACGCCTGCGAGGT GACCCACCAGGGCCTGTCCAGCCC CGTGAC CAAGAGCTTCAACAGGGGCGAGTGC

Other exemplary TIM-3 inhibitors

In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio/Tesaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a TSR-022 heavy chain or light chain sequence. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an APE5137 or APE5121 heavy chain or light chain sequence, for example, those disclosed in Table. 12. ARE5137, ARE5121 and other anti-TIM-3 antibodies are disclosed in WO 2016/161270, incorporated by reference in its entirety.

In one embodiment, the anti-TIM-3 antibody molecule is LY3321367 (Eli Lilly). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence LY3321367.

In one embodiment, the anti-TIM-3 antibody molecule is the antibody clone F38-2E2. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an F38-2E2 heavy chain or light chain sequence.

Additional known anti-TIM-3 antibodies include those described, for example, in WO 2016/111947, WO 2016/071448, WO 2016/144803, US 8552156, US 8841418 and US 9163087, incorporated by reference in their entirety.

In one embodiment, an anti-TIM-3 antibody is an antibody that competes for and/or binds to the same epitope on TIM-3 as one of the anti-TIM-3 antibodies described herein.

Table 12

Amino acid sequences of other exemplary anti-TIM-3 antibody molecules

ARE5137 SEQ GO NO: 830 VH EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVR QAPGKGLDWVSTISGGGTYTYYQDSVKGRFTISRDNSKN TLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSSA SEQIDNO: 831 VL DIQMTQSPSSLSSASVGDRVTITCRASQSIRRYLNWYHQKP GKAPKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPED FAVYYCQQSHSAPLTFGGGTKVEIKR ARE5121 SEQ GO NO: 832 VH EVQVLESGGGLVQPGGSLRLYCVASGFTFSGSYAMSWVR QAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNT LYLQMNSLRAEDTAVYYCAKKYYVGPADYWGQGTLVT VSSG SEQ GO NO: 833 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLA WYQHKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLT ISSLQAEDVAVYYCQQYYSSPLTFGGGTKIEVK

Exemplary CTLA-4 inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a CTLA-4 inhibitor. The CTLA-4 inhibitor may be an

- 236 047335 antibody, its antigen-binding fragment, immunoadhesin, fusion protein or oligopeptide. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®, BristolMyers Squibb) or tremelimumab (Pfizer). The ipilimumab antibody and other anti-CTLA-4 antibodies are disclosed in US Pat. No. 6,984,202, incorporated herein by reference. The antibody tremelimumab and other anti-CTLA-4 antibodies are disclosed in US Pat. No. 7,411,057, incorporated herein by reference.

Exemplary GITR agonists

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a GITR agonist. The GITR agonist may be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. In some embodiments, the GITR agonist is GWN323 (Novartis), BMS-986156 (BMS), MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte/Agenus), AMG 228 (Amgen), or INBRX-110 (Inhibrx).

Exemplary anti-GITR antibody molecules

In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule described in WO 2016/057846, published April 14, 2016, entitled Compositions and Methods of Use for Augmented Immune Response and Cancer Therapy, incorporated by reference in its entirety.

In one embodiment, an anti-GITR antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all CDRs) from a heavy and light chain variable region comprising the amino acid sequence shown in table 13 (eg, from the MAB7 heavy and light chain variable region sequences disclosed in Table 13), or the encoded nucleotide sequence shown in Table 13. 13. In some embodiments, CDRs are defined in accordance with the Kabat numbering scheme (eg, as set forth in Table 13). In some embodiments, the CDRs are defined in accordance with the Chothia numbering scheme (eg, as set forth in Table 13). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequence, shown in table. 13, or the encoded nucleotide sequence shown in table. 13.

In one embodiment, an anti-GITR antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 909, the amino acid sequence of VHCDR2 of SEQ ID NO: 911, and the amino acid sequence of VHCDR3 of SEQ ID NO: 913; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 914, the amino acid sequence of VLCDR2 of SEQ ID NO: 916 and the amino acid sequence of VLCDR3 of SEQ ID NO: 918, each of which is disclosed in table. 13.

In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 901 or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 901. B In one embodiment, the anti-GITR antibody molecule comprises a VL comprising an amino acid sequence of SEQ ID NO: 902, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 902. In one In an embodiment, the anti-GITR antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 901, and a VL containing the amino acid sequence of SEQ ID NO: 902.

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 905 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 905. In one embodiment An antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 906, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 906. In one embodiment, the antibody molecule contains VH encoded by the nucleotide sequence of SEQ ID NO: 905, and VL encoded by the nucleotide sequence of SEQ ID NO: 906.

In one embodiment, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 903, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 903. In one embodiment, the anti-GITR antibody molecule contains a light chain comprising the amino acid sequence of SEQ ID NO: 904 or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 904. In one embodiment, an anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 903 and a light chain comprising the amino acid sequence of SEQ ID NO: 904.

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In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 907. In one in an embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 908, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 908. In one embodiment the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 908.

The antibody molecules described herein can be produced using the vectors, host cells and methods described in WO 2016/057846, incorporated by reference in its entirety.

Table 13

Amino acid and nucleotide sequences of an exemplary anti-GITR antibody molecule

MAV7 SEQ GO NO: 901 VH EVQLVESGGGLVQSGGSLRLSCAASGFSLS SYGVDWVRQAPGKGLEWVGVIWGGGGT YYASSLMGRFTISRDNSKNTLYLQMNSLR AEDTAVYYCARHAYGHDGGFAMDYWGQ GTLVTVSS SEQ GO NO: 902 VL EIVMTQSPATLSVSPGERATLLSCRASESVSS NVAWYQQRPGQAPRLLIYGASNRATGIPA RFSGSGSGTDFTLTISRLEPEDFAVYYCGQS YSYPFTFGQGTKLEIK SEQ GO NO: 903 Heavy chain EVQLVESGGGLVQSGGSLRLSCAASGFSLS SYGVDWVRQAPGKGLEWVGVIWGGGGT YYASSLMGRFTISRDNSKNTLYLQMNSLR

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AEDTAVYYCARHAYGHDGGFAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTA ALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFN WYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK SEQ GO NO: 904 Light chain EIVMTQSPATLSVSPGERATLSCRASESVSS NVAWYQQRPGQAPRLLIYGASNRATGIPA RFSGSGSGTDFTLTISRLEPEDFAVYYCGQS YSYPFTFGQGTKLEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKV YACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 905 DNA encoding VH GAGGTGCAGCTGGTGGAATCTGGCGGCG GACTGGTGCAGTCCGGCGGCTCTCTGAG ACTGTCTTGCGCTGCCTCCGGCTTCTCCC TGTCCTCTTACGGCGTGGACTGGGTGCGA CAGGCCCCTGGCAAGGGCCTGGAATGGG TGGGAGTGATCTGGGGCGGAGGCGGCAC CTACTACGCCTCTTCCCTGATGGGCCGGT TCACCATCTCCCGGGGACAACTCCAAGAA CACCCTGTACCTGCAGATGAACTCCCTGC GGGCCGAGGACACCGCCGTGTACTACTG CGCCAGACACGCCTACGGCCACGACGGC GGCTTCGCCATGGATTATTGGGGCCAGG GCACCCTGGTGACAGTGTCCTCC SEQ ID NO: 906 DNA, GAGATCGTGATGACCCAGTCCCCCGCCA

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coding VL CCCTGTCTGTGTCTCCCGGCGAGAGAGCC ACCCTGAGCTGCAGAGCCTCCGAGTCCG TGTCCTCCAACGTGGCCTGGTATCAGCAG AGACCTGGTCAGGCCCCTCGGCTGCTGAT CTACGGCGCCTCTAACCGGGCCACCGGC ATCCCTGCCAGATTCTCCGGCTCCGGCAG CGGCACCGACTTCACCCTGACCATCTCCC GGCTGGAACCCGAGGACTTCGCCGTGTA CTACTGCGGCCAGTCCTACTCATACCCCT TCACCTTCGGCCAGGGCACCAAGCTGGA AATCAAG SEQ GO NO: 907 DNA encoding the heavy chain GAGGTGCAGCTGGTGGAATCTGGCGGCG GACTGGTGCAGTCCGGCGGCTCTCTGAG ACTGTCTTGCGCTGCCTCCGGCTTCTCCC TGTCCTCTTACGGCGTGGACTGGGTGCGA CAGGCCCCTGGCAAGGGCCTGGAATGGG TGGGAGTGATCTGGGGCGGAGGCGGCAC CTACTACGCCTCTTCCCTGATGGGCCGGT TCACCATCTCCCGGACAACTCCAAGAA CACCCTGTACCTGCAGATGAACTCCCTGC GGGCCGAGGACACCGCCGTGTACTACTG CGCCAGACACGCCTACGGCCACGACGGC GGCTTCGCCATGGATTATTGGGGCCAGG GCACCCTGGTGACAGTGTCCTCCGCTAGC ACCAAGGGCCCAAGTGTGTTTCCCCTGGC CCCCAGCAGCAAGTCTACTTCCGGCGGA ACTGCTGCCCTGGGTTGCCTGGTGAAGG CGAGCCCGTGACAGTGTCC TGGAACTCTGGGGCTCTGACTTCCGGCGT GCACACCTTCCCCGCCGTGCTGCAGAGC AGCGGCCTGTACAGCCTGAGCAGCGTGG TGACAGTGCCCTCCAGCTCTCTGGGAACC CAGACCTATATCTGCAACGTGAACCACA AGCCCAGCAACACCAAGGTGGACAAGAG AGTGGAGCCCAAGAGCTGCGACAAGACC

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CACACCTGCCCCCCCTGCCCCAGCTCCAGA ACTGCTGGGAGGGCCTTCCGTGTTCCTGT TCCCCCCCAAGCCCAAGGACACCCTGAT GATCAGCAGGACCCCCGAGGTGACCTGC GTGGTGGTGGACGTGTCCCACGAGGACC CAGAGGTGAAGTTCAACTGGTACGTGGA CGGCGTGGAGGTGCACAACGCCAAGACC AAGCCCAGAGAGGAGCAGTACAACAGCA CCTACAGGTGGTGTCCGTGCTGACCGTG CTGCACCAGGACTGGCTGAACGGCAAAG AATACAAGTGCAAAGTCTCCAACAAGGC CCTGCCAGCCCCAATCGAAAAGACAATC AGCAAGGCCAAGGGCCAGCCACGGGAGC CCCAGGTGTACACCCTGCCCCCCAGCCG GGAGGAGATGACCAAGAACCAGGTGTCC CTGACCTGTCTGGTGAAGGGCTTCTACCC CAGCGATATCGCCGTGGAGTGGGAGAGC AACGGCCAGCCCGAGAACAACTACAAGA CCACCCCCCCAGTGCTGGACAGCGACGG CAGCTTCTTCCTGTACAGCAAGCTGACCG TGGACAAGTCCAGGTGGCAGCAGGGCAA CGTGTTCAGCTGCAGCGTGATGCACGAG GCCCTGCACAACCACTACACCCCAGAAGT CCCTGAGCCTGAGCCCCGGCAAG SEQ GO NO: 908 DNA encoding the light chain GAGATCGTGATGACCCAGTCCCCCGCCA CCCTGTCTGTGTCTCCCGGCGAGAGAGCC ACCCTGAGCTGCAGAGCCTCCGAGTCCG TGTCCTCCAACGTGGCCTGGTATCAGCAG AGACCTGGTCAGGCCCCTCGGCTGCTGAT CTACGGCGCCTCTAACCGGGCCACCGGC ATCCCTGCCAGATTCTCCGGCTCCGGCAG CGGCACCGACTTCACCCTGACCATCTCCC GGCTGGAACCCGAGGACTTCGCCGTGTA CTACTGCGGCCAGTCCTACTCATACCCCT TCACCTTCGGCCAGGGCACCAAGCTGGA

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AATCAAGCGTACGGTGGCCGCTCCCAGC GTGTTCATCTTCCCCCCCAGCGACGAGCA GCTGAAGAGCGGCACCGCCAGCGTGGTG TGCCTGCTGAACAACTTCTACCCCCGGA GGCCAAGGTGCAGTGGAAGGTGGACAAC GCCCTGCAGAGCGGCAACAGCCAGGAGA GCGTCACCGAGCAGGACAGCAAGGACTC CACCTACAGCCTGAGCAGCACCCTGACC CAAGGCCGACTACGAGAAGCATA AGGTGTACGCCTGCGAGGTGACCCACCA GGGCCTGTCCAGCCCCGTGACCAAGGC TTCAACAGGGGCGAGTGC SEQ GO NO: 909 (KABAT) HCDR1 SYGVD SEQ GO NO: 910 (CHOTHIA) HCDR1 GFSLSSY SEQ ID NO: 911 (KABAT) HCDR2 VIWGGGGTYYASSLMG SEQ ID NO: 912 (CHOTHIA) HCDR2 WGGGG SEQ ID NO: 913 (KABAT) HCDR3 HAYGHDGGFAMDY SEQ ID NO: 913 (CHOTHIA) HCDR3 HAYGHDGGFAMDY SEQ ID NO: 914 (KABAT) LCDR1 RASESVSSNVA SEQ ID NO: 915 (CHOTHIA) LCDR1 SESVSSN SEQ ID NO: 916 (KABAT) LCDR2 GASNRAT SEQ ID NO: 917 (CHOTHIA) LCDR2 G.A.S. SEQ ID NO: 918 (KABAT) LCDR3 GQSYSYPFT SEQ ID NO: 919 (CHOTHIA) LCDR3 SYSYPF

Other illustrative GITR agonists

In one embodiment, the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS 986156 or BMS986156. BMS-986156 and other anti-GITR antibodies are disclosed, for example, in US 9228016 and WO 2016/196792, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a BMS-986156 heavy chain or light chain sequence, for example, those disclosed in Table 1. 14.

In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK

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1248 (Merck). MK-4166, MK-1248 and other antibodies to GITR are disclosed, for example, in US 8709424, WO 2011/028683, WO 2015/026684 and Mahne et al. Cancer Res. 2017; 77(5):1108-1118, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a MK-4166 or MK-1248 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is TRX518 (Leap Therapeutics). TRX518 and other antibodies to GITR are disclosed, for example, in US 7812135, US 8388967, US 9028823, WO 2006/105021 and Ponte J et al. (2010) Clinical Immunology; 135:S96, incorporated by reference in its entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a TRX518 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is INCAGN1876 (Incyte/Agenus). INCAGN1876 and other anti-GITR antibodies are disclosed, for example, in US 2015/0368349 and WO 2015/184099, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an INCAGN1876 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is AMG 228 (Amgen). AMG 228 and other anti-GITR antibodies are disclosed, for example, in US 9464139 and WO 2015/031667, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an AMG 228 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is INBRX-110 (Inhibrx). INBRX-110 and other anti-GITR antibodies are disclosed, for example, in US 2017/0022284 and WO 2017/015623, incorporated by reference in their entirety. In one embodiment, the GITR agonist comprises one or more CDR sequences (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or an INBRX-110 heavy chain or light chain sequence.

In one embodiment, the GITR agonist (eg, fusion protein) is MEDI 1873 (MedImmune), also known as MEDI1873. MEDI 1873 and other GITR agonists are disclosed, for example, in US 2017/0073386, WO 2017/025610 and Ross et al. Cancer Res 2016; 76(14 Suppl): Abstract No. 561, incorporated by reference in its entirety. In one embodiment, the GITR agonist comprises one or more of an IgG Fc domain, a functional multimerization domain, and a receptor binding domain from glucocorticoid-inducible TNF receptor ligand (GITRL) MEDI 1873.

Additional known GITR agonists (eg, anti-GITR antibodies) include those described, for example, in WO 2016/054638, incorporated by reference in its entirety.

In one embodiment, an anti-GITR antibody is an antibody that competes for and/or binds to the same epitope on GITR as one of the anti-GITR antibodies described herein.

In one embodiment, the GITR agonist is a peptide that activates the GITR signaling pathway. In one embodiment, the GITR agonist is an immunoadhesin binding fragment (eg, an immunoadhesin binding fragment comprising an extracellular or GITR binding portion of GITRL) fused to a constant region (eg, an immunoglobulin Fc region sequence).

Table 14

Amino acid sequences of other exemplary anti-GITR antibody molecules

BMS-986156 SEQ GO NO: 920 VH QVQLVESGGGVVQPGRSLRLSCAASGFFSSYGMHWVR QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSK NTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMD VWGQGTTVTVSS SEQ GO NO: 921 VL AIQLTQSPSSLSSASVGDRVTITCRASQGISSALAWYQQKP GKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQFNSYPYTFGQGTKLEIK

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Exemplary CD3 Multispecific Antibody Molecules

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a multispecific anti-CD3 antibody molecule (eg, a bispecific anti-CD3 antibody molecule). In one embodiment, the multispecific anti-CD3 antibody molecule binds to CD3 and a target tumor antigen (TTA). In one embodiment, the TTA is selected from CD19, CD20, CD38 or CD123. In one embodiment, the multispecific anti-CD3 antibody molecule is in the format disclosed in FIG. 1A, 1B, 1C and 125 in WO 2016/182751, which is incorporated herein by reference in its entirety.

In one embodiment, the multispecific anti-CD3 antibody molecule is a bispecific anti-CD3xCD123 antibody molecule, e.g., XENP14045 (e.g., as set forth in Table 15), or a bispecific anti-CD3xCD123 antibody molecule disclosed in WO 2016/086189 or WO 2016/182751, incorporated herein by reference in their entirety. In one embodiment, the anti-CD3xCD123 bispecific antibody molecule comprises one or more CDR sequences (or all CDR sequences), a heavy chain or light chain variable region sequence, or a XENP14045 heavy chain or light chain sequence, or an amino acid sequence substantially identical thereto (e.g. , a sequence having at least about 85%, 90%, or 95% sequence identity with them).

In one embodiment, the multispecific anti-CD3 antibody is a bispecific anti-CD3xCD20 antibody molecule, e.g., XENP13676 (e.g., as set forth in Table 15), or a bispecific anti-CD3xCD20 antibody molecule disclosed in WO 2016/086189 or WO 2016/182751, included incorporated into this document by reference in their entirety. In one embodiment, the anti-CD3xCD20 bispecific antibody molecule comprises one or more CDR sequences (or all CDR sequences), a heavy chain or light chain variable region sequence, or a XENP13676 heavy chain or light chain sequence, or an amino acid sequence substantially identical thereto (e.g. , a sequence having at least about 85%, 90%, or 95% sequence identity with them).

Table 15

Amino acid sequences of exemplary anti-CD3 bispecific antibody molecules

XENP14045 (Fab-scFv-Fc antibodies to

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CD123 x CD3) SEQ GO NO: 177 Heavy chain 1 (Fab-Fc antibodies to CD123) QVQLQQSGAEVKKPGASVKVSCKASGYTFTDY YMKWVKQSHGKSLEWMGDIIPSNGATFYNQKF KGKATLTVDRSTSTAYMELSSLRSEDTAVYYCA RSHLLRASWFAYWGQGTLVTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLG TQTYICNVNHKPSDTKVDKKVEPKSCDKTHTCP PCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV VDVKHEDPEVKFNWYVDGVEVHNAKTKPREEE YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCDVSGFYPS DIAVEWESDGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWEQGDVFSCSV MHEALHNHYTQKSLSLSPGK SEQ ID NO: 178 Heavy chain 2 (scFv-Fc antibodies to CD3) EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYA MNWVRQAPGKGLEWVGRIRSKYNNYATYYAD SVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYY CVRHGNFGDSYVSWFAYWGQGTLVTVSSGKPG SGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGT VTLTCGSSTGAVTTSNYANWVQQKPGK SPRGLI GGTNKRAPGVPARFSGSLLGGKAALTISGAQPE DEADYYCALWYSNHWVFGGGTKLTVLEPKSSD KTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTP EVTCVVVDVKHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPS REQMTKNQVKLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 179 Light chain DFVMTQSPDSLAVSLGERATINCKSSQSLLNTGN QKNYLTWYQQKPGQPPKLLIYWASTRESGVPDR FTGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYP YTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTA SVVCLLNNFYPREAKVQWKVDNALQSGNSQES

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VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC XENP13676 (Fab-scFv-Fc antibodies to CD20 x CD3) SEQ GO NO: 180 Heavy chain 1 (Fab-Fc) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSY NMHWVRQAPGQGLEWMGAIYPGNGDTSYNQK FQGRVTITADKSISTAYMELSSLRSEDTAVYYCA RSTYYGGDWYFNVWGAGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GT QTYICNVNHKPSDTKVDKKVEPKSCDKTHTC PPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCV VVDVKHEDPEVKFNWYVDGVEVHNAKTKPREE EYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCDVSGFYPSDIAVEW ESDGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWEQGDVFSCS VMHEALHNHYTQKSLSLSPGK SEQ GO NO: 181 Heavy chain 2 (scFv-Fc) EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYA MNWVRQAPGKGLEWVGRIRSKYNNYATYYAD SVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYY CVRHGNFGDSYVSWFAYWGQGTLVTVSSGKPG SGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGT VTLTCGSSTGAVTTSNYANWVQQKPGK SPRGLI GGTNKRAPGVPARFSGSLLGGKAALTISGAQPE DEADYYCALWYSNHWVFGGGTKLTVLEPKSSD KTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTP EVTCVVVDVKHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPS REQMTKNQVKLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 182 Light chain QIVLTQSPSSLSASVGDRVTITCRASSSVSYIHWF QQKPGKSPKPLIYATSNLASGVPVRFSGSGSGTD YTLTISSLQPEDFATYYCQQWTSNPPTFGGGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF YPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKV YACEVTHQGLSSP VTKSFNRGEC

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Exemplary IL15/IL-15Ra complexes

In certain embodiments, the anti-CD73 antibody molecule described herein is administered in combination with the IL-15/IL-15Ra complex. In some embodiments, the IL-15/IL-15Ra complex is selected from NIZ985 (Novartis), ATL-803 (Altor), or CYP0150 (Cytune).

Exemplary IL-15/IL-15Ra complexes

In one embodiment, the IL-15/IL-15Ra complex contains human IL-15 complexed with a soluble form of human IL-15Ra. The complex may contain IL-15 covalently or non-covalently associated with a soluble form of IL-15Ra. In a specific embodiment, human IL-15 is non-covalently associated with a soluble form of IL-15Ra. In a specific embodiment, human IL-15 of the composition contains the amino acid sequence of SEQ ID NO: 183 from table. 16, and the soluble form of IL-15Ra contains the amino acid sequence of SEQ ID NO: 184 from table. 16, described in W0 2014/066527, incorporated by reference in its entirety. The molecules described herein can be produced using the vectors, host cells and methods described in WO 2007/084342, incorporated by reference in its entirety.

Table 16

Amino acid and nucleotide sequences of exemplary IL-15/IL-15Ra complexes

NIZ985 SEQ ID NO: 183 Human IL-15 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKV TAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSS NGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS SEQ ID NO: 184 Soluble IL-15Ra person ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAG TSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPA PPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATT AAIVPGSQLMPSKSPSTGTTEISSHESSHGTPSQTTAKN WELTASASHQPPGVYPQG

Other Exemplary IL-15/IL-15Ra Complexes

In one embodiment, the IL-15/IL-15Ra complex is ALT-803, an IL-15/IL-15Ra and Fc fusion protein (soluble IL-15N72D:IL-15RaSu/Fc complex). ALT-803 is described in WO 2008/143794, incorporated by reference in its entirety. In one embodiment, the IL-15/IL-15Ra and Fc fusion protein contains the sequences disclosed in table. 17.

In one embodiment, the IL-15/IL-15Ra complex contains IL-15 fused to the sushi domain of IL-15Ra (CYP0150, Cytune). The sushi domain of IL-15Ra refers to the domain starting from the first cysteine residue after the signal peptide of IL-15Ra and ending with the fourth cysteine residue after the signal peptide. The IL-15 complex fused to the sushi domain of IL-15Ra is disclosed in WO 2007/04606 and WO 2012/175222, incorporated by reference in their entirety. In one embodiment, the IL-15/IL-15Ra sushi domain fusion protein contains the sequences disclosed in table. 17.

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Table 17

Amino acid sequences of other exemplary IL-15/IL-15Ra complexes

ALT-803 (Aitor) SEQ ID NO: 185 IL-15N72D NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTA MKCFLLELQVISLESGDASIHDTVENLIILANDSLSSNGNV TESGCKECEELEEKNIKEFLQSFVHIVQMFINTS SEQ ID NO: 186 IL- 15RaSu/Fc ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTS SLTECVLNKATNVAHWTTPSLKCIREPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK IL-15/sushi domain IL-15Ra fusion protein (Cytune) SEQ ID NO: 187 IL-15 person NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTA MKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNV TESGCKECEELEXKNIKEFLQSFVHIVQMFINTS Where X represents E or K SEQ ID NO: 188 Sushi domain and hinge domain of IL15Ra ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTS SLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPP person

Illustrative STING Agonists

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a STING agonist. In some embodiments, the combination is used to treat cancer, e.g., a cancer described herein, e.g., a solid tumor (e.g., breast cancer, squamous cell carcinoma, melanoma, ovarian cancer, fallopian tube carcinoma, peritoneal carcinoma, soft tissue sarcoma, cancer esophagus, head and neck cancer, endometrial cancer, cervical cancer, or basal cell carcinoma), such as a hematologic malignancy (eg, leukemia (eg, chronic lymphocytic leukemia (CLL)) or lymphoma (eg, marginal zone B-cell lymphoma, small cell lymphocytic lymphoma , follicular lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma)). In some embodiments, the cancer is selected from head and neck cancer (eg, head and neck squamous cell carcinoma (HNSCC), skin cancer (eg, melanoma), lung cancer (eg, non-small cell cancer). lung (NSCLC)) or breast cancer (eg, triple negative breast cancer (TNBC)).

In some embodiments, the STING agonist is a cyclic dinucleotide, such as a cyclic dinucleotide that contains purine or pyrimidine nucleotide bases (eg, adenosine, guanine, uracil, thymine, or cytosine nucleotide bases). In some embodiments, the nucleotide bases of the cyclic dinucleotide include the same nucleotide base or different nucleotide bases.

In some embodiments, the STING agonist comprises adenosine or guanosine nucleotide bases. In some embodiments, the STING agonist comprises one adenosine nucleotide base and one guanosine nucleotide base. In some embodiments, the STING agonist contains two adenosine nucleotide bases or two guanosine nucleotide bases.

In some embodiments, the STING agonist includes a modified cyclic

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In some embodiments, the STING agonist comprises a cyclic dinucleotide (eg, a modified cyclic dinucleotide) with 2',5' or 3',5' phosphate linkages. In some embodiments, the STING agonist includes a cyclic dinucleotide (eg, a modified cyclic dinucleotide) with Rp or Sp stereochemistry around phosphate bonds.

In some embodiments, the STING agonist is Rp, Rp-dithio-2',3'-c-diAMP (e.g., Rp, Rp-dithino-c-[A(2',5')pA(3',5' )p]) or its cyclic dinucleotide analogue. In some embodiments, the STING agonist is a compound shown in US Patent Publication No. US2015/0056224 (eg, the compound in FIG. 2c, eg, compound 21 or compound 22). In some embodiments, the STING agonist is c[G(2',5')pG(3',5')p], its O-substituted dithioribose derivative, or the compound shown in FIG. 4 publications according to PCT Nos. WO 2014/189805 and WO 2014/189806. In some embodiments, the STING agonist is c-[A(2',5')pA(3',5')p] or an O-substituted dithioribose derivative thereof, or the compound shown in FIG. 5 publications according to PCT Nos. WO 2014/189805 and WO 2014/189806. In some embodiments, the STING agonist is c-[G(2',5')pA(3',5')p] or an O-substituted dithioribose derivative thereof, or the compound shown in FIG. 5 publications according to PCT Nos. WO 2014/189805 and WO 2014/189806. In some embodiments, the STING agonist is 2'-O-propargylcyclic-[A(2',5')pA(3',5')p] (2'-O-propargyl-ML-CDA) or a compound shown in fig. 7 publications according to PCT No. WO 2014/189806.

Other exemplary STING agonists are disclosed, for example, in PCT Publication Nos. WO 2014/189805 and WO 2014/189806 and US Publication No. 2015/0056225.

Exemplary CSF-1/1R Binding Agents

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a CSF-1/1R binding agent. In some embodiments, the combination is used to treat cancer, such as a cancer described herein, such as a solid tumor (eg, prostate cancer, breast cancer, or pigmented villonodular synovitis (PVNS)).

In some embodiments, the CSF-1/1R binding agent is a macrophage colony-stimulating factor (M-CSF) inhibitor. M-CSF is also sometimes known as CSF-1.

In another embodiment, the CSF-1/1R binding agent is a CSF-1R tyrosine kinase inhibitor, 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl )oxy)-Nmethylpicolinamide (compound A15) or a compound disclosed in PCT Publication No. WO 2005/073224. In some embodiments, the cancer is selected from brain cancer (eg, glioblastoma multiforme (GBM)), pancreatic cancer, or breast cancer (eg, triple negative breast cancer (TNBC)).

In another embodiment, a CSF-1/1R binding agent (e.g., CSF-1R tyrosine kinase inhibitor, 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl )oxy)-N-methyl picolinamide (compound A15) or a compound disclosed in PCT Publication No. WO 2005/073224 is administered in combination with a CD73 inhibitor (eg an anti-CD73 antibody molecule).

In certain embodiments, a CSF-1/1R binding agent (e.g., a CSF-1R tyrosine kinase inhibitor), 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazole-6- yl)oxy)-Nmethylpicolinamide (compound A15) or a compound disclosed in PCT Publication No. WO 2005/073224 is administered in combination with a CD73 inhibitor (eg an anti-CD73 antibody molecule) for the treatment of cancer, eg solid tumor (eg solid advanced tumors), such as brain cancer (eg, glioblastoma multiforme (GBM), eg, recurrent glioblastoma), breast cancer (eg, triple negative breast cancer (eg, NTBC)), or pancreatic cancer (eg, pancreas at a late stage).

In some embodiments, the CSF-1/1R binding agent is an M-CSF inhibitor, Compound A33, or a CSF-1 binding agent disclosed in PCT Publication No. WO 2004/045532 or PCT Publication No. WO 2005/068503. including RX1 or 5H4 (for example, an antibody molecule or Fab fragment to M-CSF). In some embodiments, the cancer is selected from endometrial cancer, skin cancer (eg, melanoma), pancreatic cancer, or breast cancer (eg, triple negative breast cancer (TNBC)).

In some embodiments, the CSF-1/1R binding agent is a CSF1R inhibitor or 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy)-N-methylpicolinamide. 4-(2-((1R,2R)-2-hydroxycyclohexylαamino)benzothiazol-6-yloxy)-N-methylpicolinamide is disclosed as Example 157 on page 117 of PCT Publication No. WO 2007/121484.

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In some embodiments, the CSF-1/1R binding agent is pexidartinib (CAS registration number 1029044-16-3). Pexidartinib is also known as PLX3397 or 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl) pyri din-2-amine. Pexidartinib is a small molecule inhibitor of the receptor tyrosine kinases (RTKs) KIT, CSF1R and FLT3. In some embodiments, a CSF-1/1R binding agent, such as pexidartinib, is used in combination with a CD73 inhibitor, such as an anti-CD73 antibody molecule described herein.

In some embodiments, the CSF-1/1R binding agent is emactuzumab. Emactuzumab is also known as RG7155 or RO5509554. Emactuzumab is a humanized IgG1 mAb targeting CSF1R. In some embodiments, a CSF-1/1R binding agent, such as pexidartinib, is used in combination with a CD73 inhibitor, such as an anti-CD73 antibody molecule described herein.

In some embodiments, the CSF-1/1R binding agent is FPA008. FPA008 is a humanized mAb that inhibits CSF1R. In some embodiments, a CSF-1/1R binding agent, such as FPA008, is used in combination with a CD73 inhibitor, such as an anti-CD73 antibody molecule described herein.

Exemplary IDO/TDO Inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with an indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) inhibitor. In some embodiments, the combination is used to treat cancer, e.g., a cancer described herein, e.g., a solid tumor (e.g., melanoma, non-small cell lung cancer, colon cancer, squamous cell carcinoma of the head and neck, ovarian cancer, peritoneal cancer, fallopian cancer tube, breast cancer (eg, metastatic or HEK2-negative breast cancer)), for example, hematologic malignancy (eg, lymphoma, such as non-Hodgkin's lymphoma or Hodgkin's lymphoma (eg, diffuse large B-cell lymphoma (DLBCL))).

In some embodiments, the IDO/TDO inhibitor is selected from (4E)-4-[(3-chloro-4fluoroanilino)nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as INCB24360), indoximod (1-methyl -O-tryptophan) or α-cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919).

In some embodiments, the IDO/TDO inhibitor is epacadostat (CAS registration number: 1204669-58-8). Epacadostat is also known as INCB24360 or INCB024360 (Incyte). Epacadostat is a potent and selective inhibitor of indoleamine 2,3 dioxygenase (IDO1) with an IC50 of 10 nM, with high selectivity compared to other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO).

In some embodiments, the IDO/TDO inhibitor is indoximod (New Link Genetics). Indoximod, a D-isomer of 1-methyl-tryptophan, is an orally administered small molecule inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway that disrupts the mechanisms by which tumors escape immune-mediated destruction.

In some embodiments, the IDO/TDO inhibitor is NLG919 (New Link Genetics). NLG919 is a potent inhibitor of the IDO (indoleamine (2,3)-dioxygenase) pathway with a Ki/EC50 of 7 nM/75 nM in cell-free assays.

In some embodiments, the IDO/TDO inhibitor is F001287 (Flexus/BMS). F001287 is a small molecule inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1).

Exemplary TGF-β inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a transforming growth factor beta (TGF-β) inhibitor. In some embodiments, the combination is used to treat a cancer, e.g., a cancer described herein, e.g., a solid tumor (e.g., brain cancer (e.g., glioma), melanoma, kidney cancer (e.g., renal cell carcinoma), malignant mesothelioma pleura (eg, recurrent malignant pleural mesothelioma) or breast cancer (eg, metastatic breast cancer)). In certain embodiments, the cancer is selected from colorectal cancer (e.g., microsatellite stability colorectal cancer (MSS CRC), liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer (HSCLC)), breast cancer (e.g., triple negative breast cancer (TNBC), TGF-β expressing cancer, pancreatic cancer, prostate cancer, or kidney cancer (eg, renal cell carcinoma).

TGF-β belongs to a large family of structurally related cytokines, including, for example, bone morphogenetic proteins (BMPs), growth and differentiation factors, activins and inhibins. In some embodiments, TGF-β inhibitors described herein can bind and/or inhibit one or more TGF-β isoforms (e.g., one, two, or all of

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TGF-β!, TGF-e2 or TGF-v3).

In some embodiments, the TGF-β inhibitor is frezolimumab (CAS registration number: 948564-73-6). Frezolimumab is also known as GC1008. Frezolimumab is a human monoclonal antibody that binds to and inhibits TGF-beta isoforms 1, 2 and 3.

The heavy chain of frezolimumab is characterized by the amino acid sequence:

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSSNVISWVRQAPGQGLEWMGGVIPIVDIA NYAQRFKGRVTITADESTSTTYMELSSLRSEDTAVYYCASTLGLVLDAMDYWGQGTLV TVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS QEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 172).

The light chain of fresolimumab is characterized by the amino acid sequence: ETVLTQSPGTLLSLSPGERATLSCRASQSLGSSYLAWYQQKPGQAPRLLIYGASSRAPGIP

DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYADSPrrFGQGTRLEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 173).

Frezolimumab is disclosed, for example, in WO 2006/086469, US 8383780 and US 8591901.

In some embodiments, the TGF-β inhibitor is HOMA 089. HOMA 089 is also known as XPA.42.089. HOMA 089 is a fully human monoclonal antibody that binds and neutralizes TGF-beta ligands 1 and 2.

The heavy chain variable region of HOMA 089 has the amino acid sequence:

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTAN

YAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGLWEVRALPSVYWGQGTLV

TVSS (SEQ Ш NO: 174) (disclosed under SEQ Ш NO: 6 in WO 2012/167143).

The variable region of the light chain of HOMA 089 has the amino acid sequence: SYELTQPPSVSVAPGQTARITCGANDIGSKSVHWYQQKAGQAPVLVVSEDIIRPSGIPERI

SGSNSGNTATLTISRVEAGDEADYYCQVWDRDSDQYVFGTGTKVTVLG (SEQ ID NO:

175) (disclosed under SEQ ID NO: 8 in WO 2012/167143).

In certain embodiments, the combination comprises a CD73 inhibitor (eg, an anti-CD73 antibody molecule described herein) and a TGF-β inhibitor (eg, a TGF-β inhibitor described herein).

In one embodiment, the combination contains a TGF-β inhibitor, HOMA 089 or a compound disclosed in PCT Publication No. WO 2012/167143, and a CD73 inhibitor (eg, an anti-CD73 antibody described herein).

In one embodiment, a TGF-β inhibitor, HOMA 089 or a compound disclosed in PCT Publication No. WO 2012/167143 is administered in combination with a CD73 inhibitor (eg, an anti-CD73 antibody molecule) for the treatment of pancreatic cancer, colorectal cancer (eg, microsatellite stability colorectal cancer (MSS-CRC), lung cancer (eg, non-small cell lung cancer), breast cancer (eg, triple negative breast cancer), liver cancer (eg, hepatocellular carcinoma), prostate cancer, or kidney cancer (eg, clear cell renal cell carcinoma).

Exemplary VEGFR Inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a vascular endothelial growth factor (VEGF) receptor inhibitor (e.g., an inhibitor of one or more of the VEGFRs (e.g., VEGFR-1, VEGFR-2, or VEGFR-3 ) or VEGF). In some embodiments, the combination is used to treat a cancer, such as a cancer described herein, such as a solid tumor (eg, melanoma, breast cancer, colon cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), kidney cancer ( for example, renal cell carcinoma), liver cancer, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer or stomach cancer), for example, hematological malignancy (for example, lymphoma).

In other embodiments, the VEGFR inhibitor is vatalanib succinate (compound A47) or a compound disclosed in EP 296122.

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In another embodiment, the VEGFR inhibitor is one or more of VEGFR-2, PDGFRbeta, KIT or Raf C kinase, 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2yl)pyridin-4 -yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzoshimidazol-2-amine (compound A37) or a compound disclosed in PCT Publication No. WO 2007/030377.

Other exemplary VEGFR pathway inhibitors that may be used in the combinations disclosed herein include, for example, bevacizumab (AVASTIN®), axitinib (INLYTA®); brivanib alaninate (BMS-582664, ^)-(^)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo [2,1-1][1, 2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate); sorafenib (NEXAVAR®); pazopanib (VOTRIENT®); sunitinib malate (SUTENT®); cediranib (AZD2171, CAS 288383-20-1); vargatef (BIBF1120, CAS 928326-83-4); foretinib (GSK1363089); telatinib (BAY57-9352, CAS 332012-40-5); apatinib (YN968D1, CAS 811803-05-1); imatinib (GLEEVEC®); ponatinib (AP24534, CAS 943319-708); tivozanib (AV951, CAS 475108-18-0); regorafenib (BAY73-4506, CAS 755037-03-7); vatalanib dihydrochloride (PTK787, CAS 212141-51-0); brivanib (BMS-540215, CAS 649735-46-6); vandetanib (CAPRELSA® or AZD6474); motesanib diphosphate (AMG706, CAS 857876-30-3, N(2,3-dihydro-3,3dimethyl-III-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in publications according to PCT No. WO 02/066470); linfanib (ABT869, CAS 796967-16-3); cabozantinib (XL184, CAS 849217-68-1); lestaurtinib (CAS 111358-88-4); No.[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R, 4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-e][1,2,4]triazin-5-yl)methyl)piperidin- 3-ol (BMS690514); N(3,4-dichloro-2fluorophenyl)-6-methoxy-7-[[(3aα, 5β, 6aa)octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-III-pyrazolo[3,4L]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide (BHG712, CAS 940310-85-0); aflibercept (EYLEA®) and endostatin (ENDOSTAR®).

Exemplary anti-VEGF antibodies that can be used in the combinations disclosed herein include, for example, a monoclonal antibody that binds to the same epitope as the anti-VEGF monoclonal antibody A4.6.1 derived from ATCC hybridoma FIB 10709; recombinant humanized anti-VEGF monoclonal antibody prepared according to Presta et al. (1997) Cancer Res. 57:4593–4599. In one embodiment, the anti-VEGF antibody is bevacizumab (BV), also known as rhuMAb VEGF or AVASTIN®. It contains mutated human IgG1 framework regions and antigen-binding complementarity-determining regions from the murine anti-hVEGF monoclonal antibody A.4.6.1, which blocks the binding of human VEGF to its receptors. Bevacizumab and other humanized anti-VEGF antibodies are further described in US Patent No. 6,884,879, filed February 26, 2005. Additional antibodies include the G6 or B20 series antibodies (eg, G6-31, B20-4.1) described in PCT Publication No. WO2005/012359 , publication according to PCT No. WO2005/044853, the contents of these patent applications are expressly incorporated herein by reference. For additional antibodies, see US Patent Nos. 7060269, 6582959, 6703020, 6054297, WO98/45332, WO 96/30046, WO94/10202, EP 0666868B1, US Patent Application Publication No. 2006/009360, 208, 2003/ 0206899, 2003/0190317, 2003/0203409 and 2005/0112126; and Popkov et al, Journal of Immunological Methods 288: 149-164 (2004). Other antibodies include antibodies that bind to a functional epitope on human VEGF containing residues F17, Ml 8, D19, Y21, Y25, Q89, 191, K1 01, E1 03 and C104 or, alternatively, containing residues F17, Y21, Q22 Y25, D63, 183 and Q89.

Exemplary c-MET inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a c-MET inhibitor. In some embodiments, the combination is used to treat cancer, e.g., a cancer described herein, e.g., a solid tumor (e.g., non-small cell lung cancer, pancreatic cancer, liver cancer, thyroid cancer (e.g., anaplastic thyroid carcinoma), tumor brain (eg, glioblastoma), kidney cancer (eg, renal cell carcinoma), or head and neck cancer (eg, head and neck squamous cell carcinoma). In certain embodiments, the cancer is liver cancer, such as hepatocellular carcinoma (HCC). (eg, NCC with c-MET expression).

In some embodiments, the c-MET inhibitor is Compound A17 or a compound described in US Pat. Nos. 7,767,675 and 8,420,645).

In some embodiments, the c-MET inhibitor is JNJ-38877605. JNJ38877605 is an orally available small molecule c-Met inhibitor. JNJ-38877605 selectively binds to c-MET, thereby inhibiting cMET phosphorylation and disrupting c-Met signal transduction pathways.

In some embodiments, the c-Met inhibitor is AMG 208. AMG 208 is a selective small molecule inhibitor of c-MET. AMG 208 inhibits ligand-dependent and ligand-independent activation of c-MET by inhibiting its tyrosine kinase activity, which

- 252 047335 may lead to suppression of cell growth in tumors that overexpress c-Met.

In some embodiments, the c-Met inhibitor is AMG 337. AMG 337 is an orally bioavailable c-Met inhibitor. AMG 337 selectively binds to c-MET, thereby disrupting signal transduction pathways involving c-MET.

In some embodiments, the c-Met inhibitor is LY2801653. LY2801653 is an orally available small molecule c-Met inhibitor. LY2801653 selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-Met signal transduction pathways.

In some embodiments, the c-Met inhibitor is MSC2156119J. MSC2156119J is an orally bioavailable c-Met inhibitor. MSC2156119J selectively binds to c-MET, which inhibits c-MET phosphorylation and disrupts c-Met-mediated signal transduction pathways.

In some embodiments, the c-MET inhibitor is capmatinib. Capmatinib is also known as INCB028060. Capmatinib is an orally bioavailable c-MET inhibitor. Capmatinib selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways.

In some embodiments, the c-MET inhibitor is crizotinib. Crizotinib is also known as PF-02341066. Crizotinib is an orally available aminopyridine-based inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and c-Met/hepatocyte growth factor receptor (HGFR). Crizotinib binds to and inhibits ALK kinase and ALK-based fusion proteins in an ATP-competitive manner. In addition, crizotinib inhibits c-Met kinase and disrupts the c-Met signal transduction pathway. In general, this drug suppresses the growth of tumor cells.

In some embodiments, the c-MET inhibitor is golvatinib. Golvatinib is an orally bioavailable dual c-MET and VEGFR-2 kinase inhibitor with potential antitumor activity. Golvatinib binds to and inhibits the activity of both c-MET and VEGFR-2, which may suppress tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases.

In some embodiments, the c-MET inhibitor is tivantinib. Tivantinib is also known as ARQ 197. Tivantinib is an orally bioavailable small molecule c-MET inhibitor. Tivantinib binds to c-MET protein and disrupts c-Met signal transduction pathways, which can cause cell death in tumor cells that overexpress c-MET protein or constitutively express activated c-Met protein.

Exemplary IAP Inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with an inhibitor of inhibitor of apoptosis protein (IAP). In some embodiments, the combination is used to treat a cancer, e.g., a cancer described herein, e.g., a solid tumor (e.g., colorectal cancer (CRC), lung cancer (e.g., non-small cell lung cancer (NSCLC)), breast cancer (e.g. , triple negative breast cancer (TNBC), ovarian cancer, or pancreatic cancer), such as hematologic malignancy (eg, multiple myeloma).

In some embodiments, the IAP inhibitor is (S)-N-((S)-1cyclohexyl-2-(^)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)- 2-oxoethyl)-2-(methylamino)pro panamide (compound A21) or the compound disclosed in US Pat. No. 8,552,003.

In some embodiments, the combination described herein contains an IAP inhibitor, ^)-N(^)-1-cyclohexyl-2-(^)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)) pyrrolidin-1-yl)-2oxoethyl)-2-(methylamino)propanamide (compound A21) or the compound disclosed in US Pat. No. 8,552,003, and an inhibitor of an immune checkpoint molecule, e.g., a CD73 inhibitor (e.g., an antibody molecule to CD73).

Exemplary EGFR Inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with an epidermal growth factor receptor (EGFR) inhibitor. In some embodiments, the combination is used to treat cancer, e.g., a cancer described herein, e.g., a solid tumor (e.g., lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, breast cancer (e.g., triple negative breast cancer glands (TNBC)) or colon cancer). In certain embodiments, the cancer is selected from colorectal cancer (eg, microsatellite stability colorectal cancer (MSS CRC)), lung cancer (eg, non-small cell lung cancer), or breast cancer (eg, triple negative lung cancer (TNBC)).

In some embodiments, the EGFR inhibitor is (R,Ε)-Ν-(7-χλορ-1-(1(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzoshimidazol-2- yl)-2-methylisonicotinamide (compound A40) or a compound disclosed in PCT publication No. WO 2013/184757.

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In some embodiments, the combination described herein contains an EGFR inhibitor, (K„E)-H-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl )-III-benzo Imidazol-2yl)-2-methylisonicotinamide (compound A40) or a compound disclosed in PCT Publication No. WO 2013/184757 and an immune checkpoint molecule inhibitor, e.g. a CD73 inhibitor (e.g. , an anti-CD73 antibody molecule).

In some embodiments, an EGFR inhibitor, (R,E)-H-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzoSchimidazol-2- yl)-2-methylisonicotinamide (compound A40) or a compound disclosed in PCT Publication No. WO 2013/184757 is administered in combination with a CD73 inhibitor (eg, an anti-CD73 antibody molecule) for the treatment of colorectal cancer (CRC) (eg, MSS- CRC), lung cancer (eg, non-small cell lung cancer (NSCLC)), or breast cancer (eg, triple negative breast cancer (TNBC)).

In some embodiments, the EGFR inhibitor is selected from one or more of erlotinib, gefitinib, cetuximab, panitumumab, necitumumab, PF-00299804, nimotuzumab, or RO5083945.

Exemplary mTOR inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a mTOR inhibitor. In some embodiments, the combination is used to treat cancer, such as a cancer described herein, such as a solid tumor (eg, prostate cancer, breast cancer, brain cancer, bladder cancer, pancreatic cancer, kidney cancer, or liver, lung cancer (eg, small cell lung cancer or non-small cell lung cancer), respiratory tract/chest cancer, sarcoma, bone cancer, non-small cell lung cancer, endocrine cancer, astrocytoma, cervical cancer, neurological cancer, gastrointestinal cancer, or melanoma), for example, a hematological malignancy (for example, leukemia (for example, lymphocytic leukemia), for example, lymphoma, or, for example, multiple myeloma). In certain embodiments, the cancer is selected from colorectal cancer (eg, microsatellite stability colorectal cancer (MSS CRC)), lung cancer (eg, non-small cell lung cancer), or breast cancer (eg, triple negative lung cancer (TNBC)).

In some embodiments, the mTOR inhibitor is 8-(6-methoxypyridin3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo[4,5-c] quinolin-2-one (compound A41).

In some embodiments, the mTOR inhibitor is everolimus (also known as AFINITOR®; Compound A36) or a compound disclosed in PCT Publication No. WO 2014/085318.

In some embodiments, the combination described herein contains an mTOR inhibitor, everolimus (compound A36) or a compound disclosed in PCT publication No. WO 2014/085318, and an inhibitor of an immune checkpoint molecule, for example, a CD73 inhibitor ( for example, an anti-CD73 antibody molecule).

In some embodiments, an mTOR inhibitor, everolimus (compound A36) or a compound disclosed in PCT Publication No. WO 2014/085318 is administered in combination with a CD73 inhibitor (e.g., an anti-CD73 antibody molecule) for the treatment of colorectal cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)) or breast cancer (eg, triple negative breast cancer (NTBC)).

In some embodiments, the mTOR inhibitor is selected from one or more of rapamycin, temsirolimus (TORISEL®), AZD8055, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, GSK1059615, KU-0063794, WYE-354, palomide 529 ( P529), PF-04691502 or PKI-587, ridaforolimus (formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R, 21R,23S, 24E,26E,28D308,328,35K)-1D8-digadroxy-19,30-dimethoxy-15D7,21,23,29,35-hexamethyl-2,3,10,14,20pentaoxo-11,36 -dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669 and described in PCT publication No. WO 03/ 064383); everolimus (AFINITOR® or RAD001); rapamycin (AY22989, SIROLIMUS®); simapimoda (CAS registration number: 164301-51-3); (5-{2,4-bis[^)-3methylmorpholin-4-yl]pyrido[2,3D]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3D]pyrimidin7(8H)-one (PF04691502, registration CAS number: 1013101-36-4); №-|1.4-dioxo-4-||4-(4-oxo-8phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-1-arginylglycyl-1-α-aspartyl -1-serine (SEQ ID NO: 176) in the form of internal salt (SF1126, CAS registration number: 936487-67-1) or XL765 (SAR245409).

Other exemplary mTOR inhibitors include, but are not limited to, temsirolimus; ridaforolimus (1R,2R,4S)-4-[(2R)-2-[(1R,9SD2SD5RD6ED8RD9R,21R,23S,24E,26E,28Z,30S,32S,35R)-1D8-dihydroxy-19,30- dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo

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[30,3,1,0 ^4,9 ]hexa1riaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669; everolimus (RAD001); rapamycin (AY22989); simapimod; (5{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methylpyrido[2,3-1|pyrimidin-7(8H)-one (PF04691502) and N-[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran2-yl)morpholinium-4-yl]methoxy]butyl]-1-arginylglycyl -1-a-aspartyl-1-serine- (SEQ ID NO: 176), internal salt (SF1126); and XL765.

Exemplary ΡΙ3Κ-γ, -δ inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) inhibitor, such as phosphatidylinositol 4,5-bisphosphate 3-kinase gamma and/or or delta (ΡΙ3Κ-γ,δ). In some embodiments, the combination is used to treat cancer, e.g., a cancer described herein, e.g., a solid tumor (e.g., prostate cancer, breast cancer, brain cancer, bladder cancer, pancreatic cancer, kidney cancer, solid tumor, liver cancer, non-small cell lung cancer, endocrine cancer, ovarian cancer, melanoma, female reproductive system cancer, digestive/gastrointestinal cancer, glioblastoma multiforme, head and neck cancer, or colon cancer), such as hematologic malignancy (eg , leukemia (e.g., lymphocytic leukemia, e.g., chronic lymphocytic leukemia (CLL) (e.g., recurrent CLL)), e.g., lymphoma (e.g., non-Hodgkin's lymphoma (e.g., recurrent follicular B-cell non-Hodgkin's lymphoma (FL) or recurrent small cell lymphocytic lymphoma (SLL)) or, for example, multiple myeloma).

In some embodiments, the PI3K inhibitor is an inhibitor of the delta and gamma isoforms of PI3K. Exemplary PI3K inhibitors that can be used in combination are described, for example, in WO 2010/036380, WO 2010/006086, WO 09/114870, WO 05/113556, GSK 2126458, GDC-0980, GDC-0941, Sanofi XL147, XL756 , XL147, PF-46915032, VKM 120, CAL-101, CAL 263, SF1126, PX-886 and dual PI3K inhibitor.

In some embodiments, the ΡΙ3Κ-γ,δ inhibitor is idelalisib (CAS registration number: 870281-82-6). Idelalisib is also known as ZYDELIG®, GS-1101, CAL-101 or 5-fluoro-3-phenyl-2-[(P)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone . Idelalisib blocks P1108, the delta isoform of PI3K. Idelalisib is disclosed, for example, in Wu et al. Journal of Hematology & Oncology (2013) 6:36.

In some embodiments, the ΡΙ3Κ-γ,δ inhibitor is 8-(6methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo [4, 5c]quinolin-2-one (compound A41).

In some embodiments, the P3K-γ,δ inhibitor is buparlisib (compound A6) or a compound disclosed in PCT Publication No. WO 2007/084786.

Other exemplary ΡΙ3Κ-γ,δ inhibitors that may be used in combination include, for example, pictilizib (GDC-0941), LY294002, pilaralisib (XL147), PI-3065, PI-103, VS-5584 (SB2343), CZC24832, duvelisib (IPI-145, INK1197), TG100-115, CAY10505, GSK1059615, PF-04691502, AS-605240, voxtalisib (SAR245409, XL765), IC-87114, omipalisib (GSK2126458, GSK458), TG100713, gedatolisib (PF-05212384 , PKI-587), analog PKI-402, XL147, PIK-90, PIK-293, PIK-294, 3-methyladenine (3-MA), AS-252424, AS-604850 or apitolisib (GDC-0980, RG7422) .

In some embodiments, the PI3K inhibitor is Compound A8 or a compound disclosed in PCT Publication No. WO2010/029082.

In some embodiments, the PI3K inhibitor is an inhibitor of all forms of PI3K, (4S,5R)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidin]-6-yl )-4-(hydroxymethyl)5-methyloxazolidin-2-one (compound A13) or a compound disclosed in PCT Publication No. WO2013/124826.

Exemplary PΠΚ-γ,-δ inhibitors include, but are not limited to, duvelisib and idelalisib. Idelalisib (also called GS-1101 or CAL-101; Gilead) is a small molecule that blocks the delta isoform of PI3K. The structure of idelalisib (5-fluoro-3-phenyl-2-[(P)-1-(7H-purin-6ylamino)propyl|-4(3H)-quinazolinone) is shown below.

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Duvelisib (also called IPI-145; Infinity Pharmaceuticals and Abbvie) is a small molecule that blocks PBK-δ,γ. The structure of duvelisib (8-chloro-2-phenyl-3-[(^)-1-(9H-purin6-ylamino)ethyl]-1(2H)-isoquinolinone) is shown below.

In one embodiment, the inhibitor is a dual phosphatidylinositol 3-kinase (PI3K) and mTOR inhibitor selected from 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6(6-methoxy-3-pyridinyl )-4-methylpyrido[2,3^]pyrimidin-7(8H)-one (PF-04691502); \'-[4-[[4-(dimetide amino)-1-piperidinyl]carbonyl]phenyl]-N-[4-(4,6-di-4-morpholinyl-1,3,5-triazine-2- yl)phenyl]urea (PF-05212384, PKI-587); apitolisib (GDC-0980, RG7422); 2,4-difluoro-N{2-(methyloxy)-5-[4-(4pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458); 8-(6-methoxypyridin-3yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(triflutomethyl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H )-one maleic acid (NVP-BGT226); 3-[4-(4-morpholinylpyrido[3',2':4,5]furo[3,2^]pyrimidin-2-yl]phenol (PI-103); 5-(9-isopropyl-8-methyl -2-morpholino-9H-purin-6-yl)pyrimidin-2-amine (VS-5584, SB2343) or N[2-[(3,5-dimethoxyphenyl)amino]quinoxalin-3-yl]-4-[ (4-methyl-3-methoxyphenyl)carbonyl]amino phenylsulfonamide (XL765).

Exemplary JAK inhibitors

In certain embodiments, an anti-CD73 antibody molecule described herein is administered in combination with a Janus kinase (JAK) inhibitor. In some embodiments, the combination is used to treat cancer, such as a cancer described herein, such as a solid tumor (eg, colon cancer, prostate cancer, lung cancer, breast cancer, or pancreatic cancer), such as a hematologic malignancy neoplasms (eg, leukemia (eg, myeloid leukemia or lymphocytic leukemia), such as lymphoma (eg, non-Hodgkin's lymphoma), or multiple myeloma.

In some embodiments, the JAK inhibitor is 2-fluoro-\'-methide-4-(7(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]τtriazin-2-yl)benzamide (compound A17) or its dihydrochloride salt or compound disclosed in PCT publication No. WO 2007/070514.

In some embodiments, the JAK inhibitor is ruxolitinib phosphate (also known as JAKAFI; Compound A18) or a compound disclosed in PCT Publication No. WO 2007/070514.

Exemplary Cell Therapy Tools

Anti-CD73 antibody molecules can also be combined with a cell therapy, such as a chimeric antigen receptor (CAR) therapy, a T cell therapy, a natural killer (NK) cell therapy, or a dendritic cell therapy.

Combinations with CAR-based therapies

The anti-CD73 antibody molecules described herein can be administered in combination with a second therapeutic agent, for example, a chimeric antigen receptor (CAR) cell. A CAR may contain i) an extracellular antigen-binding domain, ii) a transmembrane domain, and iii) an intracellular signaling domain (which may contain one or both of a primary signaling domain and a co-stimulatory domain). The CAR may further comprise a leader sequence and/or a hinge sequence. In specific embodiments, the CAR-based construct comprises a scFv domain, where the scFv may be preceded by an optional leader sequence and may be followed by an optional hinge sequence, a transmembrane region, and an intracellular signaling domain, for example, where the domains are contiguous and in the same frame reading to form a single fusion protein.

In some embodiments, the CAR molecule includes a CAR molecule for CD19,

- 256 047335 described herein, for example, the CAR molecule for CD19 described in US 2015/0283178, for example, CTL019. In embodiments, the CD19 CAR comprises the amino acid or nucleotide sequence set forth in US 2015/0283178, incorporated herein by reference in its entirety, or a sequence substantially identical thereto (e.g., a sequence characterized by at least about 85%, 90% or 95% sequence identity with it).

In one embodiment, a CAR T cell that binds to CD19 is designated USAN TISAGENLECLEUCEL-T. CTL019 is produced by genetic modification of T cells mediated by stable insertion by transduction with a self-inactivating replication-defective lentiviral (LV) vector containing the CTL019 transgene under the control of the EF-1 alpha promoter. CTL019 may be a mixture of transgene-positive and transgene-negative T cells that are delivered to the subject based on the percentage of transgene-positive T cells.

In one embodiment, the CD19 CAR comprises the amino acid sequence set forth in SEQ ID NO: 12 in PCT publication WO2012/079000. In an embodiment, the amino acid sequence is:

MALPVTALLLPLALLLHAARPdiqmtqttsslsaslgdrvtiscrasqdiskylnwyqqkpdgtvklliyhtsr

Ihsgvpsrfsgsgsgtdysltisnleqediatyfcqqgntlpytfgggtkleitggggsggggsggggsevklqesgpglvapsqslsvtct vsgvslpdygvswirqpprkglewlgviwgsettyynsalksrltiikdnsksqvflkmnslqtddtaiyycakhyyyggsyamdy wg qgtsvtvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqp fmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqegly dkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr (SEQ ID NO: 132) or a sequence substantially identical thereto (e.g., a sequence having at least about 85%, 90%, or 95% identity), with or without a signal peptide sequence as specified in capital letters.

In one embodiment, the amino acid sequence is: slpdygvswirqpprkglewlgviwg settyynsalksrltiikdnsksqvflkmnslqtddtaiyycakhyyyggsyamdywgqgtsvtvsstttpaprpptpaptiasqplslrp eacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpv qttqeedgcscrfpeeeeggcelrvkfs rsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdgly qglstatkdtydalhmqalppr (SEQ Ш NO: 133), or a sequence essentially homologous thereto (for example, a sequence characterized by at least approximately 85%, 90% or 95% sequence identity with her).

Chimeric Antigen Receptor (CAR) Antigen Binding Domain The antigen binding domain can be any domain that binds an antigen, including, but not limited to, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, and a functional fragment thereof, including but not limited to a single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL), and a camelid-derived nanobody variable domain (VHH), as well as an alternative framework known in the art to function as an antigen-binding agent domain, such as a recombinant fibronectin domain, a T cell receptor (TCR), or a fragment thereof, such as a single chain TCR, etc. In some cases, it is advantageous for the antigen binding domain to be derived from the same species that will ultimately host apply CAR. For example, for use in humans, it may be desirable for the CAR antigen binding domain to comprise human or humanized residues in the antigen binding domain of the antibody or antibody fragment.

In some embodiments, the CAR antigen binding domain is a scFv fragment of an antibody that is humanized from the murine scFv sequence from which it is derived.

In some embodiments, the antigen binding domain binds to a tumor antigen described herein. In embodiments, the tumor antigen is selected from CD19; CD123; CD22; CD30; CD171; CS-1 (also called CD2 subgroup 1, CRACC, SLAMF7, CD319 and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(28)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); B-cell maturation antigen (BCMA), which is a member of the TNF receptor family; Tn antigen ((Tn-Ag) or (GalNAca-Ser/Thr)); prostate specific membrane antigen (PSMA); orphan receptor 1-like tyrosine kinase

- 257 047335 receptor (R0R1); Fms-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecules (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor alpha 2 subunit (IL13Ra2 or CD213A2); mesothelin; interleukin 11 receptor alpha subunit (IL-11Ra); prostate stem cell antigen (PSCA); serine protease 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis system antigen (Y); CD24; platelet-derived growth factor receptor beta (PDGFR-beta); stage-specific embryonal antigen 4 (SSEA-4); CD20; folate receptor alpha; receptor tyrosine protein kinase ERBB2 (Her2/neu); cell surface associated mucin 1 (MUC1); epidermal growth factor receptor (EGFR); nerve cell adhesion molecules (NCAM); prostases; prostatic acid phosphatase (PAP); elongation factor 2 mutant (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor receptor 1 (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, multicatalytic protease) beta type 9 subunit (LMP2); glycoprotein 100 (gp100); an oncogenic fusion protein consisting of the break point cluster region (BCR) and the Abelson murine leukemia virus (Abl) oncogene homolog 1 (bcr-abl); tyrosinase; ephrin A-type receptor 2 (EphA2); Fucosyl-GMI; adhesion molecule, which is a sialylated Lewis system antigen (sLe); ganglioside GM3 (aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); ganglioside o-acetyl-GD2 (OAcGD2); folic acid receptor beta; tumor endothelial marker 1 (TEM1/CD248); tumor endothelial marker 7-related antigen (TEM7R); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); group D representative of class C G-protein coupled receptors (GPRC5D); protein encoded by X chromosome open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific protein 1 (PLAC1); the hexasaccharide moiety of glycoceramide globoH (GloboH); breast differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); beta-3 adrenergic receptor (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen complex 6 locus antigen K9 (LY6K); olfactory receptor 51E2 (OR51E2); protein encoded by the TCR-gamma alternative reading frame (TARP); Wilms tumor protein (WT1); cancer testicular antigen 1 (NYESO-1); cancer testicular antigen 2 (LAGE-1a); melanoma-associated antigen 1 (MAGE-A1); protein encoded by translocation variant 6 of the ETS gene, localized in the p-arm of chromosome 12 (ETV6-AML); sperm protein 17 (SPA17); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (TIE-2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer testicular antigen 2 (MADCT-2); Fos-related antigen 1; tumor protein p53 (p53); mutant p53; prostein; survivina; telomerase; prostate carcinoma tumor antigen 1 (PCTA-1 or galectin 8), melanoma T-cell recognized antigen 1 (MelanA or MART1); mutant rat sarcoma antigen (Ras); human telomerase reverse transcriptase (hTERT); sarcoma antigens with point breaks during translocation; melanoma inhibitor of apoptosis (ML-IAP); ERG (a fusion gene product of transmembrane serine protease 2 (TMPRSS2) and ETS); N-acetylglucosaminyltransferase V (NA17); protein with a paired Box domain Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma homologue of the avian myelocytomatosis virus v-myc (MYCN) oncogene; member C of the Ras homologue (RhoC) family; tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP1B1); zinc finger protein-binding factor-like antigen (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); protein with paired box domain Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); anchor kinase protein 4 A (AKAP-4); X-chromosome synovial sarcoma antigen 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous protein 1 (RU1); renal ubiquitous protein 2 (RU2); legumaina; E6 human papillomavirus (E6 HPV); E7 human papillomavirus (E7 HPV); intestinal carboxylesterase; mutant heat shock protein 70-2 (mut-hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LALR1); IgA Fc receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A representative 2 (LILRA2); member f of the CD300 molecule-like protein family (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); mucin-like hormone receptor-containing EGF-like module antigen 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like antigen 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1).

In one embodiment, the CAR molecule includes a BCMA CAR molecule, for example, the BCMA CAR described in US 2016/0046724 or WO 2016/014565, incorporated herein by reference. In embodiments, the CAR for BCMA comprises an amino acid

- 258 047335 sequence or has the nucleotide sequence of a CAR molecule or antigen binding domain in accordance with US 2016/0046724 or table. 1 or 16, SEQ ID NO: 271 or SEQ ID NO: 273 of WO 2016/014565, incorporated herein by reference, or a sequence substantially identical to any of the foregoing sequences (e.g., characterized by at least about 85%, 90 % or 95% sequence identity with any of the above-mentioned BCMA CAR sequences). The amino acid sequences of CAR molecules for BCMA and antigen binding domains (e.g. containing one, two, three VH CDRs and one, two, three Kabat or Chothia VL CDRs) and the nucleotide sequences encoding them are specified in WO 2016/014565.

Chimeric antigen receptor (CAR) transmembrane domain

With respect to the transmembrane domain, in various embodiments, the CAR can be designed to contain a transmembrane domain attached to an extracellular domain of the CAR.

The transmembrane domain can be obtained from either a natural or recombinant source. If the source is natural, the domain can be obtained from any membrane-bound or transmembrane protein. In one aspect, the transmembrane domain is capable of transmitting a signal to the intracellular domain(s) whenever the CAR binds to a target. The transmembrane domain may include at least transmembrane region(s), for example, T cell receptor alpha, beta or zeta chains, Cd28, CD27, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154. In some embodiments, the transmembrane domain may include at least transmembrane region(s), e.g., KTRDS2, OX40, CD2, CD27, LFA-1 (CD11a, CD18), ICOS (CD278), 4-1BB (CD137) , GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, ^R^t^ ^R^mm^ IL7R α, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKG2D or NKG2C.

In some cases, the transmembrane domain may be attached to the extracellular region of the CAR, such as the antigen binding domain of the CAR, by a hinge region, such as a human protein hinge region. For example, in one embodiment, the hinge region may be a human Ig (immunoglobulin) hinge region (e.g., an IgG4 hinge region, an IgD hinge region), a GS linker (e.g., a GS linker described herein), a KIR2DS2 hinge region, or a hinge region CD8a.

Chimeric antigen receptor (CAR) intracellular signaling domain

The cytoplasmic domain or region of the CAR includes an intracellular signaling domain. The intracellular signaling domain is typically responsible for activating at least one of the normal effector functions of the immune cell into which the CAR has been introduced.

Examples of intracellular signaling domains for use in CARs include cytoplasmic sequences of the T cell receptor (TCR) and coreceptors that act together to initiate signal transduction upon engagement of an antigen receptor, and any derivative or variant of these sequences and any recombinant sequence that has the same functionality possibilities.

The primary signaling domain regulates the primary activation of the TCR complex in either a stimulatory or inhibitory manner. Primary intracellular signaling domains that act in a stimulatory manner may contain signaling motifs known as immunoreceptor tyrosine activating motifs or ITAMs.

Examples of primary intracellular signaling domains containing ITAMs include CD3-zeta, FcR common gamma chain (FCER1G), Fc-gamma RIIa, FcR-beta (Fc-epsilon R1b), CD3-gamma, CD3-delta, CD3-epsilon domains. , CD79a, CD79b, DAP10 and DAP12. In one embodiment, the CAR contains an intracellular signaling domain, for example, a CD3-zeta primary signaling domain.

The CAR intracellular signaling domain may comprise a CD3-zeta signaling domain alone or in combination with any other necessary intracellular signaling domain(s) useful as a component CAR according to the present invention. For example, the intracellular signaling domain of a CAR may contain a portion of the CD3 zeta chain and a co-stimulatory signaling domain. A costimulatory signaling domain refers to the portion of a CAR containing the intracellular domain of a costimulatory molecule. A costimulatory molecule is a cell surface molecule, other than an antigen receptor or its ligands, that is required for an effective lymphocyte response to an antigen. Examples of such molecules include CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen 1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7- H3 and the ligand that binds to CD83, etc. For example, there was a demonstration

- 259 047335 costimulation with CD27 has been shown to enhance the proliferation, effector function and survival of human CART cells in vitro and enhance the persistence and antitumor activity of human T cells in vivo (Song et al. Blood. 2012; 119(3):696-706 ). Additional examples of such co-stimulatory molecules include CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, CD4, CD8-alpha, CD8-beta, ^R ^t^ IL2R-gamma, IL7R-alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b , ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), NKG2D, CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR , LAT, GADS, SLP-76, PAG/Cbp and CD19a.

Activation and proliferation of immune effector cells (eg, T cells)

Immune effector cells, such as T cells, can be activated and expanded, typically using methods described, for example, in US patent No. 6352694; 6534055; 6905680; 6692964; 5858358; 6887466; 6905681; 7144575; 7067318; 7172869; 7232566; 7175843; 5883223; 6905874; 6797514; 6867041 and US Patent Application Publication No. 2006/0121005, incorporated herein by reference.

Examples of immune effector cells include T cells, such as alpha/beta T cells and gamma/delta T cells, B cells, natural killer (NK) cells, natural killer T cells (NKT), mast cells and phagocytes of myeloid origin.

Methods for producing CAR-expressing cells are described, for example, in US 2016/0185861, incorporated herein by reference.

Illustrative Cancer Vaccines

Anti-CD73 antibody molecules can be combined with an immunogenic agent such as cancer cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules), cells and cells transfected with genes encoding immunostimulatory cytokines (He et al. (2004) J Immunol. 173:4919-28). Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens such as gp100 peptides, MAGE, Trp-2, MART1 and/or tyrosinase antigens, tumor cells transfected to express the cytokine GM-CSF, DNA-based vaccines, vaccines RNA-based and viral transduction-based vaccines. A cancer vaccine can be preventive or therapeutic.

CD73 blockade can be used in combination with a collection of recombinant proteins and/or peptides expressed in the tumor to generate an immune response to these proteins.

Other cancer vaccines may include proteins from viruses implicated in human cancers, such as human papillomaviruses (HPV), hepatitis viruses (HBV and HCV), Kaposi's sarcoma herpes virus (KHSV), and Epstein-Barr virus (EBV). Another form of tumor-specific antigen that can be used in combination with CD73 blockade is purified heat shock proteins (HSPs) isolated from the tumor tissue itself. Such heat shock proteins contain protein fragments from tumor cells, and these HSPs are very effective when delivered to antigen presenting cells to induce tumor immunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura, Y. et al. (1997) Science 278:117-120).

Dendritic cells (DCs) are potent antigen-presenting cells that can be used to initiate antigen-specific responses. DCs can be generated ex vivo and loaded with various protein and peptide antigens, as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCs can also be genetically transduced to also express these tumor antigens. DCs have also been fused directly to tumor cells for immunization purposes (Kugler, A. et al. (2000) Nature Medicine 6:332-336). As a vaccination modality, immunization with DCs can be effectively combined with CD73 blockade to promote stronger antitumor responses.

Illustrative oncolytic viruses

Anti-CD73 antibody molecules can be administered in combination with oncolytic viruses. In embodiments, oncolytic viruses are capable of selectively replicating in a cancer cell and causing its death or slowing its growth. In some cases, oncolytic viruses have no or minimal effect on cells other than cancer cells. In some embodiments, the combination is used to treat cancer, such as the cancer described herein. In certain embodiments, the cancer is a brain cancer, such as glioblastoma (GBM). An oncolytic virus includes, without limitation, oncolytic adenovirus, oncolytic herpes simplex viruses, oncolytic retroviruses, oncolytic parvoviruses, oncolytic vaccinia virus, oncolytic Sindbis virus, oncolytic influenza virus, or oncolytic RNA virus (e.g., oncolytic reovirus, oncolytic Newcastle disease virus (NDV), oncolytic measles virus or oncolytic vesicular stomatitis virus (VSV)).

- 260 047335

Exemplary oncolytic viruses include, but are not limited to, the following:

group B oncolytic adenovirus (ColoAd1) (PsiOxus Therapeutics Ltd.) (see, for example, Clinical Study ID NCT02053220);

ONCOS-102 (formerly called CGTG-102), which is a granulocyte-macrophage colony-stimulating factor (GM-CSF) adenovirus (Oncos Therapeutics) (see, for example, Clinical Trial ID NCT01598129);

VCN-01, which is a genetically modified human oncolytic adenovirus encoding human hyaluronidase PH20 (VCN Biosciences, S.L.) (see, for example, clinical trial identification numbers NCT02045602 and NCT02045589);

conditionally replicative adenovirus ICOVIR-5, which is a virus derived from wild-type human adenovirus serotype 5 (Had5) that has been modified to selectively replicate in cancer cells with dysregulated retinoblastoma/E2E pathway (Institut Catala d'Oncologia) (see ., for example, clinical trial with identification number NCT01864759);

Celyvir, which contains autologous bone marrow-derived mesenchymal stem cells (MSCs) infected with ICOVIR5, an oncolytic adenovirus (Hospital Infantil Universitario Nino Jesύs, Madrid, Spain/Ramon Alemany) (see, for example, clinical trial identification number NCT01844661);

CG0070, which is a conditionally replicative oncolytic adenovirus serotype 5 (Ad5), in which the human E2F-1 promoter regulates the expression of the important E1a virus gene, thereby limiting viral replication and cytotoxicity in tumor cells defective in the Rb pathway (Cold Genesys, Inc.) (see, for example, Clinical Trial ID NCT02143804); or

DNX-2401 (formerly called Delta-24-RGD), which is an adenovirus that has been engineered to selectively replicate in retinoblastoma (Rb) pathway-deficient cells and to more efficiently infect cells that express certain RGD-binding integrins (Clinica Universidad de Navarra, Universidad de Navarra/DNAtrix, Inc.) (see, for example, clinical trial identification number NCT01956734).

In some embodiments, the oncolytic virus described herein is administered by injection, such as subcutaneous, intra-arterial, intravenous, intramuscular, intrathecal, or intraperitoneal injection. In embodiments, the oncolytic virus described herein is administered intratumorally, transdermally, transmucosally, orally, intranasally, or by inhalation.

Additional illustrative cancer therapies

Exemplary combinations of anti-CD73 antibody molecules (alone or in combination with other stimulant agents) and standard of care for cancer include at least the following. In certain embodiments, an anti-CD73 antibody molecule, such as an anti-CD73 antibody molecule described herein, is used in combination with a standard chemotherapy agent for the treatment of cancer, including, but not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane ®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran ®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), liposomal cytarabine injection (DepoCyt®), dacarbazine (DTIC-Dome ®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), liposomal daunorubicin citrate injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid® ), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®) , irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol® ), phoenix (yttrium-90/MX-DTPA), pentostatin, polypheprosan 20 and carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®) , topotecan hydrochloride injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®), ibrutinib, idelalisib, and brentuximab vedotin.

Exemplary alkylating agents include, but are not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosourea derivatives, and triazenes: uracil mustard® (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen mustard®, Uracillost®, Uracilmostaza ®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), chlorambucil ( Leukeran®), pipobroman (Amedel®, Ver

- 261 047335 cyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylene thiophosphoramine, temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine ( CeeNU®), streptozocin (Zanosar®) and dacarbazine (DTIC-Dome®). Additional exemplary alkylating agents include, but are not limited to, oxaliplatin (Eloxatin®); temozolomide (Temodar® and Temodal®); dactinomycin (also known as actinomycin-D, Cosmegen®); melphalan (also known as L-PAM, L-sarcolysine and phenylalanine mustard, Alkeran®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); carmustine (BiCNU®); bendamustine (Treanda®); busulfan (Busulfex® and Myleran®); carboplatin (Paraplatin®); lomustine (also known as CCNU, CeeNU®); cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); chlorambucil (Leukeran®); cyclophosphamide (Cytoxan® and Neosar®); dacarbazine (also known as DTIC, DIC and imidazolecarboxamide, DTIC-Dome®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); ifosfamide (Ifex®); prenumustine; procarbazine (Matulane®); mechlorethamine (also known as nitrogen mustard, mustine and mechlorethamine hydrochloride, Mustargen®); streptozocin (Zanosar®); thiotepa (also known as thiophosphamide, TESPA and TSPA, Thioplex®); cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®) and bendamustine HCl (Treanda®).

Exemplary anthracyclines include, for example, doxorubicin (Adriamycin® and Rubex®); bleomycin (lenoxane®); daunorubicin (daunorubicin hydrochloride, daunomycin and rubidomycin hydrochloride, Cerubidine®); liposomal daunorubicin (liposomal daunorubicin citrate, DaunoXome®); mitoxantrone (DHAD, Novantrone®); epirubicin (Ellence™); idarubicin (Idamycin®, Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimycin; ravidomycin and desacetylravidomycin. Exemplary vinca alkaloids that may be used in combination with anti-CD73 antibody molecules include, but are not limited to, vinorelbine tartrate (Navelbine®), vincristine (Oncovin®), and vindesine (Eldisine®); vinblastine (also known as vinblastine sulfate, vincaleucoblastine and VLB, Alkaban-AQ® and Velban®) and vinorelbine (Navelbine®).

Exemplary proteasome inhibitors that can be used in combination with anti-CD73 antibody molecules include, but are not limited to, bortezomib (Velcade®); carfilzomib (PX-171-007, (S)-4methyl-N-(^)-1-((^)-4-methyl-1-(^)-2-methyloxiran-2-yl)-1-oxopentan- 2-yl)amino)-1-oxo-3-phenylpro pan-2-yl)-2-(^)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-pentanamide); marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib (CEP-18770); and O-methyl-N-[(2-methyl-5-thiazolyl)carbonyl]1-seryl-O-methyl-N-[( 1 S)-2-[(2R)-2-methyl-2-oxiranyl] -2-oxo-1-(phenylmethyl)ethyl]-1-serinamide (ONX0912).

In some embodiments, an anti-CD73 antibody molecule, such as an anti-CD73 antibody molecule described herein, is used in combination with a tyrosine kinase inhibitor (eg, a receptor tyrosine kinase (RTK) inhibitor). Exemplary tyrosine kinase inhibitors include, but are not limited to, an epidermal growth factor (EGF) pathway inhibitor (e.g., an epidermal growth factor receptor (EGFR) inhibitor), a vascular endothelial growth factor (VEGF) pathway inhibitor (e.g., a vascular endothelial growth factor receptor (VEGFR) inhibitor (e.g. , VEGFR-1 inhibitor, VEGFR-2 inhibitor, VEGFR-3 inhibitor)), platelet-derived growth factor (PDGF) pathway inhibitor (eg, platelet-derived growth factor receptor (PDGFR) inhibitor (eg, PDGFR-β inhibitor)), RAF-inhibitor 1, KIT inhibitor and RET inhibitor. In some embodiments, the anticancer agent used in combination with a hedgehog protein inhibitor is selected from the group consisting of axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825) , erlotinib (TARCEVA®), gefitinib (TRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib ( TASIGNA®), semaxanib (semaxanib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab ( AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG) ®), ENMD-2076, PCI-32765, AC220, BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, AVT-869, MP470, BIBF 1120 (VARGATEF® ) , AP24534, JNJ26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL184, XL-647, XL228, AEE788, AG-490, AST- 6, BMS-599626, CUDC-101, PD153035, Pelitinib (EKB569), Vandetaniba (Zaktima), WZ3146, WZ4002, WZ8040, AUT-869 (Lyniphanib), AEE788, AR24534 (Ponatinib), AV-951 (Tivozanib), Aesi Tiniba , BAY 73-4506 (regorafenib), brivanib alaninate (BMS582664), brivanib (BMS-540215), cediranib (AZD2171), CP 673451, CYC116, E7080, Ki8751, masitinib (AB1010), MGCD-265, motesanib diphosphate (AMG- 706), MP-470, OSI-930, pazopanib hydrochloride, PD173074, sorafenib tosylate (Bay 43-9006), SU 5402, TSU-68 (SU6668), vatalanib, XL880 (GSK1363089, EXEL-2880). Selected tyrosine kinase inhibitors selected from sunitinib, erlotini

- 262 047335 ba, gefitinib or sorafenib.

Radiation therapy can be provided by one of several modalities or a combination of modalities, including, but not limited to, external beam radiation therapy, internal radiation therapy, radiation source implantation, stereotactic radiosurgery, systemic radiation therapy, radiation therapy, and permanent or temporary interstitial brachytherapy. The term brachytherapy refers to radiation therapy delivered by spatially confined radioactive material introduced into the body at or near a tumor or other site of proliferative tissue disease. The term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as the cell conditioning agent of the present invention include both solids and liquids. As a non-limiting example, the radiation source may be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta -particles, gamma radiation or other therapeutic rays. The radioactive material may also be a liquid prepared from any solution of radionuclide(s), for example a solution of I-125 or I-131, or the radioactive liquid may be prepared using a suspension of a suitable liquid containing fine particles of solid radionuclides such as Au-198, Y-90.

CD73 blockade can also be effectively combined with chemotherapy regimens. In these cases, it is possible to reduce the dose of the administered chemotherapy reagent.

Exemplary cytotoxic agents that may be administered in combination with an anti-CD73 antibody molecule include antimicrotubulin agents, topoisomerase inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalating agents, agents that can disrupt signal transduction, agents that stimulate apoptosis, proteasome inhibitors, and radiation (eg, local irradiation or total body irradiation).

In certain embodiments, any of the combinations disclosed herein, alternatively or in combination, further includes one or more of the agents described in Table. 18.

Table 18

Selected therapeutic agents that can be administered in combination with anti-antibody molecules

CD73, for example, as a single agent or in combination with other immunomodulators described herein. Each publication listed in this table is incorporated herein by reference in its entirety, including all structural formulas.

Connection designation

Non-patentable other name Trade name

Connection structure

Patents/Publication of Patent Applications

EP 1682103

US 2007/142401

WO 2005/039549

- 263 047335

A2 Nilotinib NS1 monohydrate TASIGNA® sn _a Ν ό HCl · Η ₂ Ο WO 2004/005281 US 7169791 A7 -Π OO x / T o >-----. )-----' ^L,i “? gnChgi ZZ -P o 2 o' ^ω J· WO 2009/141386 US 2010/0105667 A8 ^Η3 Ύζνγ /=\ 0- νη ₂ νΧ v ^r Vf n/ ^sn ' WO 2010/029082 AY 5 δ °С_/°А й й ' Q _t /—\ /—\ ^zu i -zli'< O WO 2011/076786

- 264 047335

All Deferasirox EXJADE® _N rr^ k A but OH WO 1997/049395 A12 Letrozole FEMARA® // NN jCjCX N' ^ii? US 4978672 A13 I ΞΕ O O H o z— z T WO 2013/124826 US 2013/0225574 A14 o $ j (5 _o WA O LLC / ZE Ο ^ω Tt WO 2013/111105

- 265 047335

A15 sn _e HN )=O Ν=ί O WO 2005/073224 CH ₃ ^=0 A16 Imatinib mesylate GLEEVEC® HN HN^ ^CH ₃ WO 1999/003854 V N\ \=N Mesilate

- 266 047335

A17 N _E S NH F Ν' \ n Dihydrochloride salt EP 2099447 US 7767675 US 8420645 A18 Ruxolitinium phosphate JAKAFI® O/ Ν-Ν GG5 ^Ν th Η3ΡΟ4 WO 2007/070514 EP 2474545 US 7598257 WO 2014/018632 A19 Panobinostat Oh... and. OH /¾ and ^{n ην} Λη, WO 2014/072493 WO 2002/022577 EP 1870399 A20 Ozilodrostat Ν p F WO 2007/024945

- 267 047335

A21 F Cl N ^Z Ί Vs H / ⁰ V- NH / 2 ΗΝ-СНз WO 2008/016893 EP 2051990 US 8546336 A23 Ceritinib ZYKADIA™ X z—y ZI/ /\II/ /)-(0-( y. JJ and \ -- O WO 2008/073687 US 8039479 A24 ajOx NGG YG K _N -CH ₃ Jx, /> CH ₃ 9 <J 0 H US 8415355 US 8685980

- 268 047335

- 269 047335

A28 ^N =\ сн ₅ nQ 0=( NH <р ^N NN W0 2010/101849 AZO H ₃ C M^-D-D, H-CH3 ύ · ^: N .0 N-> H _a C WO 2011/101409 A31 Human monoclonal anti-HER3 antibody WO 2012/022814 EP 2606070 US 8735551 A32 Antibody drug conjugate (ADC) WO 2014/160160 AB: 12425 (see table 1, paragraph [00191]) Linker: SMCC (see paragraph [00117] Payload: DM1 (see paragraph [00111] See also clause 29 of the claims AZZ Monoclonal antibody or Fab to M-CSF WO 2004/045532

- 270 047335

A35 Midostaurin HN~_ ⁰⁼⁼³ \ A. ΛΛ XYyv /N / L λλ Λ ³ dn, ⁿ vZy...... O WO 2003/037347 EP 1441737 US 2012/252785 A36 Everolimus AFINITOR® ,—on O—/ \ /—° 2—' сн _e )—СНз /НзС ⁴ —if /— ^сн \ I ? o /\ СНз N HO ^Z \__ф/ Н ₃ С HO )^О °=\ VV \—СНз ( o ( \—СНз o — < /=^ / \ / n ₃ s 2=/ Η ₃ Ο ^Ζ WO 2014/085318

- 271 047335

A37 pF jfj ^{F Η} 3^- _Ν -''ί _Ν h 0 /M HN j F ^F WO 2007/030377 US 7482367 AZ 8 Pasireotide dispartate SIGNIFOR® ^Q L /=\ S=o o=/ /=\ a·—\ PQA )* WH 4 A z I W02002/010192 US 7473761 A40 0 A aax Ύ 1 hc —<7 ^{n N} H ₃ C 1 , ⁿ -v=<>O H3C ⁴ 0 WO 2013/184757 A41 ΞΓ ο C/E hTOv V/-f 2->о t 0 ΞΕ WO 2006/122806

- 272 047335

A42 CH ₃ tz N -Υ ΐ ³ ίί_-Ν NH n TT HN. ο _χ X 1 n , s ._ ;s ⁵ - Yb CH ₃ WO 2008/073687 US 8372858 A43 H N CH ₃ * Ύ N XnH HN ^Fi O^ ^ch:i Yi/ 0 WO 2010/002655 US 8519129

- 273 047335

- 274 047335

In some embodiments, the additional therapeutic agent is selected from one or more of the following: 1) a protein kinase C (PKC) inhibitor; 2) heat shock protein 90 (HSP90) inhibitor; 3) phosphoinositide 3-kinase (PI3K) and/or target of rapamycin (mTOR) inhibitor; 4) a cytochrome P450 inhibitor (for example, a CYP17 inhibitor or a 17-alpha hydroxylase/C17-20 lyase inhibitor); 5) iron chelating agent; 6) aromatase inhibitor; 7) a p53 inhibitor, for example a p53/Mdm2 interaction inhibitor; 8) apoptosis inducer; 9) angiogenesis inhibitor; 10) aldosterone synthase inhibitor; 11) smoothened receptor inhibitor (SMO); 12) prolactin receptor inhibitor (PRLR); 13) Wnt signaling inhibitor; 14) CDK4/6 inhibitor; 15) fibroblast growth factor receptor 2 (FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor; 16) macrophage colony-stimulating factor (M-CSF) inhibitor; 17) an inhibitor of one or more of c-KIT, histamine release, Flt3 (eg FLK2/STK1) or PKC; 18) an inhibitor of one or more of VEGFR-2 (eg, FLK-1/KDR), PDGFR-beta, c-KIT or Raf kinase C; 19) a somatostatin agonist and/or growth hormone release inhibitor; 20) anaplastic lymphoma kinase (ALK) inhibitor; 21) inhibitor of insulin-like growth factor 1 receptor (IGF-1R); 22) P-glycoprotein 1 inhibitor; 23) vascular endothelial growth factor receptor (VEGFR) inhibitor; 24) BCR-ABL kinase inhibitor; 25) FGFR inhibitor; 26) CYP11B2 inhibitor; 27) an HDM2 inhibitor, for example an HDM2-p53 interaction inhibitor; 28) tyrosine kinase inhibitor;

29) c-MET inhibitor; 30) JAK inhibitor; 31) DAC inhibitor; 32) 11β-hydroxylase inhibitor; 33) IAP inhibitor; 34) PIM kinase inhibitor; 35) porcupine inhibitor; 36) a BRAF inhibitor, for example BRAF V600E or wild type BRAF; 37) HER3 inhibitor; 38) MEK inhibitor; or 39) a lipid kinase inhibitor described herein and in Table. 18.

Exemplary tyrosine kinase inhibitors include, but are not limited to, an epidermal growth factor (EGF) pathway inhibitor (e.g., an epidermal growth factor receptor (EGFR) inhibitor), a vascular endothelial growth factor (VEGF) pathway inhibitor (e.g., a vascular endothelial growth factor receptor (VEGFR) inhibitor (e.g. , VEGFR-1 inhibitor, VEGFR-2 inhibitor, VEGFR-3 inhibitor)), platelet-derived growth factor (PDGF) pathway inhibitor (e.g., platelet-derived growth factor receptor (PDGFR) inhibitor (e.g., PDGFR-β inhibitor)), RAF inhibitor -1, KIT inhibitor and RET inhibitor.

In one embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains or is used in combination with a PKC inhibitor, sotrastaurin (compound A1) or a compound disclosed in PCT Publication No. WO 2005/039549 to treating a disorder, such as a disorder described herein. In one embodiment, the PKC inhibitor is sotrastaurin (compound A1) or a compound disclosed in PCT Publication No. WO 2005/039549. In one embodiment, the anti-CD73 antibody molecule is used in combination with sotrastaurin (compound A1) or a compound

- 275 047335 described in publication according to PCT No. WO 2005/039549, for the treatment of a disorder such as cancer, melanoma, non-Hodgkin's lymphoma, inflammatory bowel disease, transplant rejection, ophthalmic disorder or psoriasis.

In one embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains a BCR-ABL inhibitor, TASIGNA (compound A2), or a compound disclosed in PCT Publication No. WO 2004/005281, or is used in a combination with them to treat a disorder, such as the disorder described herein. In one embodiment, the BCR-ABL inhibitor is TASIGNA or a compound disclosed in PCT Publication No. WO 2004/005281. In one embodiment, the anti-CD73 antibody molecule is used in combination with TASIGNA (compound A2) or a compound described in PCT Publication No. WO 2004/005281 for the treatment of a disorder such as lymphocytic leukemia, Parkinson's disease, neurological cancer, melanoma, digestive cancer /gastrointestinal tract, colorectal cancer, myeloid leukemia, head and neck cancer, or pulmonary hypertension.

In another embodiment, a combination, such as a combination comprising an anti-CD73 antibody molecule described herein, includes or is used in combination with an HSP90 inhibitor to treat a disorder, such as a disorder described herein, such as cancer, multiple myeloma, non-small cell lung cancer, lymphoma, gastrointestinal cancer, breast cancer, digestive/gastrointestinal cancer, pancreatic cancer, colorectal cancer, solid tumor or hematopoietic disorder.

In another embodiment, a combination, such as a combination comprising an anti-CD73 antibody molecule described herein, is used in combination with a PI3K and/or mTOR inhibitor, 8-(6-methoxypyridin-3-yl)-3-methyl-1-( 4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydro-dazo[4,5-c]quinolin-2-one (compound A41) for the treatment of a disorder, such as the disorder described herein. In one embodiment, the PI3K and/or mTOR inhibitor is 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo [4,5-c]quinolin-2-one (compound A41). In one embodiment, the anti-CD73 antibody molecule is used in combination with 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo [4,5-c]quinolin-2-one (compound A41) for the treatment of a disorder such as cancer, prostate cancer, leukemia (eg, lymphocytic leukemia), breast cancer, brain cancer, bladder cancer, pancreatic cancer glands, kidney cancer, solid tumor or liver cancer.

In another embodiment, a combination, for example, a combination containing an anti-CD73 antibody molecule described herein, contains an FGFR inhibitor, 3-(2,6-dichloro-3,5dimethoxyphenyl)-1-(6-((4-(4- ethylpiperazin-1 -yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea (compound A5) or the compound disclosed in US Pat. No. 8,552,002, or used in combination therewith, for the treatment of a disorder, such as the disorder described herein document. In one embodiment, the FGFR inhibitor is 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl) -1-methylurea (compound A5) or a compound disclosed in US Pat. No. 8,552,002. In one embodiment, an anti-CD73 antibody molecule is used in combination with compound A5 or a compound disclosed in US Pat. No. 8,552,002 to treat a disorder such as digestive/gastric cancer. -intestinal tract, hematological cancer or solid tumor. Compound A5 is characterized by the following structure:

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains a PI3K inhibitor, buparlisib (compound A6), or a compound disclosed in PCT Publication No. WO 2007/084786, or is used in a combination

- 276 047335 nations with them for the treatment of a disorder, such as the disorder described in this document. In one embodiment, the PI3K inhibitor is buparlisib (compound A6) or a compound disclosed in PCT Publication No. WO 2007/084786. In one embodiment, an anti-CD73 antibody molecule is used in combination with buparlisib (compound A6) or a compound disclosed in PCT Publication No. WO 2007/084786 for the treatment of a disorder such as prostate cancer, non-small cell lung cancer, endocrine cancer, leukemia, ovarian cancer, melanoma, bladder cancer, breast cancer, female reproductive system cancer, digestive/gastrointestinal cancer, colorectal cancer, glioblastoma multiforme, solid tumor, non-Hodgkin's lymphoma, hematopoietic disorder, or head and neck cancer. Compound A6 is characterized by the following structure:

In another embodiment, the combination, for example the combination containing the anti-CD73 antibody molecule described herein, contains the FGFR inhibitor, 8-(2,6-difluoro-3,5dimethoxyphenyl)-N-(4-((dimethylamino)methyl)- N-imidazol-2-yl)quinoxaline-5-carboxamide (compound A7), or a compound disclosed in PCT Publication No. WO 2009/141386, or used in combination therewith for the treatment of a disorder, such as the disorder described herein. In one embodiment, the FGFR inhibitor is 8-(2,6-difluoro-3,5dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide (compound A7 ) or a compound disclosed in publication according to PCT No. WO 2009/141386. In one embodiment, the FGFR inhibitor is 8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4((dimethylamino)methyl)-N-imidazol-2-yl)quinoxaline-5-carboxamide (compound A7). In one embodiment, the anti-CD73 antibody molecule is used in combination with 8-(2,6-difluoro-3,5dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5- carboxamide (compound A7) or a compound disclosed in PCT Publication No. WO 2009/141386 for treating a disorder such as cancer characterized by angiogenesis.

In another embodiment, a combination, such as a combination comprising an anti-CD73 antibody molecule described herein, contains a PI3K inhibitor, (8)-III-(4-methyl-5-(2-(1,1,1trifluoro-2-methylpropane -2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidin-1,2-dicarboxamide (compound A8) or the compound disclosed in PCT No. WO 2010/029082, or used in combination with them for the treatment of a disorder, such as the violation described in this document. In one embodiment, the PI3K inhibitor is ^)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2yl)pyridin-4-yl)thiazol-2-yl )pyrrolidine-1,2-dicarboxamide (compound A8) or a compound disclosed in PCT publication No. WO 2010/029082. In one embodiment, the anti-CD73 antibody molecule is used in combination with ^)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin4-yl)thiazole -2-yl)pyrrolidin-1,2-dicarboxamide (compound A8) or a compound disclosed in PCT publication No. WO 2010/029082, for the treatment of a disorder such as gastrointestinal cancer, breast cancer, pancreatic cancer, digestive cancer gastrointestinal tract, solid tumor and head and neck cancer.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains a cytochrome P450 inhibitor, (for example, a CYP17 inhibitor) or a compound disclosed in PCT Publication No. WO 2010/149755, or is used in combination with them to treat a disorder, such as the disorder described herein. In one embodiment, a cytochrome P450 inhibitor (eg, a CYP17 inhibitor) is CFG920 or a compound disclosed in PCT Publication No. WO 2010/149755, US 8263635 B2 or EP 2445903 B1. In one embodiment, an anti-CD73 antibody molecule is used in combination with a compound disclosed in PCT Publication No. WO 2010/149755 for the treatment of prostate cancer.

In another embodiment, a combination, such as a combination containing an anti-CD73 antibody molecule described herein, contains an HDM2 inhibitor, ^)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(( (1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (compound A10) or the compound disclosed in publication according to PCT No. WO 2011/076786, or used in combination with them for the treatment of a disorder, for example the disorder described in this document). In one embodiment, the HDM2 inhibitor is (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4methyl-3 - oxopiperazin-1 -yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3 (4H)-one (compound A10) or a compound disclosed in PCT Publication No. WO 2011/076786. In one option

- 277 047335 those implementations, the antibody molecule to CD73 is used in combination with (b)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1g^)-4-(4- methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (compound A10) or a compound disclosed in PCT publication No. WO 2011/076786, for treating a disorder such as a solid tumor.

In another embodiment, the combination, for example the combination containing the anti-CD73 antibody molecule described herein, contains an iron chelating agent, deferasirox (also known as EXJADE; Compound A11) or a compound disclosed in PCT Publication No. WO 1997/049395, or used in combination therewith to treat a disorder, such as the disorder described herein. In one embodiment, the iron chelating agent is deferasirox or a compound disclosed in PCT Publication No. WO 1997/049395. In one embodiment, the iron chelating agent is deferasirox (compound A11). In one embodiment, an anti-CD73 antibody molecule is used in combination with deferasirox (compound A11) or a compound disclosed in PCT Publication No. WO 1997/049395 for the treatment of iron overload, hemochromatosis, or myelodysplasia.

In another embodiment, a combination, such as a combination containing an anti-CD73 antibody molecule described herein, contains or is used in combination with an aromatase inhibitor, letrozole (also known as FEMARA; Compound A12) or a compound disclosed in US Pat. No. 4,978,672 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the aromatase inhibitor is letrozole (Compound A12) or the compound disclosed in US Pat. No. 4,978,672. In one embodiment, the anti-CD73 antibody molecule is used in combination with letrozole (Compound A12) or the compound disclosed in US Pat. No. 4,978,672 to treat disorders such as cancer, leiomyosarcoma, endometrial cancer, breast cancer, cancer of the female reproductive system or hormonal deficiency.

In another embodiment, the combination, e.g., a combination comprising an anti-CD73 antibody molecule described herein, contains a PI3K inhibitor, e.g., an inhibitor of all forms of PI3K, ^,5K)-3-(2'-amino-2-morpholino-4' -(trifluoromethyl)-[4,5'-bipyrimidin|-6-yl)-4-(hydroxymethyl)5-methyloxazolidin-2-one (compound A13) or a compound disclosed in PCT publication No. WO2013/124826, or used in combination with them to treat a disorder, such as the disorder described herein. In one embodiment, the PI3K inhibitor is ^,5K)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidin|-6-yl)-4-(hydroxymethyl )-5methyloxazolidin-2-one (compound A13) or a compound disclosed in PCT publication No. WO2013/124826. In one embodiment, the anti-CD73 antibody molecule is used in combination with (4S,5R)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidin]-6-yl) -4-(hydroxymethyl)-5methyloxazolidin-2-one (compound A13) or a compound disclosed in PCT publication No. WO2013/124826, for the treatment of a disorder such as cancer or advanced solid tumor.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains a p53 inhibitor and/or a p53/Mdm2 interaction inhibitor, ^)-5-(5-chloro-1-methyl-2-oxo- 1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4D]imidazol- 4(1H)-one (compound A14) or a compound disclosed in PCT Publication No. WO2013/111105, or used in combination therewith, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the p53 inhibitor and/or the p53/Mdm2 interaction inhibitor is (S)-5-(5chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl )-2-(2,4-dimethoxypyrimidin-5-yl)-1isopropyl-5,6-dihydropyrrolo[3,4D]imidazol-4(1H)-one (compound A14) or a compound disclosed in PCT publication No. WO2013 /111105. In one embodiment, the anti-CD73 antibody molecule is used in combination with ^)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4chlorophenyl)-2-( 2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4D]imidazol-4(1H)one (compound A14) or a compound disclosed in PCT publication No. WO2013/111105, for treating a disorder such as cancer or soft tissue sarcoma.

In another embodiment, the combination, for example, a combination containing an anti-CD73 antibody molecule described herein, contains a CSF-1R tyrosine kinase inhibitor, 4-((2(((1R,2R))-2-hydroxycyclohexyl)amino)benzo Thiazol- 6-yl)oxy)-N-methylpicolinamide (compound A15) or a compound disclosed in PCT Publication No. WO 2005/073224, or used in combination therewith, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the CSF-1R tyrosine kinase inhibitor is 4-((2-(((1R,2R)-2hydroxycyclohexyl)amino)benzothiazol-6-yl)oxy)-N-methylpicolinamide (compound A15) or a compound disclosed in publications according to PCT No. WO 2005/073224. In one embodiment, the anti-CD73 antibody molecule is used in combination with 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzothiazol-6-yl)oxy)-N-methylpicolinamide (compound A15) or compound , disclosed in publication according to PCT No. WO 2005/073224, for the treatment of a disorder such as cancer.

In certain embodiments, the CSF-1R tyrosine kinase inhibitor 4-((2-(((1R,2R)-2hydroxycyclohexyl)amino)benzothiazol-6-yl)oxy)-N-methylpicolinamide (compound A15) or co

- 278 047335 The compound disclosed in PCT Publication No. WO 2005/073224 is administered in combination with a CD73 inhibitor (eg, an anti-CD73 antibody molecule) for the treatment of cancer, eg, a solid tumor (eg, an advanced solid tumor). Exemplary cancers that may be treated with the combination include, but are not limited to, brain cancer (e.g., glioblastoma multiforme (GBM), e.g., recurrent glioblastoma), breast cancer (e.g., triple negative breast cancer (e.g., NTBC)), or pancreatic cancer glands (for example, advanced pancreatic cancer). Common features of these cancers include, for example, tumor biology characterized by high levels of TAMs in the tumor microenvironment, which may contribute to immune evasion and immune suppression. In some embodiments, CSF-1R blockade in combination with an anti-CD73 antibody therapy may, for example, promote TAM reprogramming and/or reverse tumor-infiltrating lymphocyte (TIL) immunosuppression.

In another embodiment, the combination, for example, a combination containing an anti-CD73 antibody molecule described herein, contains an apoptosis inducer and/or angiogenesis inhibitor, such as imatinib mesylate (also known as GLEEVEC®; compound A16), or a compound disclosed in publication according to PCT No. WO1999/003854, or used in combination with them for the treatment of a disorder, for example the described disorder. In one embodiment, the apoptosis inducer and/or angiogenesis inhibitor is imatinib mesylate (compound A16) or a compound disclosed in PCT Publication No. WO1999/003854. In one embodiment, an anti-CD73 antibody molecule is used in combination with imatinib mesylate (compound A16) or a compound disclosed in PCT Publication No. WO1999/003854 for the treatment of a disorder such as cancer, multiple myeloma, prostate cancer, non-small cell lung cancer, lymphoma, gastrointestinal cancer, melanoma, breast cancer, pancreatic cancer, digestive/gastrointestinal cancer, colorectal cancer, glioblastoma multiforme, liver cancer, head and neck cancer, asthma, multiple sclerosis, allergies, Alzheimer's disease, amyotrophic lateral sclerosis or rheumatoid arthritis.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains the JAK inhibitor, 2-fluoro-N-methyl-4-(7(quinolin-6)-ylmethyl)imidazo[1,2- b][1,2,4]triazin-2-yl)benzamide (compound A17) or its dihydrochloride salt or compound disclosed in PCT Publication No. WO 2007/070514, or used in combination therewith for the treatment of a disorder, e.g. described in this document. In one embodiment, the JAK inhibitor is 2-fluoro-N-methyl-4-(7-(quinolin-6ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (compound A17) or its dihydrochloride salt or compound disclosed in PCT publication No. WO 2007/070514. In one embodiment, the anti-CD73 antibody molecule is used in combination with 2-fluoro-N-methyl-4-(7-(quinolin-6ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl )benzamide (compound A17) or its dihydrochloride salt or compound disclosed in PCT publication No. WO 2007/070514, for the treatment of a disorder such as colorectal cancer, myeloid leukemia, hematological cancer, autoimmune disease, non-Hodgkin's lymphoma or thrombocythemia.

In another embodiment, the combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains a JAK inhibitor, ruxolitinib phosphate (also known as JAKAFI; Compound A18) or a compound disclosed in PCT Publication No. WO 2007/070514, or used in combination with them to treat a disorder, such as the disorder described herein. In one embodiment, the JAK inhibitor is ruxolitinib phosphate (compound A18) or a compound disclosed in PCT Publication No. WO 2007/070514. In one embodiment, an anti-CD73 antibody molecule is used in combination with ruxolitinib phosphate (compound A18) or a compound disclosed in PCT Publication No. WO 2007/070514 to treat a disorder such as prostate cancer, lymphocytic leukemia, multiple myeloma, lymphoma, lung cancer, leukemia, cachexia, breast cancer, pancreatic cancer, rheumatoid arthritis, psoriasis, colorectal cancer, myeloid leukemia, hematological cancer, autoimmune disease, non-Hodgkin's lymphoma or thrombocythemia.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains a deacetylase inhibitor (DAC), panobinostat (compound A19) or a compound disclosed in PCT Publication No. WO 2014/072493, or is used in combination with them to treat a disorder, such as the disorder described herein. In one embodiment, the DAC inhibitor is panobinostat (compound A19) or a compound disclosed in PCT Publication No. WO 2014/072493. In one embodiment, the anti-CD73 antibody molecule is used in combination with panobinostat (compound A19), a compound disclosed in PCT publication No. WO 2014/072493, for the treatment of a disorder such as colorectal cancer, small cell lung cancer, respiratory tract/chest cancer , prostate cancer, multiple myeloma, myelodysplastic syndrome, bone cancer, non-small cell lung cancer, endocrine cancer, lymphoma, neurological cancer, leukemia, HTV/AIDS, immune

- 279 047335 nological disorder, transplant rejection, gastrointestinal cancer, melanoma, breast cancer (e.g. triple negative breast cancer (NTBC)), pancreatic cancer, colorectal cancer, glioblastoma multiforme, myeloid leukemia, hematological cancer, kidney cancer, non-Hodgkin's lymphoma, head and neck cancer, hematopoietic disorders or liver cancer. In some embodiments, the cancer is selected from colorectal cancer (eg, microsatellite stability colorectal cancer (MSS CRC)), lung cancer (eg, non-small cell lung cancer), or breast cancer (eg, triple negative lung cancer (TNBC)).

In some embodiments, the combination described herein contains a deacetylase (DAC) inhibitor, panobinostat (compound A19) or a compound disclosed in PCT publication No. WO 2014/072493, and an inhibitor of an immune checkpoint molecule, e.g. CD73 (eg, an anti-CD73 antibody molecule).

In one embodiment, a DAC inhibitor, panobinostat (compound A19) or a compound disclosed in PCT Publication No. WO 2014/072493 is administered in combination with a CD73 inhibitor (e.g., an anti-CD73 antibody molecule) for the treatment of colorectal cancer (e.g., MSS CRC) , lung cancer (eg, non-small cell lung cancer (NSCLC)) or breast cancer (eg, triple-negative breast cancer (TNBC)).

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains an inhibitor of one or more of cytochrome P450 (eg, 11B2), aldosterone or angiogenesis, oslodrostat (compound A20) or a compound disclosed in the publication according to PCT No. WO2007/024945, or used in combination with them to treat a disorder, such as the disorder described herein. In one embodiment, an inhibitor of one or more of cytochrome P450 (eg, 11B2), aldosterone, or angiogenesis is osillodrostat (compound A20) or a compound disclosed in PCT Publication No. WO2007/024945. In one embodiment, the anti-CD73 antibody molecule is used in combination with osilodrostat (compound A20) or a compound disclosed in PCT Publication No. WO2007/024945 to treat a disorder such as Cushing's syndrome, hypertension or heart failure.

In another embodiment, a combination, for example, a combination containing an anti-CD73 antibody molecule described herein, contains an IAP inhibitor, ^)-N-(^)-1-cyclohexyl-2-(^)2-(4-(4- fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide (compound A21) or the compound disclosed in US 8552003, or used in combination therewith for the treatment of a disorder, e.g. described in this document. In one embodiment, the IAP inhibitor is ^)-N-(^)-1-cyclohexyl-2-(^)-2-(4-(4-fluorobenzoyl)thiazol-2yl)pyrrolidin-1-yl)-2- oxoethyl)-2-(methylamino)propanamide (compound A21) or the compound disclosed in US Pat. No. 8,552,003. In one embodiment, the anti-CD73 antibody molecule is used in combination with ^)-H-(^)-1-cyclohexyl-2-( ^)-2-(4-(4-fluorobenzoyl)thiazol-2)-yl)pyrrolidin-1-yl)2-oxoethyl)-2-(methylamino)propanamide (compound A21) or the compound disclosed in US Pat. No. 8,552,003 , for the treatment of a disorder such as multiple myeloma, colorectal cancer (CLC), lung cancer (eg, non-small cell lung cancer (NSCLC), breast cancer (eg, triple negative breast cancer (TNBC)), ovarian cancer, pancreatic cancer or a hematopoietic disorder. In some embodiments, the cancer is selected from colorectal cancer (e.g., microsatellite stable colorectal cancer (MSS CRC)), lung cancer (e.g., non-small cell lung cancer), or breast cancer (e.g., triple negative lung cancer (TNBC) ).

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains a smoothened (SMO) inhibitor, (R)-2-(5-(4-(6)benzyl-4,5-dimethylpyridazin- 3-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2-ol (compound A25) or a compound disclosed in PCT publication No. WO 2010/007120, or used in combination with them for the treatment violations, such as the violations described herein. In one embodiment, the SMO inhibitor is ^)-2-(5-(4-(6-benzyl-4,5dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2 -ol (compound A25) or a compound disclosed in PCT publication according to WO 2010/007120. In one embodiment, the anti-CD73 antibody molecule is used in combination with ^)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3yl)-2-methylpiperazin-1-yl)pyrazin-2-yl )propan-2-ol (compound A25) or a compound disclosed in PCT Publication No. WO 2010/007120, for the treatment of a disorder such as cancer, medulloblastoma, small cell lung cancer, prostate cancer, basal cell carcinoma, pancreatic cancer or inflammation .

In another embodiment, a combination, such as a combination containing an anti-CD73 antibody molecule described herein, contains or is used in combination with the Alk inhibitor, ceritinib (also known as ZYKADIA; Compound A23) to treat a disorder, such as a disorder described herein. document. In one embodiment, the Alk inhibitor is ceritinib (compound A23). In one embodiment, the anti-CD73 antibody molecule

- 280 047335 is used in combination with ceritinib (compound A23) to treat a disorder such as non-small cell lung cancer or solid tumors.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains a JAK and/or CDK4/6 inhibitor, 7-cyclopentyl-U N-dimethyl-2-((5-(piperazin-1-yl )pyridin-2-yl)amino)-7H-pyrrolo[2,3L]pyrimidine-6-carboxamide (compound A24) or the compound disclosed in US Pat. No. 8,415,355 or US Pat. No. 8,685,980, or used in combination therewith for the treatment of a disorder, such as the violation described in this document. In one embodiment, the JAK and/or CDK4/6 inhibitor is 7cyclopentyl-N,Ndimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3L ]pyrimidine-6carboxamide (compound A24) or the compound disclosed in US Patent 8,415,355 or US Patent 8,685,980. In one embodiment, the anti-CD73 antibody molecule is used in combination with 7-cyclopentyl-N, N-dimethyl-2-((5-(piperazine-1 -yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3L]pyrimidine-6carboxamide (compound A24) or the compound disclosed in US 8415355 or US 8685980, for the treatment of a disorder such as lymphoma, neurological cancer, melanoma , breast cancer or solid tumor.

In another embodiment, a combination, such as a combination containing an anti-CD73 antibody molecule described herein, contains or is used in combination with a prolactin receptor (PRLR) inhibitor, a human monoclonal antibody molecule (compound A26) described in US Pat. No. 7,867,493 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the PRLR inhibitor is a human monoclonal antibody (Compound A26) disclosed in US Pat. No. 7,867,493. In one embodiment, an anti-CD73 antibody molecule is used in combination with a human monoclonal antibody molecule (Compound A26) disclosed in US Pat. No. 7,867,493 for the treatment of disorders such as cancer, prostate cancer or breast cancer.

In another embodiment, the combination, for example, a combination containing an anti-CD73 antibody molecule described herein, contains a PIM kinase inhibitor, N-(4-((1R,3S,5S)-3amino-5-methylcyclohexyl)pyridine-3- yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (compound A27) or a compound disclosed in PCT Publication No. WO 2010/026124, or used in combination therewith for the treatment of a disorder, such as the disorder described herein document. In one embodiment, the PIM kinase inhibitor is H-(4-((1K., ^p ^^)-3-amino-5methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5- fluoropicolinamide (compound A27) or a compound disclosed in PCT publication No. WO 2010/026124. In one embodiment, the anti-CD73 antibody molecule is used in combination with H-(4-((1C, ⁿ ^^)-3-amino-5methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)- 5-fluoropicolinamide (compound A27) or a compound disclosed in PCT publication No. WO 2010/026124, for the treatment of a disorder such as multiple myeloma, myelodysplastic syndrome, myeloid leukemia or non-Hodgkin's lymphoma.

In another embodiment, the combination, for example, a combination containing an anti-CD73 antibody molecule described herein, contains a Wnt signaling inhibitor, 2-(2',3dimethyl-[2,4'-bipyridine)]-5-yl)-Y -(5-(pyrazin-2-yl)pyridin-2-yl)acetamide (compound A28) or a compound disclosed in PCT Publication No. WO 2010/101849, or used in combination therewith for the treatment of a disorder, e.g. described in this document. In one embodiment, the Wnt signaling inhibitor is 2-(2',3-dimethyl-[2,4'bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl )acetamide (compound A28) or a compound disclosed in PCT publication No. WO 2010/101849. In one embodiment, the Wnt signaling inhibitor is 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-H-(5-(pyrazin-2yl)pyridin-2-yl) acetamide (compound A28). In one embodiment, the anti-CD73 antibody molecule is used in combination with 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-H-(5-(pyrazin-2-yl)pyridin- 2yl)acetamide (compound A28) or a compound disclosed in PCT publication No. WO 2010/101849, for the treatment of a disorder such as a solid tumor (for example, head and neck cancer, squamous cell carcinoma, breast cancer, pancreatic cancer or colon cancer intestines). In certain embodiments, the cancer is selected from skin cancer (eg, melanoma), microsatellite instability-high (MSI-high) solid tumor, pancreatic cancer, or breast cancer (eg, triple negative breast cancer (TNBC)).

In another embodiment, a combination, such as a combination containing an anti-CD73 antibody molecule described herein, contains or is used in combination with a BRAF inhibitor to treat a disorder, such as a disorder described herein, such as small cell lung cancer, melanoma, or colorectal cancer .

In another embodiment, a combination, such as a combination comprising an anti-CD73 antibody molecule described herein, contains a CDK4/6 inhibitor, 7-cyclopentyl-Y Ndimethyl-2-((5-((^^)-9-methyl-4 -oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-yl)amino)-7Hpyrrolo[2,3L]pyrimidine-6-carboxamide (compound A30) or a compound disclosed in the publication

- 281 047335 according to PCT No. WO 2011/101409, or used in combination with them for the treatment of a disorder, for example the disorder described in this document. In one embodiment, the CDK4/6 inhibitor is 7-cyclopentyl-K^dimethyl-2-((5-((1K..6^)-9-methyl-4-oxo-3.9diazabicyclo[4.2.1]nonan- 3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3D]pyrimidine-6-carboxamide (compound A30) or a compound disclosed in PCT Publication No. WO 2011/101409. In one embodiment, the anti-CD73 antibody molecule is used in combination with 7-cyclopentyl-H,Ndimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1 ]nonai-3-yl)pyridin-2-yl)αmino)-7H-pyr rolo[2,3D]pyrimidine-6-carboxamide (compound A30) or a compound disclosed in PCT Publication No. WO 2011/101409, for the treatment disorders such as cancer, mantle cell lymphoma, liposarcoma, non-small cell lung cancer, melanoma, squamous cell carcinoma of the esophagus, or breast cancer.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains or is used in combination with a HER3 inhibitor, compound A31 or a compound disclosed in PCT Publication No. WO 2012/022814 to treat a disorder, such as the violation described in this document. In one embodiment, the HER3 inhibitor is compound A31 or a compound disclosed in PCT publication WO 2012/022814. In one embodiment, an anti-CD73 antibody molecule is used in combination with compound A31 or a compound disclosed in PCT publication WO 2012/022814 to treat a disorder such as gastrointestinal cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma, gastric cancer, breast cancer (eg, metastatic breast cancer) or digestive/gastrointestinal cancer.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains an inhibitor of FGFR2 and/or FGFR4, compound A32 or a compound disclosed in PCT publication No. WO 2014/160160 (for example, a drug-drug conjugate antibody molecules to FGFR2 and/or FGFR4, for example mAb 12425), or used in combination with them to treat a disorder, such as a disorder described herein. In one embodiment, the FGFR2 and/or FGFR4 inhibitor is compound A32 or a compound disclosed in PCT Publication No. WO 2014/160160. In one embodiment, the anti-CD73 antibody molecule is used in combination with compound A32 or a compound described in table. 18, for the treatment of a disorder such as cancer, gastrointestinal cancer, breast cancer, rhabdomyosarcoma, liver cancer, adrenal cancer, lung cancer, esophageal cancer, colon cancer or endometrial cancer.

In some embodiments, Compound A32 is a conjugate of a drug and an anti-FGFR2 and/or FGFR4 antibody molecule, such as mAb 12425.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains an M-CSF inhibitor, compound A33, or a compound disclosed in PCT Publication No. WO 2004/045532 (for example, an anti-CD73 antibody molecule or Fab fragment). M-CSF), or used in combination with them, to treat a disorder, such as the disorder described herein. In one embodiment, the M-CSF inhibitor is compound A33 or a compound disclosed in PCT Publication No. WO 2004/045532. In one embodiment, an anti-CD73 antibody molecule is used in combination with compound A33 or a compound that is described in PCT Publication No. WO 2004/045532 for the treatment of a disorder such as cancer, prostate cancer, breast cancer or pigmented villonodular synovitis (PVNS). ).

In another embodiment, a combination, such as a combination containing an anti-CD73 antibody molecule described herein, contains or is used in combination with a MEK inhibitor to treat a disorder such as non-small cell lung cancer, a multisystem genetic disorder, melanoma, ovarian cancer, digestive cancer /gastrointestinal tract, rheumatoid arthritis or colorectal cancer.

In another embodiment, the combination, for example, a combination containing an anti-CD73 antibody molecule described herein, contains an inhibitor of one or more of c-KIT, histamine release, Flt3 (eg, FLK2/STK1) or PKC, midostaurin (compound A35), or a compound disclosed in PCT Publication No. WO 2003/037347, or used in combination therewith for the treatment of a disorder, for example a disorder described herein. In one embodiment, the inhibitor is midostaurin (compound A35) or a compound disclosed in PCT Publication No. WO 2003/037347. In one embodiment, an inhibitor of one or more of c-KIT, histamine release, Flt3 (eg, FLK2/STK1), or PKC is midostaurin. In one embodiment, the anti-CD73 antibody molecule is used in combination with midostaurin (compound A35) or a compound disclosed in PCT Publication No. WO 2003/037347 for the treatment of a disorder such as cancer, colorectal cancer, myeloid leukemia, myelodysplastic syndrome, age-related macular degeneration, diabetic complication or dermatological disorder.

In another embodiment, a combination, for example a combination comprising an anti

- 282 047335 anti-CD73 body described herein contains a TOR inhibitor (for example, an mTOR inhibitor), everolimus (also known as AFINITOR; compound A36) or a compound disclosed in PCT publication No. WO 2014/085318, or used in combination with them to treat a disorder, such as the disorder described herein. In one embodiment, the TOR inhibitor is everolimus (compound A36) or a compound disclosed in PCT Publication No. WO 2014/085318. In one embodiment, an anti-CD73 antibody molecule is used in combination with everolimus (compound A36) to treat a disorder such as colorectal cancer, interstitial lung disease, small cell lung cancer, respiratory tract/chest cancer, prostate cancer, multiple myeloma, sarcoma, age-related macular degeneration, bone cancer, tuberous sclerosis, non-small cell lung cancer, endocrine cancer, lymphoma, neurological disorders, astrocytoma, cervical cancer, neurological cancer, leukemia, immunological disorders, transplant rejection, gastrointestinal cancer, melanoma, epilepsy, breast cancer ( for example, triple negative lung cancer (TNBC) or bladder cancer. In some embodiments, the cancer is selected from colorectal cancer (eg, microsatellite stable colorectal cancer (MSS CRC)), lung cancer (eg, non-small cell lung cancer), or breast cancer. (eg, triple negative lung cancer (TNBC)).

In some embodiments, the combination described herein contains an mTOR inhibitor, everolimus (compound A36) or a compound disclosed in PCT Publication No. WO 2014/085318, and an inhibitor of an immune checkpoint molecule, such as a CD73 inhibitor (eg , an anti-CD73 antibody molecule).

In another embodiment, a combination, such as a combination comprising an anti-CD73 antibody molecule described herein, contains an inhibitor of one or more of VEGFR-2, PDGFRbeta, KIT or Raf C kinase, 1-methyl-5-((2-(5 -(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4yl)oxy)-N(4-(trifluoromethyl)phenyl)-1H-benzoSchimidazol-2-amine (compound A37) or a compound disclosed in a PCT publication No. WO 2007/030377, or used in combination with them to treat a disorder, such as the disorder described herein. In one embodiment, the inhibitor of one or more of VEGFR-2, PDGFRbeta, KIT or Raf C kinase is 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4 -yl)oxy)-N(4-(trifluoromethyl)phen yl)-1H-benzoshimidazol-2-amine (compound A37) or a compound disclosed in PCT Publication No. WO 2007/030377. In one embodiment, the anti-CD73 antibody molecule is used in combination with 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N(4- (trifluoromethyl)phenyl)-1H-benzoshimidazol-2-amine (compound A37) or a compound disclosed in PCT publication No. WO 2007/030377, for the treatment of a disorder such as cancer, melanoma or solid tumor.

In another embodiment, the combination, for example, a combination containing an anti-CD73 antibody molecule described herein, contains a somatostatin agonist and/or growth hormone release inhibitor, pasireotide diaspartate (also known as SIGNTFOR; compound A38), or a compound disclosed in the publication according to PCT No. WO2002/010192 or US Patent No. 7473761, or used in combination therewith, to treat a disorder, such as the disorder described herein. In one embodiment, the somatostatin agonist and/or growth hormone release inhibitor is pasireotide diaspartate (compound A38) or a compound disclosed in PCT Publication No. WO2002/010192 or US Patent No. 7473761. In one embodiment, the anti-CD73 antibody molecule is used in combination with pasireotide diaspartate (compound A38) or a compound disclosed in PCT Publication No. WO2002/010192 or US Patent No. 7,473,761 for the treatment of a disorder such as prostate cancer, endocrine cancer, neurological cancer, neuroendocrine tumor (NET) (eg, atypical carcinoid tumor of the lung), skin cancer (eg, melanoma or Merkel cell carcinoma), pancreatic cancer, liver cancer, Cushing's syndrome, gastrointestinal dysfunction, acromegaly, liver and bile duct dysfunction, or cirrhosis.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains or is used in combination with a signal transduction modulator and/or an angiogenesis inhibitor, for example, to treat a disorder such as cancer, respiratory tract cancer. chest, multiple myeloma, prostate cancer, non-small cell lung cancer, endocrine cancer, or a neurological genetic disorder.

In another embodiment, a combination, for example a combination comprising an anti-CD73 antibody molecule described herein, contains an EGFR inhibitor, (E..E)-I-(7-chloro-1-(1)-(4(dimethylamino)but -2-enoyl)azepan-3-yl)-1H-benzoSchimidazol-2-yl)-2-methylisonicotinamide (compound A40) or the compound disclosed in PCT No. WO 2013/184757, or used in combination with them for the treatment of a disorder, such as the violation described in this document. In one embodiment, the EGFR inhibitor is N,E)-N(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzoSchimidazol-2-yl )-2-methylisonicotinamide (compound A40) or a compound disclosed in PCT publication No. WO 2013/184757. In one embodiment, the molecule

- 283 047335 antibodies to CD73 are used in combination with (K,E)-H-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan3-yl)-1H-benzoIII|imidazole -2-yl)-2-methylisonicotinamide (compound A40) or a compound disclosed in PCT Publication No. WO 2013/184757, for treating a disorder such as cancer, eg solid tumor.

In some embodiments, an EGFR inhibitor, (K.E)-H-(7-chloro-G(G(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzoI|imidazol-2- yl)-2-methylisonicotinamide (compound A40) or a compound disclosed in PCT Publication No. WO 2013/184757 is administered in combination with a CD73 inhibitor (eg an anti-CD73 antibody molecule) for the treatment of colorectal cancer (CRC), lung cancer (eg , non-small cell lung cancer (NSCLC)) or breast cancer (eg, triple negative breast cancer (TNBC)).

In another embodiment, the combination, for example, a combination containing an anti-CD73 antibody molecule described herein, contains an ALK inhibitor, N(2-isopropoxy-5-methyl-4-(1methylpiperidin-4-yl)phenyl)-N(2- (isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4D]pyrimidine-4,6diamine (compound A42) or a compound disclosed in PCT Publication No. WO 2008/073687, or used in combination therewith for the treatment of a disorder, e.g. described in this document. In one embodiment, the ALK inhibitor is ^N6- (2isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3, 4D]pyrimidine-4,6-diamine (compound A42) or a compound disclosed in PCT publication No. WO 2008/073687. In one embodiment, the anti-CD73 antibody molecule is used in combination with N(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo [3,4D]pyrimidine-4,6-diamine (compound A42) or a compound disclosed in PCT publication No. WO 2008/073687, for the treatment of a disorder such as cancer, anaplastic large cell lymphoma (ALCL), non-small cell lung carcinoma (NSCLC ) or neuroblastoma.

In another embodiment, a combination, such as a combination comprising an anti-CD73 antibody molecule described herein, contains an IGF-1R inhibitor, 3-(4-(4-((5-chloro-4-((5-methyl1H-pyrazol- 3-yl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thiethane-1,1-dioxide (compound A43), 5-chloro-N-(2 -fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4yl)phenyl)-^-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4 -diamine (compound A44) or 5-chloro-Y-(4-(1ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-^-(5-methyl-1H-pyrazol-3-yl)pyrimidin- 2,4-diamine (compound A45) or a compound disclosed in publication according to PCT No. WO 2010/002655, or used in combination with them for the treatment of a disorder, for example the described disorder. In one embodiment, the IGF-1R inhibitor is 3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3yl)amino)pyrimidin-2-yl)amino)-5 -fluoro-2-methylphenyl)piperidin-1-yl)thiethane-1,1-dioxide (compound A43), 5-chloro-^-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H- pyran-4-yl)piperidin-4-yl)phenyl)-N-(5methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A44), 5-chloro-N-(4-( 1-ethylpiperidin-4-yl)2-fluoro-5-methylphenyl)-^-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A45) or a compound disclosed in the publication according to PCT No. WO 2010/002655. In one embodiment, the anti-CD73 antibody molecule is used in combination with 3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3yl)amino)pyrimidin-2-yl)amino) -5-fluoro-2-methylphenyl)piperidin-1-yl)thiethane-1,1-dioxide (compound A43), 5-chloro-^-(2-fluoro-5-methyl-4-(1-(tetrahydro- 2H-pyran-4-yl)piperidin-4-yl)phenyl)-^-(5methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A44), 5-chloro-Y-(4 -(1-ethylpiperidin-4yl)-2-fluoro-5-methylphenyl)-^-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A45) or a compound disclosed in the publication according to PCT No. WO 2010/002655, for the treatment of a disorder such as cancer or sarcoma.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains the P-glycoprotein 1 inhibitor, valspodar (also known as AMDRAY; compound A46) or a compound disclosed in EP 296122, or is used in combination with them to treat a disorder, such as the disorder described herein. In one embodiment, the P-glycoprotein 1 inhibitor is valspodar (compound A46) or a compound disclosed in EP 296122. In one embodiment, the anti-CD73 antibody molecule is used in combination with valspodar (compound A46) or a compound disclosed in EP 296122 to treating a disorder such as cancer or a drug-resistant tumor.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains or is used in combination with a VEGFR inhibitor, vatalanib succinate (compound A47) or a compound disclosed in EP 296122 for the treatment of violations, such as the violations described herein. In one embodiment, the VEGFR inhibitor is vatalanib succinate (compound A47) or a compound disclosed in EP 296122. In one embodiment, the anti-CD73 antibody molecule is used in combination with vatalanib succinate (compound A47) or a compound disclosed in EP 296122 for the treatment of cancer.

In another embodiment, a combination, for example a combination comprising an anti-CD73 antibody molecule described herein, contains an IDH inhibitor or a compound disclosed in

- 284 047335

WO2014/141104, or used in combination with them to treat a disorder, such as the disorder described herein. In one embodiment, the IDH inhibitor is a compound disclosed in PCT Publication No. WO2014/141104. In one embodiment, an anti-CD73 antibody molecule is used in combination with a compound described in WO2014/141104 to treat a disorder, such as cancer.

In another embodiment, a combination, for example a combination containing an anti-CD73 antibody molecule described herein, contains a BCL-ABL inhibitor or a compound disclosed in PCT Publication No. WO2013/171639, WO2013/171640, WO2013/171641 or WO2013/171642, or used in combination therewith to treat a disorder, such as the disorder described herein. In one embodiment, the BCL-ABL inhibitor is a compound disclosed in PCT Publication No. WO2013/171639, WO2013/171640, WO2013/171641 or WO2013/171642. In one embodiment, an anti-CD73 antibody molecule is used in combination with a compound disclosed in PCT Publication No. WO2013/171639, WO2013/171640, WO2013/171641 or WO2013/171642 to treat a disorder, such as cancer.

In another embodiment, a combination, such as a combination comprising an anti-CD73 antibody molecule described herein, contains or is used in combination with a c-RAF inhibitor or a compound disclosed in PCT Publication No. WO2014/151616 to treat a disorder, e.g. described in this document. In one embodiment, the c-RAF inhibitor is compound A50 or a compound disclosed in PCT Publication No. WO2014/151616. In some embodiments, the c-RAF inhibitor or compound A50 is a compound of formula (I):

(I) or a pharmaceutically acceptable salt thereof, wherein

Z ¹ represents O, S, S(=O) or SO2;

Z ² represents N, S or CR ^a , where R ^a represents H, halogen, ^^-alkyl or C1.4haloalkyl;

R ¹ represents CN, halogen, OH, C^-alkoxy or C^-alkyl, which is optionally substituted with one to three groups selected from halogen, C1. ₄ -alkoxy, CN or hydroxyl;

Ring B is selected from phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrimidone, pyrazinone, pyridazinone and thiazole, each of which is optionally substituted with no more than two groups selected from halogen, OH, CN, C1. ₄ -alkyl, C ₂ . ₄ -alkenyl, -O-(C1. ₄ -alkyl), NH ₂ , NH-(C1. ₄ alkyl), -IXC^-alkyl)^ -SO2R ² , NHSO2R ² , NHC(O)R ² , NHCO2R ² , C ₃ . ₆ -cycloalkyl, 5-6-membered heteroaryl, -O-C ₃ . ₆ -cycloalkyl, -O-(5-6-membered heteroaryl), C4-8-heterocycloalkyl and -O-(4-8-membered heterocycloalkyl), where each heterocycloalkyl and heteroaryl contains no more than three heteroatoms selected from N, O and S, as members of a ring, where each is C1. ₄ -alkyl, C ₂ . ₄ -alkenyl, C ₃ . ₆ -cycloalkyl, 5-6 membered heteroaryl and 4-8 membered heterocycloalkyl, each optionally substituted with no more than three groups selected from oxo, hydroxyl, halogen, C1. ₄ -alkyl, C1. ₄ -haloalkyl, C1. ₄ -alkoxy and -(CH ₂ )1. ₂ Q, where Q is OH, Ci-4-alkoxy, -CN, NH2, -NHR ³ , -N(R ³ )2, -SO2R ³ , NHSO2R ³ , NHC(O)OR ³ or NHC(O) R ³ ; R ² and R ³ are each independently C1. ₄ -alkyl; And

Ring B is optionally fused to a 5-6 membered aromatic or non-aromatic ring containing no more than two heteroatoms selected from N, O and S, which 5-6 membered ring may be substituted with halogen, C1. ₄ -alkyl, C1. ₄ -haloalkyl or C1. ₄ -alkoxy, and if the fused ring is not aromatic, substituent options may further include oxo;

each Y is independently selected from C1. ₄ -alkyl, C1. ₄ -alkoxy, CN, halogen, oxo, -(CH ₂ )POR ⁴ , -(CH2)р N(R ⁴ )2, -(CH ₂ )pNHC(O)R ⁴ , -(CH ₂ )рКНСОО(С1 . ₄ -alkyl) and imidazole.

or two Y groups on ring A optionally together form a ring fused to or bridged by ring A, wherein said fused or bridged ring optionally contains a heteroatom selected from N, O and S as a member rings, and is optionally substituted with no more than two groups selected from C1. ₄ -alkyl, Ci-4-alkoxy, CN, halogen, oxo, -(CH2)pOR ⁴ , -(CH2)p N(R ⁴ )2, -(CH2)pNHC(O)R ⁴ , and -(CH ₂ )рШСОО(С1.4alkyl);

each R ⁴ is independently H or C1. ₄ -alkyl;

each p is independently equal to 0, 1 or 2;

q is 0, 1 or 2;

Z ³ , Z ⁴ and Z ⁵ are independently selected from CH and N, and optionally NO;

L represents -C(=O)-NR ⁴ -[CY] or -NR ⁴ -C(=O)-[CY], where [CY] indicates which atom of L

- 285 047335 attached to CY; And

CY is an aromatic ring selected from phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, thiazole, isothiazole, oxazole, pyrazole and isoxazole, the ring being optionally fused to a ring of thiophene, imidazole, oxazolone or pyrrole;

and CY is substituted with no more than two groups selected from halogen, CN, R ⁵ , OR ⁵ , SO2R ⁵ , S(=NH)(=O)R ⁵ , OH, NH2, NHR ⁵ and -N(R ⁵ )2 where each R ⁵ independently represents C1.4-alkyl, C2-4-alkenyl, C2-6-heterocyclyl, 5-membered heteroaryl containing up to three heteroatoms selected from N, O and S as ring members or C3-8 -cycloalkyl, and ^R5 is optionally substituted with no more than four groups selected from oxo, halogen, CN, ^R6 , OH, ^OR6 , ^SO2R6 , NH2, ^NHR6 , N( ^R6 )2, ^NHSO2R6 , ^NHCOOR6 , NHC(=O)R ⁶ , -CH2OR ⁷ , -CH2N(R ⁷ ) ₂ , where each

R ⁶ is independently C1-4 alkyl, and each R ⁷ is independently H or C1-4 alkyl;

and two R ⁴ , R ⁵ , R ⁶ or R ⁷ on the same nitrogen atom can be taken together to form a 5-6 membered heterocyclic ring, optionally containing an additional N, O or S as a ring member and optionally substituted with not more than two groups selected from C _1-4 alkyl, oxo, halogen, OH and C _1-4 alkoxy.

Methods for administering antibody molecules are known in the art and are described below. Suitable dosages of the molecules used will depend on the age and weight of the subject and the particular drug used. Dosages and therapeutic regimens for the anti-CD73 antibody molecule can be determined by one skilled in the art.

In certain embodiments, the anti-CD73 antibody molecule is administered by injection (e.g., intravenously) at a dose (e.g., fixed dose) of from about 60 mg to 2400 mg, such as from about 100 mg to 2400 mg, from about 100 mg to 2200 mg, from from about 100 mg to 2000 mg, from about 100 mg to 1800 mg, from about 100 mg to 1600 mg, from about 100 mg to 1400 mg, from about 100 mg to 1200 mg, from about 100 mg to 1000 mg, from about 100 mg to 800 mg, from about 100 mg to 600 mg, from about 100 mg to 400 mg, from about 100 mg to 200 mg or about 100 mg, about 180 mg or about 200 mg. The dosing schedule may vary from, for example, once a week to every 2, 3 or 4 weeks. In some embodiments, the anti-CD73 antibody molecule is administered at a dose of approximately 100 mg biweekly by intravenous infusion. In some embodiments, the anti-CD73 antibody molecule is administered at a dose of at least about 180 mg biweekly by intravenous infusion. In some embodiments, the anti-CD73 antibody molecule is administered at a dose of approximately 200 mg biweekly by intravenous infusion.

In some embodiments, the anti-CD73 antibody molecule disclosed herein is administered by injection (e.g., subcutaneously or intravenously) at a dose (e.g., fixed dose) of about 5 mg to 100 mg, about 100 mg to 500 mg, from about 500 mg to 1000 mg, from about 1000 mg to 1500 mg, from about 1500 mg to 2000 mg, from about 2000 mg to 2500 mg, from about 2500 mg to 3000 mg, from about 3000 mg to 3500 mg, or from about 3500 mg up to 4000 mg, for example once a week (QW), every two weeks (Q2W) or every four weeks (Q4W). In certain embodiments, the antibody molecule is administered, for example, intravenously, at a dose of about 6 mg, about 20 mg, about 60 mg, about 200 mg, about 600 mg, about 1200 mg, about 2400 mg, about 3000 mg, or about 3600 mg, for example QW, Q2W or Q4W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 60 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 200 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 600 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 1200 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 2400 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 3000 mg Q2W. In certain embodiments, the antibody molecule is administered, for example intravenously, at a dose of approximately 3600 mg Q2W.

In certain embodiments, the anti-CD73 antibody molecule is administered by injection (e.g., intravenously) at a dose of about 1 to 30 mg/kg, such as about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg or approximately 3 mg/kg. In some embodiments, the anti-CD73 antibody molecule is administered at a dose of about 1 mg/kg, about 3 mg/kg, or 10 mg/kg, about 20 mg/kg, about 30 mg/kg, or about 40 mg/kg. In some embodiments, the anti-CD73 antibody molecule is administered at a dose of about 1-3 mg/kg or about 3-10 mg/kg. In some embodiments, the anti-CD73 antibody molecule is administered at a dose of about 0.5-2, 2-4, 2-5, 5-15, or 5-20 mg/kg. The dosing schedule may vary from, for example, once a week to every 2, 3 or 4 weeks. In one embodiment, the molecule

- 286 047335 anti-CD73 antibody is administered at a dose of approximately 10 to 20 mg/kg once every two weeks.

The antibody molecules may be used in unconjugated forms or conjugated to a second agent, such as a cytotoxic drug, a radioisotope, or a protein, such as a protein toxin or viral protein. Such a method involves: administering an antibody molecule, alone or conjugated to a cytotoxic drug, to a subject in need of such treatment. Antibody molecules can be used to deliver various therapeutic agents, for example a cytotoxic moiety, such as a therapeutic drug, a radioisotope, molecules of plant, fungal or bacterial origin, or proteins of biological origin (eg, protein toxins) or particles (eg, recombinant viral particles, e.g. using the virus envelope protein) or a mixture thereof.

Diagnostic Applications

In one aspect, the present invention provides a diagnostic method for detecting the presence of CD73 protein in vitro (eg, in a biological sample, such as a tissue biopsy, such as from cancer tissue) or in vivo (eg, imaging in a subject in vivo). The method involves: (i) contacting a sample with an antibody molecule described herein or administering an antibody molecule to a subject; (optional) (ii) contacting a reference sample, such as a control sample (eg, a control biological sample such as blood plasma, tissue, biopsy) or a control subject)); and (iii) detecting complex formation between the antibody molecule and the sample or subject, or a control sample or subject, wherein a change, such as a statistically significant change, in complex formation in the sample or subject relative to the control sample or subject is indicative of the presence of CD73 in the sample. The antibody molecule can be directly or indirectly labeled with a detection agent to enable detection of bound or unbound antibody. Suitable detection substances include the various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials described above and described in more detail below.

The term sample, when referring to samples used for the detection of polypeptides, includes, without limitation, cells, cell lysates, protein or membrane extracts of cells, biological fluids or tissue samples.

Formation of a complex between an antibody molecule and CD73 can be detected by measuring or imaging either a binding molecule bound to a CD73 antigen or an unbound binding molecule. Traditional detection assays, such as enzyme-linked immunosorbent assay (ELISA) variants, radioimmunoassay (RIA) or tissue immunohistochemistry, can be used. As an alternative to labeling the antibody molecule, the presence of CD73 can be analyzed in a sample using a competitive immunoassay using standards labeled with a detection agent and an unlabeled antibody molecule. In this assay, a biological sample, labeled standards, and an antibody molecule are combined and the amount of labeled standard bound to an unlabeled binding molecule is determined. The amount of CD73 in a sample is inversely proportional to the amount of labeled standard bound to the antibody molecule.

Nucleic acids

The present invention also provides nucleic acids comprising nucleotide sequences that encode heavy and light chain variable regions and CDRs or hypervariable loops of the anti-CD73 antibody molecules described herein. For example, the present invention provides first and second nucleic acids encoding the heavy and light chain variable regions, respectively, of an anti-CD73 antibody molecule selected from one or more antibody molecules disclosed herein. The nucleic acid may contain the nucleotide sequence set out in table. 1, or a sequence substantially identical thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto, or that differs by no more than 3, 6, 15, 30 or 45 nucleotides from the sequences shown in Table 1).

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two or three CDRs or hypervariable loops from a heavy chain variable region having the amino acid sequence set forth in Table. 1, or a sequence substantially homologous thereto (eg, a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or having one or more substitutions, such as conservative substitutions). In other embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two or three CDRs or hypervariable loops from a light chain variable region having the amino acid sequence set forth in Table. 1, or a sequence substantially homologous thereto (eg, a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or having one or more substitutions, such as conservative substitutions). In still other embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least

- 287 047335 at least one, two, three, four, five or six CDRs or hypervariable loops from the variable regions of the heavy and light chains having the amino acid sequence set out in table. 1, or a sequence substantially homologous thereto (eg, a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or having one or more substitutions, such as conservative substitutions).

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two or three CDRs or hypervariable loops from a heavy chain variable region having the nucleotide sequence set forth in Table. 1, or a sequence substantially homologous thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or capable of hybridizing under the stringent conditions described herein). In other embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two or three CDRs or hypervariable loops from a light chain variable region having the nucleotide sequence set forth in Table. 1, or a sequence substantially homologous thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or capable of hybridizing under the stringent conditions described herein). In other embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five or six CDRs or hypervariable loops from light chain variable regions having the nucleotide sequence set forth in Table. 1, or a sequence substantially homologous thereto (e.g., a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto and/or capable of hybridizing under the stringent conditions described herein).

In one aspect, the present application relates to host cells and vectors containing the nucleic acids described herein. Nucleic acids may be present in a single vector or separate vectors present in the same host cell or a separate host cell, as described in more detail below herein.

Vectors

Further provided herein are vectors containing nucleotide sequences encoding an antibody molecule described herein. In one embodiment, the vectors contain nucleotides encoding an antibody molecule described herein. In one embodiment, the vectors contain the nucleotide sequences described herein. Vectors include, but are not limited to, virus, plasmid, cosmid, lambda phage, or yeast artificial chromosome (YAC).

Numerous vector systems can be used. For example, one class of vectors uses DNA elements that are derived from animal viruses, such as, for example, bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retroviruses (Rouse sarcoma virus, MMTV or MOMLV) or SV40 virus. Another class of vectors uses RNA elements derived from RNA viruses such as Semliki Forest virus, Eastern equine encephalitis virus, and flaviviruses.

In addition, cells that have stably integrated DNA into their chromosomes can be selected by introducing one or more markers that allow selection of transfected host cells. The marker may provide, for example, prototropy for an auxotrophic host, resistance to biocides (e.g., antibiotics), or resistance to heavy metals such as copper or the like. The selectable marker gene can either be directly linked to the DNA sequences to be expressed, or introduced into the same cell by cotransformation. Additional elements may also be required for optimal mRNA synthesis. These elements may include splicing signals as well as transcriptional promoters, enhancers, and termination signals.

Once the expression vector or DNA sequence containing the constructs is ready for expression, the expression vectors can be transfected or introduced into the appropriate host cell. To achieve this, various techniques can be used, such as, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun, lipid-based transfection or other conventional methods. For protoplast fusion, cells are grown in media and screened for appropriate activity. Methods and conditions for culturing the resulting transfected cells and recovering the resulting antibody molecule are known to those skilled in the art and may vary or be optimized depending on the particular expression vector and mammalian host cell used based on the present disclosure.

Cells

The present invention also relates to host cells containing a nucleic acid encoding an antibody molecule described herein.

- 288 047335

In one embodiment, the host cells are genetically engineered to contain nucleic acids encoding an antibody molecule.

In one embodiment, the host cells are genetically engineered using an expression cassette. The phrase expression cassette refers to nucleotide sequences that are capable of influencing gene expression in hosts compatible with such sequences. Such cassettes may include a promoter, an open reading frame with or without nitrones, and a termination signal. Additional factors necessary or useful to influence expression, such as, for example, an inducible promoter, can also be used.

The present invention also relates to host cells containing the vectors described herein.

The cell may be, without limitation, a eukaryotic cell, a bacterial cell, an insect cell, or a human cell. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells (eg, CHO-C8TD cells), HEK293 cells, BHK cells, and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells.

Examples

The following examples are provided to facilitate understanding of the present invention, but are not intended and should not be construed as limiting its scope in any way.

Example 1. Production and characterization of antibodies to CD73

Selection and optimization of anti-CD73 antibodies from synthetic yeast antibody libraries

Anti-CD73 monoclonal antibodies representing five different epitope bins were selected from eight synthetic yeast libraries of intact human antibodies using the methods described below.

Materials and methods

Antigens were biotinylated using the EZ-Link Sulfo-NHS-Biotinylation kit from Pierce. Goat F(ab') ₂ to human kappa-FITC (LC-FITC), ExtrAvidin-PE (EA-PE) and strenmavidin-AF633 (SA633) were obtained from Southern Biotech, Sigma and Molecular Probes, respectively. Streptavidin microbeads and MACS LC separation columns were purchased from Miltenyi Biotec. Goat anti-human IgG-PE (Human-PE) was obtained from Southern Biotech.

Primary detection

Eight synthetic yeast libraries of intact human antibodies, each with a diversity of ~10 ⁹ , were propagated as previously described (see, e.g., Y. Xu et al, Addressing polyspecificity of antibodies selected from an in vitro yeast presentation system: a FACS-based, high-throughput selection and analytical tool. PEDS 26.10, 663-70 (2013); WO2009036379; WO2010105256 and WO2012009568, incorporated herein by reference in their entirety. For the first two rounds of selection, a magnetic bead sorting technique was performed using the Miltenyi system. MACS as previously described (see, for example, Siegel et al, High efficiency recovery and epitope-specific sorting of an scFv yeast display library. J Immunol Methods 286(1-2), 141-153 (2004), incorporated herein Briefly, yeast cells (~10 ¹⁰ cells/library) were incubated with 3 ml of 100 nM biotinylated antigen for 30 min at 30°C in wash buffer (phosphate-buffered saline (PBS)/0 .1% bovine serum albumin (BSA)). After washing once with 40 ml of ice-cold wash buffer, the cell pellet was resuspended in 20 ml of wash buffer and streptavidin microbeads (500 μl) were added to the yeast and incubated for 15 min. at 4°C. Yeast cells were then pelleted, resuspended in 20 ml wash buffer and loaded onto a Miltenyi LS column. After loading 20 ml, the column was washed 3 times with 3 ml wash buffer. The column was then removed from the magnetic field and the yeast cells were eluted with 5 ml of growth medium and then grown overnight. Subsequent rounds of selection were performed using flow cytometry. Approximately 2x10 yeast cells were pelleted, washed three times with wash buffer, and incubated at 30°C with either decreasing concentrations of biotinylated antigen (100 to 1 nM) at equilibrium conditions, with 30 nM biotinylated antigens from different species to obtain species cross-reactivity, or with a depletion reagent polyspecificity (PSR) to remove nonspecific antibodies from selection. To deplete PSR, libraries were incubated with a 1:10 dilution of biotinylated PSR reagent as described previously (see, e.g., Y. Xu et al, Addressing polyspecificity of antibodies selected from an in vitro yeast presentation system: a FACS-based, high-throughput selection and analytical tool. PEDS 26.10, 663-70 (2013), incorporated herein by reference in its entirety). Yeast cells were then washed twice with wash buffer and stained with LC-FITC (diluted 1:100) and either SA-633 (diluted 1:500) or EARE (diluted 1:50) secondary reagents for 15 min at 4°C. After washing twice with wash buffer, cell pellets were resuspended in 0.3 ml wash buffer and transferred to sorting tubes with filter caps. Sorting was performed using a FACS ARIA sorter (BD Biosciences) and sorting gates were determined to select antibodies with the desired characteristics. The qualifying rounds were repeated until they got their ass

- 289 047335 lation with all the desired characteristics. After the final round of sorting, yeast cells were seeded and individual colonies were selected for characterization.

A light chain diversification protocol was applied during the primary discovery phase to further discover and improve antibodies.

Light chain batch diversification protocol. Heavy chain plasmids from intact selection were recovered from yeast by shear and capture, propagated and then purified from E. coli and transformed into a light chain library at 5x10 ⁶ diversity. Screenings were performed using one round of MACS and four rounds of FACS using the same conditions as intact detection.

Antibody optimization

Antibody optimization was performed by introducing differences in the heavy chain and light chain variable regions as described below.

Selection of CDRH1 and CDRH2. CDRH3 of one antibody was recombined into a pre-built library with CDRH1 and CDRH2 variants at a diversity of 1x 10 ⁸ and selection was performed using one round of MACS and four rounds of FACS as described for intact detection. In different rounds of FACS, libraries were screened for PSR binding, species cross-reactivity, and affinity pressure by titration or pre-complexation of the original Fab and sorted to obtain a population with the desired characteristics.

Antibody production and purification

Yeast clones were grown to saturation and then induced for 48 h at 30°C with shaking. After induction, yeast cells were pelleted and supernatants were collected for purification. IgG was purified using a protein A column and eluted with acetic acid, pH 2.0. Fab fragments were obtained by papain digestion and purified using KappaSelect (GE Healthcare LifeSciences).

KD measurements using ForteBio

ForteBio affinity measurements were performed on Octet RED384 generally as described previously (see, e.g., Estep et al, High throughput solution-based measurement of antibody-antigen affinity and epitope binning. Mabs 5(2), 270-278 ( 2013), incorporated herein by reference in its entirety). Briefly, affinity measurements using ForteBio were performed by loading IgG online onto the AHQ sensors. The sensors were equilibrated offline in assay buffer for 30 min. and then monitored online for 60 seconds to establish baseline. IgG-loaded sensors were exposed to 100 nM antigen for 3 min and then transferred to assay buffer for 3 min. to measure discrepancy. All kinetic parameters were analyzed using a 1:1 binding model. The antigens used were:

Human CD73-His: recombinant human protein 5'-nucleotidase/CT73, CF from R&D Systems, cat.: 5795-EN;

Mouse CD73-His: Recombinant mouse protein 5'-nucleotidase/CD73, CF from R&D Systems, cat.: 4488-EN;

Cynomolgus CD73-His: Cynomolgus CD73/NT5E (His Tag) protein from SinoBiological, cat.: 90192-С08Н-50.

Epitope-specific ligand sorting/blocking ForteBio

Epitope-specific ligand sorting/blocking was performed using a standard cross-blocking assay in a sandwich format. Target control IgG was loaded onto AHQ sensors, and unoccupied Fc-binding sites on the sensor were blocked with an irrelevant human IgG1 antibody. The sensors were then exposed to 100 nM of the target antigen, followed by the addition of a second target antibody or ligand. Additional binding by a second antibody or ligand after antigen association indicates an unoccupied epitope (non-competitor), whereas lack of binding indicates blocking of the epitope (competitor or ligand blocking).

MSD-SET Kinetic Analysis

Equilibrium affinity measurements were performed as previously described ( Estep et al., 2013 ). Solution equilibrium titrations (SET) were performed in PBS+0.1% BSA without IgG (PBSF) with the antigen constant at 10-100 pM and incubated with 3-5 fold serial dilutions of antibodies starting at 5-100 nM ( experimental condition depends on the sample). Antibodies (20 nM in PBS) were applied to standard MSD-ECL binding plates overnight at 4°C or at room temperature for 30 min. The plates were then blocked for 30 min with shaking at 700 rpm and then washed three times with wash buffer (PBSF + 0.05% Tween 20). SET samples were applied and incubated on the plates for 150 s with shaking at 700 rpm, followed by a single wash. The antigen captured on the plate was detected with sulfotag-labeled streptavidin at a concentration of 250 ng/ml in PBSF by incubation on the plate for 3 min. The plates were washed three times with wash buffer and then read on an MSD Sector Imager 2400 using 1x Reading Buffer T with surfactant. Percentage containing

- 290 047335 free antigen dilution was plotted against titrated antibody in Prism and fitted to a quadratic equation to obtain KD. Automated liquid handling devices were used to improve throughput during MSD-SET experiments, including SET sample preparation.

Cell binding assays

Approximately 100,000 antigen overexpressing cells were washed with wash buffer and incubated with 100 μl of 100 nM IgG for 5 minutes at room temperature. Cells were then washed twice with wash buffer and incubated with 100 μl of 1:100 Human-PE for 15 min on ice. Cells were then washed twice with wash buffer and analyzed on a FACS Canto II analyzer (BD Biosciences).

results

Yeast cells expressing a library of human antibodies on their surface were screened for binding to human CD73. Two antibodies from epitope bin 4, 918 and 930, bound well to CD73 and inhibited CD73 enzymatic activity (data not shown). These two antibodies were subjected to affinity maturation, which resulted in the formation of two lines of related antibodies, designated line 1 and line 3, respectively (Table 19). These CD73 antibodies were expressed in three different formats: IgG1 antibodies (designated as constructs.C, e.g. 350.C), IgG4 antibodies containing the S228P mutation in the Fc region (IgG4 S228P, designated constructs.A, e.g. 350. A), or IgG4 antibodies containing mutations S228P and L235E in the Fc region (IgG4 S228P/L235E, designated as constructs.B, for example, 350.B), numbered according to Eu numbering. The sequences of these antibodies are disclosed in table. 1. For antibody 350.A, two batches of antibodies were prepared, which are hereinafter designated as 350.A1 and 350.A2.

Table 19

Two anti-CD73 antibody lines

Line 1 Antibody IgGl format IgG4 S228P format IgG4 format S228P/L235E Original 918 918.С 918.A 918.B Subsidiary 350 350.С 350.A1, 350.A2 350.V Subsidiary 356 356.C 356.A 356.B Subsidiary 358 358.С 358.A 358.V Line 3 Antibody IgGl format IgG4 S228P format IgG4 format S228P/L235E Original 930 930.С 930.A 930.V Subsidiary 373 373.С 373.A 373.V Subsidiary 374 374.С 374.A 374.V Subsidiary 376 376.С 376.A 376.V Subsidiary 377 377.С 377.A 377.V Subsidiary 379 379.С 379.A 379.V

All CD73 antibodies tested bind to human and cynomolgus monkey CD73. Lineage 1 antibodies also bind to mouse CD73. In table 20 shows the K _D values of these antibodies measured using Octet as described above.

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Table 20

Antibody affinity values for CD73

mAb Kd (M) total human IgG, ForteBio Kd (M) total IgG macaque- crabeater, ForteBio Kd (M) of total mouse IgG, ForteBio 918.С 1.53E-09 No data 8.88E-09 350.С 2.48E-10* 6.35E-10 4.09E-10* 356.C 2.43E-10* 6.93E-10 4.01E-10 358.С ZD7E-10 8D4E-10 ZD1E-09 930.С 1.83E-09 No data No binding 373.С 6.21E-10 9D4E-10 No binding 374.С 3.58E-10 1, OZE-10 No binding 376.С 3.01E-10 No data No binding 377.С 5.72E-10 1D2E-09 No binding 379.С 5.50E-10 1.62E-09 No binding

*Value approaches the upper limit of KD measurements

Next, using epitope-specific sorting/ligand blocking studies, parent antibody 918 was shown to compete for CD73 binding with daughter antibodies 350, 356, and 358. Similarly, parent antibody 930 competed for CD73 binding with daughter antibodies 373, 374, 376, 377 and 379. Both 918 and 930 were shown to compete with the internal reference CD73 antibody, suggesting that these antibodies belong to the same epitope bin.

Measuring Fab and Antibody Affinities Using Surface Plasmon Resonance

Fab mAbs 350 and 373 were generated by constructing a stop codon between two proline residues above the heavy chain core hinge region of 350 and 373. Both were expressed in Expi293F cells (ThermoFisher) and purified using CaptureSelect IgG CH1 affinity resin (ThermoFisher).

Biacore was used to measure cross-species affinity for Fab materials mAbs 350 and 373. The proteins used were: recombinant human CD73 (R&D Systems 5795-EN); recombinant CD73 from cynomolgus macaque (Sino Biological 90912-С08Н); recombinant mouse CD73 (R&D Systems 4488-EN) and recombinant rat CD73 (Sino Biological 80375-R08H). Anti-human Fab antibody (GE Healthcare Life Sciences) was immobilized on all 4 flow cells (Fc) on the CM5 chip (GE). Fabs 350 and 373 were captured on Fc2 and Fc4 at ~20 RU. From 0.01 nM to 90 nM CD73 (3-fold dilution series) passed through all 4 Fcs. All samples were diluted in HBS-EP+ running buffer (pH 7.4, 0.01 M HEPES, 150 mM NaCl, 3 mM EDTA, and 0.05% (v/v) P20).

In table Figure 21 shows the Kd(M) affinity results for the interspecies cross-linking of Fab 350 and 373.

Table 21

Fab affinity values for CD73

Fab Antigen Kd(M) Fab 350 hCD73 <1E-1O Fab 350 cCD73 <1E-1O Fab 350 mCD73 l,728E-8 Fab 350 rCD73 2.829E-8 Fab 373 hCD73 l,304E-8 Fab 373 cCD73 9D65E-9 Fab 373 mCD73 No binding Fab 373 rCD73 No binding

In a separate study, the affinity of full-length 373.A antibody or Fab 373.A fragments for human, cynomolgus, mouse and rat CD73 was determined using the Biacore method for surface plasmon resonance (SPR) capture of anti-histidine (His) antibodies. Ab to His was directly immobilized on the surface of the CM5 chip using immobilization at the amino group.

- 292 047335

His-tagged human CD73/His, cynomolgus CD73/His, mouse CD73/His, or rat CD73/His flowed and was captured at the desired resonance unit (RU) for an Rmax of 20. Antibody analyte concentrations in serial dilutions of IgG or Fab flowed at a rate of 60 µl/min. Sensograms were analyzed using the manufacturer's software for a 1:1 binding model. Binding to mouse CD73/His protein and rat CD73/His protein was not detected for Fabs 373.A and 373.A, demonstrating that 373.A is not cross-reactive in rodents.

The affinity for human and cynomolgus CD73 was determined for both Fab 373.A and 373.A. Hydrogen-deuterium exchange mass spectrometry and size exclusion chromatography studies support a model of conformational trapping of the CD73 dimer by 373.A into an open-open (inactive-inactive) conformation, maintaining a 1:1 bidentate binding of CD73 dimer 1 Ab:1 (see Figure 1). example 2). Therefore, given that 1:1 bidentate binding would favor avidity, total Ab affinity measures were used rather than Fab measurements. Full-length antibody 373.A binds recombinant human CD73 with a Kd of 0.991 ± 0.267 nM and cross-reacts with recombinant cynomolgus CD73 with a Kd of 0.068 ± 0.009 nM, as determined in Biacore kinetic binding studies.

Binding of anti-CD73 antibodies to targets in whole blood

Target binding in whole blood was assessed by flow cytometry using whole blood from healthy donors. Briefly, biotinylated antibodies were incubated with whole blood for 30 min to lyse and fix the red blood cells. Fixed cells were stained for CD3 and CD8 to identify CD8+ T cells and with streptavidin-APC to detect biotin. After staining, cells were washed and analyzed by flow cytometry.

Dose-dependent binding, as measured by the mean fluorescence intensity (MFI) of the APC signal, was observed for the anti-CD73 antibodies tested (Fig. 1). The biotinylated isotype control antibody showed no binding to CD8+ T cells (Fig. 1).

CD73 target occupancy in human whole blood samples

A conceptual demonstration of CD73 target (TO) occupancy in human whole blood samples was performed by treating ex vivo donor blood with unlabeled 373.A. The control isotype 373.A or DNP-IgG4sm was titrated from 10 μg/ml to 0.17 ng/ml. As shown in FIG. 24A, samples from two donors that were treated with higher doses of unlabeled 373.A (10 μg/mL to ~0.1 μg/mL) prevented biotinylated 373.A from binding to cells, reducing geometric mean fluorescence intensity (gMFI ) to a plateau at background fluorescence levels (~550 gMFI for both donors). This indicates full occupancy of the CD73 target. In contrast, gMFI values for cells that were pretreated with lower amounts of unlabeled 373.A (0.17 ng/ml and 0.51 ng/ml) were similar to samples that were pretreated with the isotype control DNP-IgG4sm (~1600 gMFI for donor 1 and ~2200 gMFI for donor 2). Samples treated with the isotype control resembled blood, which had zero target occupancy. The resulting %TO values are shown in FIG. 24V.

Inhibition of enzymatic activity of soluble recombinant CD73

CD73 5'-ectonucleotidase is the rate-limiting step in the conversion of AMP to adenosine. The ability of anti-CD73 antibody to inhibit CD73 enzymatic activity was measured using phosphate quantification by the malachite green reaction. Briefly, 25 ng/ml recombinant human CD73 was incubated with a titrated dose of substrate adenosine monophosphate (AMP) (0-500 μM) with buffer alone or in the presence of an isotype control antibody at a concentration of 1 μg/ml or an anti-CD73 antibody 350.C at a concentration of 1. 0.3 or 0.1 µg/ml. Inorganic phosphate (Pi) release was measured using a malachite green phosphate quantitation kit (Enzo Life Sciences, catalog no. BML-AK111).

As shown in FIG. 2A, the control antibody at the concentration tested did not affect the Michaelis constant (K _m ) of recombinant human CD73. In contrast, anti-CD73 antibody 350.C caused a dose-dependent decrease in V _max in the K _m curves (Fig. 2B), indicating that antibody 350.C is a noncompetitive inhibitor of human CD73.

Antibodies to CD73, 350, 356, 373 and 374, expressed in .A or .B format, were then tested for their ability to inhibit the enzymatic activity of recombinant human and macaque beetle CD73 using a similar malachite green phosphate assay as described above. Briefly, anti-CD73 antibodies were incubated for 10 min with 25 ng/ml recombinant human or cynomolgus CD73 in the presence of 25 μM AMP. Inorganic phosphate (Pi) release was measured using a malachite green phosphate quantitation kit (Enzo Life Sciences, catalog no. BML-AK111). Normalized percent inhibition (%INH) was determined using the control at time zero as 100% INH and no control antibody as 0% INH.

As shown in FIG. 3A-3C, all tested antibodies to CD73 inhibited the enzymatic amino acid

- 293 047335 activity of soluble recombinant CD73 from humans and cynomolgus macaques.

Inhibition of enzymatic activity of soluble endogenous CD13

In addition, inhibition of the enzymatic activity of anti-CD73 antibodies was studied against soluble endogenous CD73, for example, CD73 isolated from the cell surface.

In the first study, CD73 antibodies 350 and 373 expressed in .A or .B format or isotype control antibodies were incubated for 240 minutes with MDA-MB-231 (a human breast cancer cell line) in serum-free medium in the presence of 100 μM AMP. AMP disappearance was measured using a modified Cell Titer Glo (CTG) assay (Promega, cat. no. G9242/3). AMP inhibits the luciferase signal in the CTG array. The luciferase signal increases when the added AMP is enzymatically consumed by CD73. Normalized percent inhibition (%INH) was determined using the control at time zero as 100% INH and no control antibody as 0% INH.

As shown in FIG. 4, antibodies to CD73 dose-dependently inhibited the enzymatic activity of CD73 isolated from the breast cancer cell line MDA-MB-231.

In the second study, anti-CD73 antibodies 350, 356, 358, 373, 374, 377 and 379, all expressed in format .B, were incubated for 60 minutes with diluted (12.5% v/v in PBS) serum from the patient with pancreatic cancer in the presence of 100 μM AMP. As in the first study, AMP disappearance was measured using a modified Cell Titer Glo (CTG) assay and normalized percent inhibition (%INH) was determined using time zero control as 100% INH and no control antibody as 0% INH.

Antibodies to CD73 also suppressed CD73 enzymatic activity in serum from a patient with pancreatic cancer in a dose-dependent manner (Fig. 5).

Inhibition of the enzymatic activity of CD73 expressed on the cell surface

First, to evaluate the ability of anti-CD73 antibodies 350, 356, 358, 373, 374, 377, and 379 (all in .B format) to inhibit CD73 expressed in a breast cancer cell line. MDA-MB-231, quantitative determination of phosphate by reaction with malachite green was used. Briefly, antibodies were incubated for 180 min with cells in the presence of 100 μM AMP. The release of inorganic phosphate from AMP was measured using a malachite green phosphate quantitation kit (Enzo Life Sciences, catalog no. BML-AK111). Normalized percent inhibition (%INH) was determined using the control at time zero as 100% INH and no control antibody as 0% INH.

As shown in FIG. 6, all CD73 antibodies tested inhibited the enzymatic activity of CD73 expressed on the surface of MDA-MB-231 breast cancer cells.

Next, because lineage 1 antibodies cross-react with mouse CD73, whereas lineage 3 antibodies do not, antibodies from both lineages were tested against CD73 expressed on the surface of human or mouse breast cancer cell lines. Anti-CD73 antibodies were incubated for 240 minutes with the human breast cancer cell line MDA-MB-231 or the breast cancer cell line 4T1 in the presence of 100 μM AMP. AMP disappearance was measured using a modified Cell Titer Glo (CTG) assay described by you, and normalized percent inhibition (%INH) was determined using time zero control as 100% INH and no control antibody as 0% INH.

Consistent with their binding profiles, lineage 1 antibodies 918, 350, 356, and 358 inhibited both human and mouse CD73 (Figures 7A and 7B), whereas lineage 3 antibodies 930, 373, 374, 376, 377, and 379 inhibited Human but not mouse CD73 (Figures 7C and 7D).

In addition, two modified Cell Titer Glo (CTG) assays were performed to test the inhibition of enzymatic activity by anti-CD73 antibodies against CD73 expressed in the human breast cancer cell line MDA-MB-231 or the human ovarian cancer cell line SKOV3. In both studies, 1000 ng/ml anti-CD73 antibodies were incubated for 240 minutes with 20,000 cells/ml cells in the presence of 100 μM AMP at 37°C. AMP disappearance was measured using a modified Cell Titer Glo (CTG) assay described above, and normalized percent inhibition (%INH) was determined using time zero control as 100% INH and no antibody control as 0% INH.

In both studies, all CD73 antibodies tested were able to inhibit surface CD73 expressed in the human breast cancer cell line MDA-MB-231 or the human ovarian cancer cell line SKOV3 (Figs. 8A, 8B, 9A and 9B).

A similar Cell Titer Glo (CTG) assay was then performed to examine the ability of anti-CD73 antibodies to inhibit human CD73 expressed in the HEK 293 cell line. Briefly, the HEK 293 cell line was engineered to stably overexpress human CD73 and incubated with anti-CD73 antibodies for 150 minutes. in the presence of 100 μM AMP. AMP disappearance was measured using a modified Cell Titer Glo (CTG) assay described by you, and normalized percent inhibition (%INH) was determined using time zero control as 100% INH and no control antibody as 0% INH.

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As shown in FIG. 10, anti-CD73 antibodies 350, 356, 373 and 374 in .A or .B format inhibited membrane-bound human CD73 in a dose-dependent manner.

In addition, inhibition of enzymatic activity by anti-CD73 antibodies was also studied using human PBMC. Briefly, primary human PBMCs were isolated from two separate donors and incubated with anti-CD73 antibodies for 480 min in the presence of 25 μM AMP. AMP disappearance was measured using a modified Cell Titer Glo (CTG) assay described by you, and normalized percent inhibition (%INH) was determined using time zero control as 100% INH and no control antibody as 0% INH.

As shown in FIG. 11A and 11B, the CD73 antibodies tested inhibited the enzymatic activity of CD73 expressed on primary human PBMCs from both donors.

Restoration of proliferation of CD4+ and CD8+ T cells in the presence of AMP

Anti-CD73 antibodies were then examined for their ability to attenuate AMP-mediated suppression of CD4+ T cells. Briefly, CD4+ T cells were isolated from pooled peripheral blood mononuclear cells (PBMCs) from a healthy human donor. Before stimulation with anti-CD3/28 beads in the presence of 800 μM AMP, CD4+ T cells were stained with CellTrace Violet (CTV) (Thermo Fisher Scientific, cat. no. C34557) to monitor cell division. On day 4, proliferation was determined by CTV dilution using flow cytometry. Cells stained with CTV lose approximately half of their fluorescent signal, as measured on a flow cytometer, with each division. The proliferation index was calculated as a measure of the level of T cell division for each condition, with 100 representing maximum proliferation and 0 representing no proliferation.

As shown in FIG. 12A and 12B, all CD73 antibodies tested were able to restore CD4+ T cell proliferation in the presence of AMP.

A separate study examined both CD4+ and CD8+ T cells. Briefly, CD4+ and CD8+ T cells were purified from peripheral blood mononuclear cells (PBMCs) isolated from healthy human donors and labeled with carboxyfluorescein succinimidyl ester (CFSE). CFSE-labeled CD4+ or CD8+ T cells were activated for 4 days with anti-CD3/CD28 T-cell activating beads (1 bead/16 cells) in the presence of 800 μM AMP and with serial dilutions of hIgG4 or 373.A isotype control. Representative data are shown for CD4+ T cells (FIG. 25A) and CD8+ T cells (FIG. 25B), in each case from three donors. Data are presented as percentage of CD4+ (FIG. 25A) or CD8+ (FIG. 25B) T cell proliferation, where isotype control demonstrates that maximal proliferation is suppressed in the presence of AMP and the presence of 373.A restores proliferation in a dose-dependent manner. Although the magnitude of the response varies between donors, all three CD4+ T cell donors shown in (Figure 25A) and 2/3 of the donors shown for CD8+ T cells (Figure 25B) 373. A demonstrates activity in vitro in restoring T cell proliferation.

Inhibition of CD73 enzymatic activity in vivo

In addition, anti-CD73 antibodies were tested for their inhibition of enzymatic activity in vivo. Female athymic nude mice (6-8 weeks old) were implanted with the breast cancer cell line MDA-MB231 with high expression of CD73 (ATCC NTV-26) at a dose of 10x106 cells/mouse/200 μl. Five mice per group were randomized when tumors were 200 mm ³ and either 20 or 200 μg/mouse of control polyclonal human IgG or a panel of anti-CD73 mAbs were administered intraperitoneally. The antibodies tested are anti-CD73 350, 356, 373 and 374, expressed in .A or .B format.

Plasma was collected three days after dosing at a ratio of one portion of plasma to five portions of methanol by volume. Methanol-quenched samples were stored at -80°C before use, after which the samples were centrifuged. The pellets were discarded and the supernatants were transferred to new Eppendorf tubes. Stock solutions of internal standards (IS, C-13 labeled adenosine and N-15 labeled inosine, Cambridge Isotope Laboratories, Massachusetts) were added to a final concentration of 50 nM. The prepared samples were then analyzed using an API-6500 QTrap LC/MS system (AB Sciex, USA) with a Shimadzu LC pump (LC-20AD) and a CTC autosampler with DLW washing. For each sample, 5 μl was injected and separated using a SeQuant ZIC-pHILIC column (5 μm, 150 x 2.1 mm, Millipore, MA) maintained at 40°C. A binary gradient was used for elution, where mobile phase B was 100% acetonitrile without additives and mobile phase A was 12 mM ammonium formate and 12 mM formic acid in a 1:1 (v/v) mixture of water and acetonitrile. Elution was programmed as (0.85, 0.6), (0.5, 85, 0.4), (2, 10, 0.4), (4.5, 10, 0.4), (5, 85, 0.4), (5.5, 85, 0.6), where the values in parentheses represent time in minutes, percentage of mobile phase B, and flow rate in ml/min, in order. Adenosine and C13-adenosine were controlled from 0.5 to 4.5 minutes at ESI-positive mode and mass transitions 268->136 and 273->136, respectively. Inosine and N15-uho3uh were controlled from 0.5 to 4.5 minutes at ESI-negative mode and mass transitions 267->135 and 271->139, respectively. Results were presented as nM adenosine or inosine.

All CD73 antibodies tested effectively reduced the accumulation of adenosine and inosine in serum

- 295 047335 in a group of immunodeficient mice implanted with the MDA-MB231 breast cancer cell line with high expression of CD73 (Fig. 13).

Example 2. Determination of the epitope and binding mode of antibodies to CD73

In this example, the epitope and binding mode of CD73 antibodies 350.A2, 350.B, 373.A and 373.B were determined by amide fragmentation hydrogen/deuterium exchange (HDx) and size exclusion chromatography (SEC).

Methods

Hydrogen-deuterium exchange fragmentation mass spectrometry (HDx-MS)

HDx-MS experiments were performed as previously described (Park IH, et al., J. Chem. Inf. Model.; 55(9): 1914–1925 (2015); Chalmers MJ, et al., Anal. Chem.; 78(4): 1005-14 (2006)). Antibody-antigen complexes were prepared and used in a 1:1 molar ratio by incubation overnight at 4°C. Importantly, this means that complex mixtures have a 2-fold excess of Fab binding sites.

Exchange experiments at room temperature were performed by manually adding 50 μl of exchange buffer (50 mM phosphate, 150 mM NaCl, pH 7.1, in D20) to 10 μl of 0.5 mg/ml rhCD73 protein (R&D systems, catalog no. 5795 , Trp27-Lys547 AAH65937 fused to a C-terminal 6-His tag (SEQ ID NO: 922)) or a molar equivalent amount of CD73-mAb complex (50 mM phosphate, 150 mM NaCl, pH 7.1). Samples were quenched after 60 s exchange at room temperature by adding 250 μl of quenching buffer (4 M guanidinium hydrochloride, 0.5 M Tris(2-carboxyethyl)phosphine hydrochloride (TCEP-HCl), 0.2 M phosphate, pH 2.5, 0°C) and after 30 s further diluted with 300 μl ice-cold storage buffer (20% glycerol, 0.25% formic acid in water) before flash freezing in liquid nitrogen and storing at -80°C until use or transfer to a drawer at -70°C attached to fluidic manipulator rails (PAL HTS, LEAP Technologies, Carrboro, NC) located inside a 0°C housing. Frozen samples were thawed for 120 s by passing N2 gas through the sample vessel (facilitated using a fluid handler coupled with a thaw attachment) and loaded into the sampling loop of an injection valve (Valco, Houston, TX). Loading of samples (loading buffer 0.05% trifluoroacetic acid (TFA), 500 μl/min) into the pre-column of the chromatography system and online pepsin digestion (immobilized pepsin on Poros AL20, 2.1x150 mm, kept at 15°C) was performed using a dual pump system (2x, Accela 1250, Thermo Scientific, Waltham, MA) that allowed a second mixing flow of 550 μL/min. (0.05% TFA, 500 µl/min.) after loading the digestion buffer through the mixing tee. The combined stream was sent to a chromatography system maintained at 0°C for desalting and LC gradient separation at a flow rate of 15 μL/min. (Dionex UltiMate 3000, Thermo Scientific, Waltham, MA) and simultaneous mass spectrometric analysis (QExactive, Thermo Scientific, Waltham, MA) of chromatographic flows. The chromatography system consisted of a valve (15 kPa, Valco, Houston, TX), a 4 μL EXP Halo C18 reverse phase cartridge (Optimize Technologies Inc., Oregon City, OR), and an analytical column (ID 2.1 x 10 mm, prozap 1, 5 µm C18, Grace). The gradient separation was from 0 to 40% B over 20 min and then from 40 to 75% B over 5 min. using buffer compositions A: 99.75:0.25% v/v. (H ₂ O: formic acid) and B: 99.75:0.25% v/v. (acetonitrile:formic acid).

MS scans were acquired at a resolution of 70,000 in the m/z range of 350–2000 for MS and 35,000 for MS/MS. Instrument parameters used for all experiments, including spray voltage of 2.5 kV, maximum injection time of 120 ms, AGC MS target of 500,000 ions, were kept the same for all runs. Samples were analyzed in triplicate.

Peptide identification was performed by converting raw data to .mgf format using Proteome Discoverer 1.4, construct sequence searching using MASCOT 2.4 (Matrix Science, London, UK) and filtering using Scaffold 1.4. Filtered results were imported into HDExaminer (v1.3, Sierra Analytics, Modesto, CA) along with raw data files for deuteration quantification. Deuteration values were exported to Microsoft Excel to calculate deuteration differences and normalize deuterium incorporation by the number of amide groups observed (number of residues minus 2, further subtracting the number of proline residues in the sequence excluding the N-terminus and penultimate residues) in the peptide. To reduce peptide sequence difference data, normalized difference deuteration values were averaged for each primary sequence residue according to observations of peptides in which the corresponding amide group was observed.

Water, deuterium oxide, guanidine hydrochloride, sodium chloride, glycerin, formic acid, trifluoroacetic acid (TFA), trifluoroethanol (TFE), acetonitrile (ACN) were obtained from Sigma Chemical Company (St. Louis, MO). Tris-(2-Kap6oKcromn)phosphine)TCEP was from Gold Biotechnology Inc (St. Louis, MO).

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Size exclusion chromatography (SEC)

An equimolar amount of rhCD73 (3.2 μl, 1.6 mg/ml) was mixed with mAb (2.6 μl, 5 mg/ml) and complexed overnight at 4°C. Samples were processed using an Agilent autosampler connected to an Agilent 1200 series pump with an Agilent UV detector. The system was controlled using Agilent Chemstation software. The column used was a Shodex Protein KW-803 column (ID 8 x 300 mm). Mobile phase: 90% 2x PBS, 10% isopropanol by volume. Flow rate: 500 µl/min. Injected sample volume: 8 µl. Detection wavelength: 220 nm. Analysis time: 30 min.

Antibody-antigen complexes were prepared and used in a 1:1 ratio using the provided concentration values with overnight incubation at 4°C. Importantly, this means that there is a nominally 2-fold excess of Fab binding sites in complex mixtures.

Structural data

Structural data used for interpretation were obtained from the Protein Structure Database (www.rcsb.org) and consisted of 4H2F, 4H2I, and 4H1S entries. Alignments of different models and visualization were performed using PyMOL (PyMOL molecular graphics system, version 1.8 of Schrodinger, LLC).

results

Hydrogen exchange data

HDx MS 373.A and 373.B protection profiles as shown in FIG. 14, overlap throughout the CD73 sequence. This demonstrates the equivalence of the antibodies in terms of their epitope.

HDx MS 350.A2 and 350.B protection profiles as shown in FIG. 15 are in good agreement with each other throughout the CD73 sequence. This demonstrates the equivalence of the antibodies in terms of their epitope.

The sequences exhibiting the strongest protection are indicated in the figures and generally correspond to CD73 loop regions. Their relative spatial arrangement is depicted in the structure models shown in FIG. 16A and 16B. While the protection observed for the A-, B-, and D-loop sequences is due to antibody-CD73 interactions, the protective effects observed for the sequence annotated as C-loop are likely due to a conformational block. The C-loop is folded in the open/inactive conformation of CD73 and unfolded in the closed/active conformation (Fig. 16A). Soluble as well as membrane-bound CD73 forms a dimer via its C-terminal domains (Fig. 16B). Equilibrium between the open and closed conformations exists when the N-terminal domain is rotated approximately 90 degrees to convert from the open to the closed form. The C-loop represents this equilibrium. If, after antibody binding to CD73, the equilibrium shifts more towards the open conformation, most of the C-loops will be folded, which is a protected state. On the other hand, if the equilibrium is shifted more toward the closed conformation upon antibody binding to CD73, then deprotection is expected. The unusually strong protection observed for 373.A and 373.B in the C-loop (Fig. 14) suggests that they are most effective at maintaining CD73 in an inactive conformation and/or do so through a different mechanism.

From the profiles it can be concluded that the maximum protected sequences have a range of residues 158-172, YLPYKVLPVGDEVVG (SEQ ID NO: 108), designated as A-loop, range of residues 206-215, KLKTLNVNKI (SEQ ID NO: 109), designated as B -loop, and the range of residues 368387, MINNNLRHADETFWNHVSMC (SEQ ID NO: 110) designated as C-loop in all figures numbered according to SEQ ID NO: 105.

For antibodies 373.A and 373.B, residues in the A- and B-loop regions appear to be equally important for the epitope, as indicated by the comparable levels of protection observed in FIG. 14. In the case of antibodies 350.A2 and 350.B, it is mainly the A-loop residues that appear to be important for the epitope, even if there is some B-loop protection, but it is unclear whether this should be interpreted as a direct interaction of the antibody with residues in this range or is it simply an indirect effect due to proximity to the A-loop.

Size exception data

The size exclusion data correlates well with the HDx data discussed above. The equivalence of antibodies 373.A and 373.B is reflected in the similarity of their size exclusion chromatography (SEC) profiles, which reflect the distribution of oligomerization state (Fig. 17A and 17B). The same assessment holds for antibodies 350.A2 and 350.B (FIGS. 18A and 18B).

Characteristics around 17 min correspond to CD73 dimer and free antibody according to the molecular weight scale based on calibrants, which are provided for reference. The characteristic of approximately 14.8 min or approximately 300 kDa is consistent with a CD73 dimer/mAb complex. After about 12.4 minutes, a signature of about 600 kDa was observed, corresponding to a composition of two CD73+2 mAb dimers (2x CD73 dimer/2x mAb). Additional characteristics above 600 kDa are affected by the exclusion limit for the column. However, they can be classified as higher oligomeric states, meaning complexes consisting of 3 or more CD73 dimers in addition

- 297 047335 reaction to 3 or more mAbs (3 ⁺ xCD73 dimer/3'xmAb).

The dominant species in the CD73-373.A and CD73-373.B profiles shown in Fig. 17A and 17B represent a CD73 dimer/mAb complex. Only a small number of 2x dimer CD73/2x mAb species are observed. This is consistent with the preferred bidentate mode of binding of one antibody to the CD73 dimer.

SEC profiles for CD73-350.A2 and CD73-350.B shown in Fig. 18A and 18B show comparable abundances for the CD73 dimer/mAb species and the CD73 2x dimer/2x mAb species. A shoulder with a shorter elution time indicates the presence of some higher oligomers. This shows that 350.A2 and 350.B are able to bind CD73, like 373.A and 373.B, in a bidentate manner, but this mode is not necessarily thermodynamically favored, at least at the high concentrations used in the experiment.

The percentage of CD73 antibodies that formed a CD73 1x dimer/1x mAb complex, a CD73 2x dimer/2x mAb complex, or a higher oligomer was assessed by integrating SEC profiles across species (FIG. 19). A zero baseline was used for all integrations, with integration intervals ranging from 10.5 min to 11.65 min for higher oligomers and 11.65 min to 13.5 min for the 2x CD73 dimer/2x mAb complex applied sequentially to all samples. Integration intervals for the types of 1x dimer CD73/1x mAb complexes varied slightly and were selected as 13.5-16.2 min for CD73-373.A, 13.5-16 min for CD73-373.B, 13.5- 15.75 min for CD73-350. A2 and 13.5-15.75 min for CD73-350.B to obtain optimal separation from the free antibody signal, which was not integrated as it was not relevant to the assay (antibodies were used in pseudo-excess, providing approximately twice the number of sites Fab binding to CD73 binding sites that were present in complex mixtures).

Conclusion and discussion

The above HDx and SEC data provide strong evidence for the equivalence of 373.A and 373.B, as well as 350.A2 and 350.B, in terms of their mode of interaction with CD73. This was expected given that the only sequence difference between the pairs was a single mutation (L235E to remove residual FcR interactions) in the constant region.

Data from the HDx and SEC experiments are consistent and fully support the model presented in FIG. 20. According to the model, epitopes for all antibodies are located on the N-terminal domains. Antibodies 373.A and 373.B react with the CD73 dimer to form almost exclusively homogeneous particles, shown on the left in Fig. 20. In this species, both active sites of the CD73 dimer are locked in an inactive conformation. Additionally, in this conformation, both N-terminal domains of the CD73 dimer point away from the cell surface in the case of membrane-bound CD73, allowing 373.A and 373.B to inhibit soluble and membrane-bound variants of the target with equal potency.

Antibodies 350.A2 and 350.B can form a bidentate homogeneous complex on the left, but do not show a preference for this form compared to the 2x dimer CD73/2x mAb species shown in the center of Fig. 20. Higher oligomeric species were also observed, shown on the right in FIG. 20. Presumably, the species distribution would shift toward a homogeneous bidentate complex in the case of membrane-bound CD73 or at low antibody and antigen concentrations, a likely scenario in vivo. It is assumed that antibodies 350.A2 and 350.B are able to effectively inhibit all forms of CD73 through an inactive site blocking mechanism. It is clear that even in the active conformation, the target may still be catalytically inactive due to antibody binding due to other mechanisms of allosteric inhibition.

Based on the model, it would be expected that an anti-CD73 antibody that predominantly forms the oligomeric species shown in the middle and right panels of FIG. 20 will be less effective in inhibiting soluble and membrane-bound CD73, especially at low concentrations. The reason for this is that most of the CD73 will always be in the active conformation, and even if the antibody can inhibit catalysis under such circumstances by an indirect mechanism, any separation of the antibody will immediately result in catalytically active CD73. In addition, since the total concentration of antigen and antibody tends to zero, two antibody molecules will be required to inhibit one CD73 dimer, whereas for antibodies 373 and 350 one molecule will still be sufficient.

Short description

The putative binding sites for antibodies 373.A, 373.B, 350.A2, and 350.B on rhCD73 and how they interact with the rhCD73 dimer were determined. The epitopes are characterized as likely discontinuous and consisting of residues located in the sequence ranges 158-172 YLPYKVLPVGDEVVG (SEQ ID NO: 108) and 206-215 KLKTLNVNKI (SEQ ID NO: 109) of human CD73, numbered according to SEQ ID NO: 105 If we consider a model that requires CD73 to be locked in an inactive conformation for inhibition, then based on experimental observations of HDx MS and SEC, one would predict that 373.A, 373.B, 350.A2, and 350.B are capable of inhibiting soluble and membrane-bound ones. CD73 forms.

Example 3. Activation of CD73 in stromal cells after TGFe blockade in vivo

CD73 expression in cancer has been reported not only in cancer cells, but also in

- 298 047335 research of stromal elements that make up the tumor microenvironment. In addition, several stromal factors, including TGFe, have been proposed to provide potential amplification mechanisms for adenosine generation in the tissue microenvironment. In this example, a study was conducted to determine whether blockade of TGFe in vivo could cause changes in CD73 expression in tumor stromal cells.

For this purpose, a humanized IgG2 monoclonal antibody was used, which binds to human and mouse TGFe1 and TGFe2 with high affinity and to TGFe3 with lower affinity. This antibody has been demonstrated to have neutralizing activity against TGFe isoforms in vitro and in vivo. Immunocompetent female BALB/c mice (6-8 weeks old) were implanted into the right flank with cells from the mouse triple-negative breast cancer line 4T1 at 10±10 ⁴ cells/mouse/100 μl. Ten mice per group were treated intraperitoneally every other day with either a pan-TGFe blocking antibody or an isotype control (hIgG2), both at a final concentration of 10 mg/kg body weight. Tumors were allowed to grow for 14 days, after which the animals were euthanized and the tumors were collected and analyzed by flow cytometry. Briefly, tumors from mice were excised and digested using a combination of physical and enzymatic dissociation (DNasel, collagenase P, dispase). Single cell suspensions were Fc blocked for 30 minutes to prevent nonspecific antibody binding and stained with a panel of antibodies that bind to specific cell surface markers, including CD45 (to exclude hematopoietic cells), CD31 (endothelial cells), CD90 (pan-mesenchymal marker ), CD26 and podoplanin, to identify stromal cell populations. CD73 expression was assessed using eFluor450-conjugated CD73 antibody (eBioscience no. 48-0731-82) compared to stained samples with isotype controls (eFluor 450-conjugated rat IgG1, eBioscience no. 48-4301-82). After staining for 40 minutes at 4°C, samples were washed with FACS buffer (PBS, 5 mM EDTA, 2% fetal bovine serum), fixed with Fix/Perm solution (eBioscience no. 00-5523), following the manufacturer's instructions, and analyzed on a flow cytometer BD LSRFortessa™ . CD73 was highly expressed in endothelial cells in mice treated with isotype control, while minimal expression was detected in mesenchymal stromal cells (CD26+ and CD26-CAF and pericytes) (Fig. 21A and 21B). Surprisingly, treatment of mice with TGFe-neutralizing antibodies caused significant activation of CD73 in cancer-associated fibroblasts (CAFs), independent of CD26 expression (Figures 21A and 21B). CD73 activation was also noticeable in endothelial cells, although to a lesser extent, whereas activation was not observed in pericytes (Fig. 21A and 21B). Overall, these data indicate that neutralization of TGFe in the tumor microenvironment induces CD73 expression in stromal cells, suggesting that CD73 activation and adenosine production by tumor fibroblasts may provide an alternative mechanism recruited by tumors to maintain immune quiescence upon TGFe blockade.

Example 4: Effect of Anti-CD73 Antibodies on B Cells

To evaluate whether blockade of CD73-dependent adenosine formation could specifically suppress class-switch recombination (CSR) without affecting the efficiency of the B cell response, the anti-CD73 antibody 350.B was tested. Intact B cells (CD19+CD27-IgM+IgD+) were purified from the peripheral blood of two healthy donors based on CD73 expression and stimulated with TLR9 agonist, anti-CD40 antibody, and cytokines (IL-2 and IL-21) in the presence of antibody 350.B. Three different concentrations of antibody were tested, 1 ng/ml, 10 ng/ml and 100 ng/ml, along with an isotype control IgG4. IgM secretion was measured on day 7 in culture supernatants, and no differences were observed compared to the isotype control (Fig. 22A). Notably, inhibition of CD73 enzymatic activity by 350.B treatment resulted in decreased differentiation of IgG-secreting cells as measured by an ELISPOT assay for detection of IgG-secreting plasma cells (Millipore MSIPS4510 plates coated with 10 μg/ml goat anti-human IgG (Southern Biotechnologies ), with a strong effect at a concentration of 100 ng/ml (Fig. 22C), the number of viable cells was also assessed, and no difference was observed (Fig. 22B), excluding the relationship between low survival and low CSR efficiency observed in intact B cells. CD73+ after 350 V treatment. As a control, intact CD73− cells were stimulated identically and no difference was observed (Figure 22A-C). Finally, evaluation of CSR under isotype control conditions confirmed an increased number of IgG ISCs in the intact CD73+ compartment (Figure 22C). Taken together, these results demonstrated that blockade of CD73 enzymatic activity affected class switch recombination without altering the IgM response.

Example 5 Co-blockade with anti-CD73 and anti-PD-1 antibodies in syngeneic mouse tumor models

To determine the role of co-blockade of the CD73 and PD-1 pathways in tumor-bearing mice, anti-PD-1 antibodies and anti-CD73 antibodies (350.B) were administered to immunocompetent mice inoculated with cells from the syngeneic colon carcinoma line CT-26. BALB/c mice aged 6-10 weeks were inoculated

- 299 047335 roll to the side using 1x 10 ⁵ ST-26 tumor cells. On day 2 after inoculation, mice (n=10 per group) were treated intraperitoneally with any isotype control antibody, 350.B, 600 μg per dose, followed by 400 μg for 4 doses; anti-PD-1 antibody, 300 mcg for 5 doses (low dose); anti-PD-1 antibody, 600 mcg for 5 doses (high dose); a combination of high doses of antibody to PD-1+350.B; or a combination of low doses of anti-PD-1+350.B antibody. Tumor size and body weight were recorded three times a week with an interval of 2 to 3 days between measurements, and each animal was euthanized when the tumor size reached >2000 mm ³ when the mouse died or the tumor was ulcerated. Percent tumor growth inhibition was calculated after 25 days (since the control group was euthanized on day 26).

Treatment with 350.B or low dose anti-PD-1 antibody alone (300 μg) showed partial tumor growth inhibition (30.96% and 52.04%, respectively) at day 25. In contrast, low doses of anti-PD-1+350.B antibody in combination resulted in 88.41% tumor growth inhibition (FIG. 23). Tumor control with a high dose of anti-PD-1 antibody was sufficient, so no additional benefit was observed with 350 V. No noticeable loss in body weight was observed in any of the groups, and there were no significant clinical observations in the animals in the study. These data demonstrate that combination treatment with suboptimal doses of anti-CD73 and anti-PD-1 antibodies can result in enhanced tumor suppression in the CT-26 syngeneic tumor model.

Example 6: Pharmacokinetic and toxicological study of anti-CD73 antibody 373.A in cynomolgus monkeys

As a single agent, anti-CD73 antibody 373.A was well tolerated when administered intravenously once a week for four weeks in cynomolgus monkeys at doses up to 100 mg/kg. There was no effect on cardiac function assessed by electrocardiogram, and there was no significant toxicological effect on clinical pathology, immunophenotyping or histopathological results. Therefore, the no adverse effect level (NOAEL) for 373.A in cynomolgus monkeys is 100 mg/kg, whereas the highest non-hazardous toxic dose (HNSTD) is >100 mg/kg.

In a non-GLP single-dose toxicology study, cynomolgus monkeys were administered single intravenous doses of control, 3, 30, or 100 mg/kg of antibody 373.A. After intravenous injection, 373.A levels decreased rapidly in the 3 mg/kg group, likely due to target-mediated drug distribution. In the 30 mg/kg and 100 mg/kg groups, the decrease was usually multi-exponential. There were no gender differences in the values of 373.A Cmax and AUC ₀ 168 _h . Exposure, as assessed by mean Cmax 373.A and AUC _o-1684 , increased with increasing dose levels from 3 to 100 mg/kg. The increase in mean values of Cmax 373.A and AUCo168 _h was generally dose proportional, with the exception of AUC _{o-168 h} between dose levels from 3 to 30 mg/kg. In the 100 mg/kg dose cohort, mean Cmax and AUC _{o-168 hours} were 2540 mcg/mL and 173,000 mcg/h/mL, respectively. The possible emergence of anti-drug antibodies (ADA) did not affect PK in this study.

In a GLP toxicology study, monkeys were administered once weekly four IV doses of control, 10, 30 or 100 mg/kg 373.A. Sex differences in Cmax and AUC _{o-168 h} in the case of 373.A were minimal (0.7-1.2 times). Exposure, as assessed by mean Cmax and AUC _{o-168 h} , increased proportionally from 10 to 100 mg/kg. Following an IV bolus injection of 373.A, PK decreased in a biexponential manner, with a mean elimination phase t1 _/2 of 266 hours following the recovery phase on day 22 in the 100 mg/kg group. In the 100 mg/kg dose cohort, mean Cmax and AUC _{o-168 hours} on day 22 were 5030 mcg/mL and 365,000 mcg-h/mL, respectively. Occurrence of ADA reduced exposure levels in one animal in the 30 mg/kg group.

In a separate study, cytokine release was assessed in an in vitro solubility assay after 24-hour stimulation of human whole blood with 373.A at 50, 100, 500, and 1000 μg/mL. Blood samples were collected from ten healthy donors. For each sample, negative (whole blood and whole blood with medium) and positive (anti-human CD3 antibody) controls were included. Cytokine levels were measured using the Luminex multiplex method for IL-Ιβ, IL-2, IL-6, IL-8, IL-10, IFNy and TNFa. Results obtained using the control buffer were similar to those obtained using the negative control (blood only), and there was no trend toward decreased or increased cytokine release with diluent (0.5% dextrose). For all donors, induction of cytokine release was observed in the case of positive controls with anti-CD3 antibody for all cytokines, indicating that stimulation was appropriate and cytokine release was induced in all samples. Cytokine levels obtained after 373.A stimulation were similar to those measured in negative controls. In conclusion, in vitro stimulation of human whole blood with 373.A did not induce cytokine release at concentrations up to 1000 μg/ml.

Example 7: Phase I/Ib Study of Anti-CD73 Antibody 373.A as a Single Agent and in

- 300 047335 combination with BAP049-clone-E and/or PBF509 in patients with late-stage malignant neoplasms.

Over the past decade, immunotherapies targeting various immune checkpoints (eg, PD-1, PD-L1, and CTLA-4) have shown efficacy in a number of cancer conditions. However, while some patients achieve objective and durable responses to checkpoint blockade, most patients demonstrate little or no clinical response, indicating that tumors use alternative immunosuppressive mechanisms to achieve immune escape (Allard et al., Clin Cancer Res. 2013; 19(20):5626-35; Vesely et al., Annu Rev Immunol 29:235-271). Thus, concomitant blockade of multiple immunosuppressive pathways may be required to induce clinically significant responses in more patients.

In recent years, adenosine production and signaling have emerged as potential therapeutic targets in cancer treatment. Adenosine creates an immunosuppressive tumor microenvironment by reducing the cytotoxic antitumor immune response, increasing proliferation and polarization of immunosuppressive cells, and increasing neovascularization (Young et al., Cancer Discovery 2014; 4(8):879-88). Preclinical data demonstrate that CD73 blockade can significantly delay primary tumor growth and suppress the development of lung metastases in an immunocompetent syngeneic mouse model (Stagg et al 2010). Similar results were observed in a study in which genetic deletion of A2aR in the host resulted in rejection of injected immunogenic tumors in A2aR-deficient mice, with a lack of rejection observed in control wild-type mice (Ohta et al., PNAS 2006; 103(35): 13132- 37).

An open-label, multicenter, Phase I/Ib study was designed to evaluate the safety, tolerability, preliminary antitumor activity, pharmacokinetics (PK) and pharmacodynamics (PD) of the anti-CD73 antibody 373.A as a single agent and in combination with the A2aAR antagonist PBF509 and/or the anti-PD antibody -1 BAP049-clone-E in patients with late-stage malignant neoplasms. The primary objectives are to characterize safety and tolerability and to determine the recommended dose (RD) for 373.A alone and in combination with PBF509 and/or BAP049-clone-E. Secondary objectives are to evaluate the preliminary antitumor activity and PK 373.A alone and in combination with PBF509 and/or BAP049-clone-E, assess the immunogenicity of 373.A and BAP049-clone-E, and characterize changes in the immune infiltrate in tumors after treatment , such as changes from baseline in tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), CD8+ T cells, and PDL-1 expression.

BAP049-clone-E is a high-affinity ligand-blocking humanized IgG4 anti-programmed cell death protein-1 (PD-1) antibody that blocks the binding of PD-L1 and PDL2 to PD-1. BAP049-clone-E is being investigated in a phase I/II study in advanced malignancies. PBF509, a novel nexanthine compound, is a potent orally administered adenosine A2aAR receptor antagonist. The sequence of BAP049-clone-E is disclosed in table. 5.

Two ongoing phase I/Ib and phase II studies are evaluating PBF509 as a single agent and/or in combination with BAP049-clone-E in patients with advanced non-small cell lung cancer (NSCLC) and solid tumors and non-Hodgkin's lymphoma, respectively.

This I/Ib study will initially enroll adult patients with advanced cancer who have progressed or are intolerant to standard-of-care therapy in cases where moderate or high CD73 expression is associated with poorer outcome, indicating adenosine-mediated immune escape (Wu et al., Journal of Surgical Oncology 2012, 106(2): 130-137; Gaudreau et al., Oncoimmunology 2016, 5(5): e1127496; Oncotarget 2017, 8(5):8738; -8751). These indications include non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), pancreatic cancer (PDAC), renal cell carcinoma (RCC), ovarian cancer and microsatellite stable (MSS) colorectal cancer, although additional indications may be reported based on emerging clinical data (eg, efficacy data or demonstrated pathway activation).

The study consists of two parts: (1) a dose escalation portion of 373.A as a single agent, the doublet combinations of 373.A/PBF509 and 373.A/BAP049-clone-E, or the triplet combination of 373.A/PBP509/BAP049-clone -E, which results in a declaration of recommended doses (RD) for each treatment, and (2) a dose expansion portion where patients will be treated by RD for single agent, doublet combinations, and triplet combinations. The portion with the increase will include patients with NSCLC, TNBC, PDAC, RCC, ovarian cancer and colorectal cancer (MSS) at an advanced stage; and there are no restrictions on the number of previous treatments. The dose expansion portion will include patients with advanced cancer who have received up to 3 lines of prior treatment.

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For the dose expansion portion, patients in each indication will be equally randomized to combination treatment groups. Randomization will be by indication and further stratified by specific indication prior to treatment with PD-1/PD-L1 (intact or resistant).

Selection of dose and regimen

Monotherapy with 373.A

The starting dose, a fixed dose of 60 mg 373.A administered intravenously every 2 weeks (Q2W), was selected based on preclinical safety, tolerability, and PK data observed in cynomolgus monkeys and published case reports of patients with CD73 deficiency.

The 60 mg dose is considered to be the minimum pharmacologically active dose (mPAD) because it is predicted to provide (1) approximately 20 hours of >90% CD8+ CD73 T cell occupancy, (2) approximately 22 hours of >90% adenosine inhibition, (3 ) approximately 17 h >90% of implied total CD73 occupancy.

Based on MC modeling data from toxicology studies in cynomolgus monkeys, ex-vivo CD8+ CD73 T cell occupancy data, and in vitro adenosine inhibition data, a dose of >1200 mg Q2W is predicted to provide >90% target occupancy at CD8+ T cells over the dosing interval, and doses >600 mg Q2W are predicted to provide >90% inhibition of adenosine production.

The 373.A dose will be titrated in successive cohorts guided by a Bayesian logistic regression model (BLRM) combined with an overdose control criterion (EWOC) until the maximum tolerated dose (MTD) or recommended dose (RD) for expansion is determined. Preclinical data and modeling suggest that high antigen-dependent clearance may occur and that high doses (eg, >1200 mg Q2W) may be required to achieve continuous target occupancy over the dose range. Dose escalation will primarily be performed on a Q2W regimen. However, if this regimen demonstrates rapid elimination of 373.A and lack of target saturation within the dosing interval, a more frequent QW regimen may be explored. If, on the other hand, the Q4W regimen is predicted to provide slower elimination within the dosing interval, the Q4W regimen may be studied instead.

Combination 373.A/PBF509

The maximum starting doses for the 373.A/PBF509 doublet combination will be 200 mg Q2W 373.A and 80 mg BID PBF509.

200 mg Q2W 373.A is a low dose of 373.A that is predicted to provide ~2.3 days of >90% target occupancy on CD8+ T cells. The 200 mg dose of Q2W 373.A is 16% of the 1200 mg dose of Q2W, which is expected to provide >90% CD8+ T cell target occupancy during the dosing interval.

PBF509 was studied as a single agent at concentrations up to 640 mg BID without any safety concerns in advanced/metastatic NSCLC (only 1 DLT of 5 patients evaluated at 640 mg BID). In the same study, PBF509 demonstrated activity as a single agent ranging from 80 mg BID to 480 mg BID with 2 partial responses (PR) and 6 stable disease (SD) in 18 dosed patients.

A dose escalation approach of 373.A and PBF509 will be undertaken to determine the appropriate dose of each drug in combination, guided by a Bayesian logistic regression model (BLRM) combined with the principle of overdose control (EWOC) criteria.

Combination 373.A/VAR049-clone-E

The maximum starting dose for the 373.A/BAP049-clone-E doublet combination will be 200 mg Q2W 373.A and 400 mg Q4W BAP049-clone-E.

The rationale for using 200 mg Q2W 373.A was described above. The 200 mg dose of Q2W 373.A will be combined with the RD for BAP049-clone-E, which is 400 mg Q4W, which has been shown to be safe and effective.

The 373.A dose level will be escalated sequentially at a fixed dose of BAP049-clone-E, guided by a Bayesian logistic regression model (BLRM) combined with the principle of overdose control (EWOC) criteria.

Combination 3 7.3.A/BAP049-k.toh-E/PBF509

The maximum starting dose for the triplet combination 37.3.A/BAP049-k.toh-E/PBF509 will be 200 mg Q2W 373.A, 400 mg Q4W BAP049-clone-E and 80 mg BID PBF509.

PBF509 was safely administered up to 160 mg BID in combination with 400 mg Q4W BAP049-clone-E (only 1 DLT out of 6 patients evaluated) with a combined efficacy rate of 2 PR and 6 SD out of a total of 10 patients. The Ph2 study is currently using 160 mg BID PBF509 and 400 mg Q4W BAP049-clone-E.

A dose escalation approach will be used for 373.A/BAP049-clone-E/PBP509 at a fixed dose of BAP049-clone-E to determine the appropriate dose of 373.A and PBF509 in a triplet combination

- 302 047335 when guided by a Bayesian Logistic Regression Model (BLRM) combined with an Overdose Control Criterion (EWOC).

Antibody 373.A (100 mg powder for solution for infusion) will be administered intravenously over 1 hour by infusion (up to 2 hours if clinically indicated). BAP049-clone-E (100 mg powder for solution for infusion) will be administered intravenously over 30 minutes by infusion (up to 2 hours if clinically indicated). When used in combination, 373.A and BAP049-clone-E should be administered on the same day, using separate infusion materials (bag, lines, filters) for each infusion. The same injection site can be used for both infusions. 373.A should be administered first, followed by a 30-minute break before infusion of BAP049-clone-E. PBF509 (40 mg and/or 80 mg and/or 160 mg oral capsules) must be taken orally twice daily (BID) continuously. During visits during which 373.A and/or BAP049-clone-E will be administered, the patient will first take a dose of PBF509 and then receive an infusion of 373.A. A break between the administration of PBF509 and the 373.A infusion is not required. Infusion of 373.A should be started as soon as possible and no later than 60 minutes after administration of PBF509.

In table 22-25 describe the starting dose and dose levels that can be assessed during this trial. Patients receiving 373.A alone or 373.A in combination with BAP049clone-E and/or PBF509 will begin study treatment on cycle 1, day 1. Each cycle will consist of 28 days. 373.A Q2W will be administered on days 1 and 15 of the cycle. 373.A QW will be administered on days 1, 8, 15 and 22 of the cycle. 373.A Q4W will be administered on day 1 of the cycle. VAR049-clone-E Q4W will be administered on day 1 of the cycle. The PBF509 BID will be administered each day of the cycle.

Table 22

Preliminary dose levels for 373.A

Dose level Suggested dose* scheme Increasing the previous dose -2** 6 mg Q2W -233% -1** 20 mg Q2W -200% 1 60 mg Q2W (initial dose) 2 200 mg Q2W 233% 3 600 mg Q2W 200% 4 1200 mg Q2W 100% 5 2400 mg Q2W 100% 6 3600 mg Q2W 50%

*It is possible that additional and/or intermediate dose levels will be added during the course of the study. Cohorts can be added at any dose level below the MTD to improve understanding of safety, PK, or PD.

**Dose levels -1 and -2 represent treatment doses for patients requiring a dose reduction from the initial dose level. No dose reduction below dose level -2 is allowed for this study.

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Table 23

Preliminary dose levels for 373.A in combination with PBF509

Level doses Proposed dose 373.A* Increase Increase in previous dose of PBF509 previous dose 373.A Suggested dose of PBF509* -2** 20 mg Q2W -200% 40 mg VS 0% -1** 60 mg Q2W -233% 40 mg VS -100% 1 200 mg Q2W (initial dose) 80 mg VS (initial dose) 2 200 mg Q2W 0% 160 mg VS 100% 3 600 mg Q2W 200% 160 mg VS 0% 4 1200 mg Q2W 100% 160 mg VS 0% 5 2400 mg Q2W 100% 160 mg VS 0% 6 2400 mg Q2W 100% 320 mg VS 100% 7 2400 mg Q2W 480 mg VS 8 2400 mg Q2W 620 mg VS 9 3600 mg Q2W 320 mg VS 10 3600 mg Q2W 480 mg VS eleven 3600 mg Q2W 620 mg VS

*It is possible that additional and/or intermediate dose levels will be added during the course of the study. Cohorts can be added at any dose level below the MTD to improve understanding of safety, PK, or PD.

**Dose level -1 and -2 represent therapeutic doses for patients requiring dose reduction from the initial dose level. No dose reduction below dose level -2 is allowed for this study.

Table 24

Preliminary dose levels for 373.A in combination with BAP049-clone-E

Increase Proposed Increase Level Suggested dose 373.A* previous dose VAR049- previous dose of VAR049- doses doses 373.A clone-E clone-E

-2** 20 mg Q2W -200% 400 mg Q4w 0% -1** 60 mg Q2W -233% 400 mg Q4w 0% 1 200 mg Q2W (initial dose) 400 mg Q4w (initial dose) 2 600 mg Q2W 200% 400 mg Q4w 0% 3 1200 mg Q2W 100% 400 mg Q4w 0% 4 2400 mg Q2W 100% 400 mg Q4w 0% 5 3600 mg Q2W 50% 400 mg Q4W 0%

*It is possible that additional and/or intermediate dose levels will be added during the course of the study. Cohorts can be added at any dose level below the MTD to improve understanding of safety, PK, or PD.

**Dose level -1 and -2 represent therapeutic doses for patients requiring dose reduction from the initial dose level. No dose reduction below dose level -2 is allowed for this study.

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Table 25 Preliminary dose levels for PBF509 in combination with 373.A and BAP049-clone-E Dose level Suggested dose 373.A* Increased from the previous dose 373.A Suggested dose of BAP049clone-E Increased from the previous dose of BAR049clone-E Suggested dose of PBF509* Increased from the previous dose of PBF509 -2** 20 mg Q2W -200% 400 mg Q4W 0% 40 mg VS 0% -1** 60 mg Q2W -233% 400 mg Q4W 0% 40 mg VS -100% 1 200 mg Q2W (initial dose) 400 mg Q4W (initial dose) 80 mg VS (initial dose) 2 200 mg Q2W 0% 400 mg Q4W 0% 160 mg VS 100% 3 600 mg Q2W 200% 400 mg Q4W 0% 160 mg VS 0% 4 1200 mg Q2W 100% 400 mg Q4W 0% 160 mg VS 0% 5 2400 mg Q2W 100% 400 mg Q4W 0% 160 mg VS 0% 6 2400 mg Q2W 400 mg Q4W 320 mg VS 7 2400 mg Q2W 400 mg Q4W 480 mg VS 8 2400 mg Q2W 400 mg Q4W 620 mg VS 9 3600 mg Q2W 400 mg Q4W 320 mg VS 10 3600 mg Q2W 400 mg Q4W 480 mg VS eleven 3600 mg Q2W 400 mg Q4W 620 mg VS

*It is possible that additional and/or intermediate dose levels will be added during the course of the study. Cohorts can be added at any dose level below the MTD to improve understanding of safety, PK, or PD.

**Dose levels -1 and -2 represent therapeutic doses for patients requiring dose reductions from the initial dose level. No dose reduction below dose level -2 is allowed for this study.

Example 8 Crystal Structure Analysis

Cloning

The Fab 350.A2 fragment was generated by constructing a stop codon between two proline residues upstream of the heavy chain core hinge region of antibody 350.A2. Fab 350.A2 contains a heavy chain containing the amino acid sequence of SEQ ID NO: 331, and a light chain containing the amino acid sequence of SEQ ID NO: 23. His-tagged CD73 ECD (SEQ ID NO: 171) was cloned into the pRS5a vector .

Expression and purification

Expi293F cells were transfected at a 1:1 ratio of 350.A2 to ECD CD73, and five days after transfection, cells were pelleted at 2000 rpm. During this time, the Fab:CD73 complex was secreted into the supernatant. The supernatant was filtered through a 0.2 μm SteriFlip filter. Granular cell debris was discarded. The Fab-ECD complex was purified using a Protein L column followed by a Mono Q column. After elution from the MonoQ column, the complex (captured in the flow)

- 305 047335 was re-purified using a protein L column. The purified sample was dialyzed against 10 mM Tris, pH 7.5, 100 mM NaCl and analyzed by SEC-MALS for purity. It was then concentrated to 9 mg/ml.

Crystallization, cryopreservation and data collection

The Fab 350.A2-CD73 complex was crystallized using the hanging drop method. Before installing the crystallization trays, the purified complex was rotated at 14,000 rpm for 10 minutes to remove aggregated protein and debris. After this, 1.0 μl of the complex at a concentration of 9 mg/ml was mixed with 1.0 μl of a protein precipitant consisting of 0.2 M Li ₂ SO ₄ , 1.2 M NaH ₂ PO ₄ , 0.8 M K2HPO4, 0. 1 M glycine, pH 10.5, and then suspended in a well with 300 μl of protein precipitant. The crystals were grown for approximately 3-4 days. The crystals were collected and then cryopreserved using a protein precipitant solution in combination with 25% (v:v) glycerol. X-ray diffraction data were collected at the Advanced Light Source, beamline 5.0.1. The diffraction data could be applied down to about 2.85 Angstroms.

Resolution and clarification of the structure

The structure of 350.A2 was modeled using the AL-57 Fab fragment (RCSB accession code 3HI5) as a template using the MOE modeling suite. The joint structure was resolved using the PHASER program and the dimeric structure of human glycosylated CD73 (RCSB 4H1S) and the Fab homology model as search models. Briefly, the dimeric structure of human CD73 was used as a first search model to determine the position of two human CD73 dimers in an asymmetric unit. This initial structure was refined using Phenix-Refine. Subsequently, the heavy and light chain homology models were used as separate search models, thereby determining the position of the two Fabs relative to the two human CD73 dimers. The completed structure was refined and combined through several stages of refinement and reorganization in real space. The final R-factor and free R-factor were 22.78% and 27.12%, respectively. Electron density maps show that each CD73 monomer is glycosylated at asparagine-311. However, such glycosylation is heterogeneous, and thus the precise chemical structure of the glycosylation event cannot be determined. Therefore, glycosylation is not included in the structural model.

The co-crystal structure of Fab 350.A2-CD73 provides insight into the interaction of the antibody with CD73. These interactions can be divided into direct enthalpic interactions, such as hydrogen bonds or electrostatic interactions, and van der Waals and hydrophobic interactions, which are due to shape complementarity between the antibody and CD73.

The key enthalpic and VDW/hydrophobic interactions identified through the co-crystal structure are as follows. The following interactions occur between the Fab heavy chain and CD73. The Fab heavy chain residues are numbered according to Kabat and are highlighted in FIG. 26C and 26D (bold, italic and underlined). CD73 residues are numbered according to SEQ ID NO: 105 and are highlighted in FIG. 26A and 26B (bold, italic and underlined).

R54 of the Fab heavy chain is positioned for electrostatic interactions with the backbone carbonyl groups of Y110 and K136 in CD73.

R31 of the Fab heavy chain is positioned for electrostatic interactions with the backbone carbonyl groups of L132 and L157 in CD73.

The S99 backbone carbonyl group, the R31 backbone carbonyl group, and the E95 side chain of the Fab heavy chain are positioned to interact electrostatically with the K162 side chain of CD73.

The E98 side chain of the Fab heavy chain is positioned to hydrogen bond with the S155 side chain of CD73.

Shape complementarity and van der Waals interactions between amino acids 33, 50, 52, 56, 97, 98, 100 and 100a of the Fab heavy chain and amino acids 155-170 of CD73.

Shape complementarity and van der Waals interactions between amino acids 30-31 of the Fab heavy chain and amino acids 136-138 of CD73.

The following interactions occur between the Fab light chain and CD73. Fab light chain residues are numbered according to Kabat and are highlighted in FIG. 26G and 26H (in bold, italics and underlined). CD73 residues are numbered according to SEQ ID NO: 105 and are highlighted in FIG. 26E and 26F (bold, italic and underlined).

The W32 side chain of the Fab light chain is positioned to hydrogen bond with the T209CD73 side chain.

Shape complementarity and van der Waals interactions between amino acids 30-32 of the Fab light chain and amino acids 209-210 of CD73.

Example 9: Epitope Mapping Using Tandem Mass Spectrometry (TMT) Isotope Labeling

Antibody comparisons using TMT isotope-encoding reagents were generally performed as described in John D. et al., Analytical Chemistry 2015 87 (15), 7540-7544, incorporated herein by reference in its entirety.

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Methods

Labeling with TMT

Antibodies in DPBS had the following concentrations and were used without further processing: 374 (1.37 mg/ml), 377.B (2.25 mg/ml), 379.B (2.82 mg/ml), 373 (1 mg/ml) and 350 (1 mg/ml). CD73 (R&D Systems, cat. no. 5795-EN) was buffer exchanged with 100 mM triethylammonium bicarbonate (TEAB) buffer, pH 8, and concentrated to 5 mg/ml to remove free amine in the resulting material and mock sample for labeling with using TMT using microconcentrators with a molecular weight cutoff of 10 kDa (Millipore Amicon Ultra). Antigen/antibody complexes (CD73/anti-CD73 mAb complexes) were prepared by combining 10 μg CD73 with 12.8 μg mAb (equinormal amounts or 2:1 molar ratio CD73:mAb or 1:1 site-binding equivalents) at a concentration of approximately 2 μM against CD73 in 100 mM TEAB, pH 8 buffer, and equilibration for 30 min. at room temperature. Labeling was performed by adding 5 μl of 35 mM TMT reagent. For labeling, a control consisting of CD73 alone was obtained in a similar manner. The labeling time was 30 s and 300 s, respectively, after which the labeling reaction was quenched by adding 50 μL of 5% hydroxylamine solution. All reactions were carried out in duplicate.

Split

Samples were pooled 15 min after hydroxylamine quenching in a centrifuge concentrator and the total volume was reduced to ∼30 μL. This was followed by deglycosylation by PNGase F and reducing/denaturing SDS PAGE separation using standard methods.

Bands containing CD73 were excised from the gel for in-gel digestion. Gel processing was carried out according to standard decolorization, reduction, alkylation and dehydration procedures. For conditioning before elastase digestion, dehydrated gel pieces were rehydrated with 50 mM Tris buffer, pH 8, while for pepsin digestion, 1% formic acid was used as the last rehydration step before complete dehydration in vacuo.

Samples for elastase digestion were rehydrated for 1 hour on ice by adding 25 μl of 12.5 ng/μl elastase in 50 mM Tris, pH 8. Samples for pepsin digestion were rehydrated for 1 hour on ice by adding 25 μl of 10 ng/μl µl of pepsin in 1% formic acid.

After enzyme rehydration, excess enzyme solution was discarded and 50 μl of appropriate digestion buffer was added before digestion for 4 h at 37°C. Digestion was again followed by recovery of the peptides according to standard in-gel digestion procedures.

LCMSMS

LCMSMS was performed using an Orbitrap Lumos mass spectrometer (Thermo Scientific, Waltham, MA) coupled to an Easy-nLC 1200 chromatography system (Thermo Scientific, Waltham, MA). The separation column was a 75 µm capillary with an elongated tip, filled with 15 cm of ReproSil-Pur 120 C18 AQ 3 µm (catalog no. r13.aq). Proteolytic fragments were eluted using a segmented gradient from 0-35% B 120 min, 35-63% B 30 min, 63-100% B 5 min, 100% B held for 5 min, 100-0% B 2 min, 0% B incubated for 2 min at a flow rate of 500 nL/min using elution buffers A=0.1% formic acid in water and B=0.1% formic acid in 80%-MCN.

The data collection method used the default method parameters according to the manufacturer for the TMT experiment with MSMS detection.

Data pre-processing and analysis

Raw data were searched against CD73 protein sequence using MASCOT 2.5.1 (MatrixScience, UK) with MASCOT Daemon (MatrixScienc, UK) and ExtractMSn (Thermo Scientific, Waltham, MA) to convert and merge raw files for elastase and pepsin to the lists of peaks.mgf. The default TMTlOplex method built into MASCOT was used for quantitation. Search results, including TMT reporter ion intensities, were exported kok.csv and further refined/calibrated to remove outliers before calculating intensity-weighted mean reporter ion intensities from peptide spectral matches (PSMs) for a given primary sequence lysine residue using Microsoft Excel. Only PSMs of peptides containing a single lysine residue were used in the analysis to avoid ambiguity in the labeling site.

results

CD73 intensity-weighted normalized reporter ion intensity ratios covering observed primary sequence lysine residues are presented as the difference between the ratio of CD73/mAb complex to CD73 and CD73 (1 by definition of normalization). Plotting the relationship in this manner provides a direct estimate of the changes in labeling rate resulting from complex formation. Negative difference values indicate a decrease in the level of labeling in antibody/antigen complexes and are interpreted similarly to the HDX data as the introduction of protection. The strongest protective effects are expected to reflect

- 307 047335 shielding the protein surface of the antigen from the reagent using an antibody. Apart from direct shielding at the protein-protein interface, changes at other locations are not unexpected since protein formation as a whole and the conformational array as a whole can be disrupted by complex formation. Despite the difficulties, this facilitates the interpretation of molecular events on an absolute scale. It is likely that antibodies exhibiting similar overall effects (labeling profiles) upon complex formation will have similar epitopes and exert their effector function through similar molecular mechanisms. All residues shown in this example are numbered according to SEQ ID NO: 105.

In fig. 27A and 27B show the difference in ratios for 29 of the 35 lysine residues in the CD73 primary sequence observed when labeling was carried out for 30 seconds. The presence of protection at lysine residues K162, K206 and K214 (Fig. 27A) correlates well with the previous interpretation of the HDX epitope 373 (Example 2). Specifically, the HDX study identified residues 158-172 (YLPYKVLPVGDEVVG, SEQ ID NO:108, A-loop), which spans K162; and residues 206-215 (KLKTLNVNKI, SEQ ID NO:109, B-loop), which span K206 and K214, as part of epitope 373. The presence of protection at lysine residues K285 and K291 (Fig. 27B) is consistent with the minor protection observed in the previous HDX data in the area around residue 300 (Fig. 14 and Example 2). K262 and K274 are located on opposite sides of the N-terminal domain relative to the epitope (K162, K206 and K214), and the increase in labeling at these two residues (Fig. 27A) may reflect destabilization in this region as a consequence of mAb engagement. K136 is spatially close to K162, but located closer to the center of the dimer. The K136 protection for antibodies 374, 377, 379 and 373 (Fig. 27A) is consistent with the bidentate binding mode described for 373 in Example 2. These data suggest that antibodies 374, 377, 379 and 373 may form a very homogeneous group . K341 is located at the N/C-terminal domain interface and close to the dimer interface.

In fig. 28A and 28B show the difference in ratios for 29 of the 35 lysine residues in the CD73 primary sequence observed when labeling was carried out for 300 seconds. Protection at K162 is no longer observed for mAbs 374, 377, 379, and 373, while protection for 350 remains strong. In contrast, the protection in the case of K206 and K214 is unchanged. This provides further evidence of the highly homologous nature of antibodies 374, 377, 379 and 373 as assessed by their spatiotemporal labeling characteristics.

It is noteworthy that for all of these antibodies, protection in the case of K206 is comparable to that in the case of K214 (Fig. 27A and 28A).

Incorporation by reference

All publications, patents and accession numbers mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually identified as being incorporated by reference.

Equivalents

Although specific embodiments of the present invention have been discussed, the above description is illustrative and not limiting. Many variations of the present invention will be apparent to those skilled in the art upon reading the present specification and the following claims. The full scope of the present invention is to be determined by reference to the claims along with the full scope of their equivalents, as well as the description along with such variations.

Claims (31)

1. An antibody molecule that binds to human CD73, containing: (a) (i) a heavy chain variable region (VH) comprising the amino acid sequence of heavy chain complementarity determining region 1 (VHCDR1) of SEQ ID NO: 88, the amino acid sequence of VHCDR2 of SEQ ID NO: 89, and the amino acid sequence of VHCDR3 of SEQ ID NO: : 37; and (ii) a light chain variable region (VL) comprising the amino acid sequence of light chain complementarity determining region 1 (VLCDR1) of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50 ; or (b) (i) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 189, the amino acid sequence of VHCDR2 of SEQ ID NO: 89 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and (ii) VL comprising the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49, and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. 2. Antibody molecule according to claim 1, which contains: (i) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (ii) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 72, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (iii) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (iv) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (v) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (vi) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 137, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (vii) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 190, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (viii) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 191, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (ix) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 192, the amino acid sequence of VHCDR2 of SEQ ID NO: 71 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL containing the amino acid sequence VLCDR1 under - 309 047335 SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (x) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 193, the amino acid sequence of VHCDR2 of SEQ ID NO: 136 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (xi) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 194, the amino acid sequence of VHCDR2 of SEQ ID NO: 146 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (xii) VH comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 195, the amino acid sequence of VHCDR2 of SEQ ID NO: 154 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50. 3. Antibody molecule according to claim 1 or 2, containing: (i) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 44, 77, 84, 142, 151 or 159, or an amino acid sequence having at least 85%, 90%, 95% or 99% identity sequences with SEQ ID NO: 44, 77, 84, 142, 151 or 159; (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence having at least 85%, 90%, 95% or 99% sequence identity to SEQ ID NO: 55; (iii) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 44 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto, and a light chain variable region containing the amino acid the sequence of SEQ ID NO: 55 or a sequence having at least about 85%, 90%, 95% or 99% sequence identity thereto; (iv) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 77 or a sequence having at least about 85%, 90%, 95% or 99% sequence identity thereto, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 or a sequence having at least about 85%, 90%, 95% or 99% sequence identity thereto; (v) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 84 or a sequence having at least about 85%, 90%, 95% or 99% sequence identity thereto, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 or a sequence having at least about 85%, 90%, 95% or 99% sequence identity thereto; (vi) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 142 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto, and a light chain variable region containing the amino acid the sequence of SEQ ID NO: 55 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto; (vii) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 151 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto, and a light chain variable region containing the amino acid the sequence of SEQ ID NO: 55 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto; or (viii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 159 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto; (ix) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 44, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 55. 4. Antibody molecule according to any one of claims 1-3, containing: (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 46, 79, 86, - 310 047335 114, 116 or 117, or an amino acid sequence having at least 85%, 90%, 95% or 99% sequence identity with SEQ ID NO: 46, 79, 86, 114, 116 or 117; (ii) a light chain containing the amino acid sequence of SEQ ID NO: 57, or an amino acid sequence characterized by at least 85%, 90%, 95% or 99% sequence identity with SEQ ID NO: 57; (iii) a heavy chain containing the amino acid sequence of SEQ ID NO: 46 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto, and a light chain containing the amino acid sequence of SEQ ID NO: 57 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto; (iv) a heavy chain containing the amino acid sequence of SEQ ID NO: 114 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto, and a light chain containing the amino acid sequence of SEQ ID NO: 57 or a sequence having at least about 85%, 90%, 95% or 99% sequence identity thereto; (v) a heavy chain containing the amino acid sequence of SEQ ID NO: 79 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto, and a light chain containing the amino acid sequence of SEQ ID NO: 57 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto; (vi) a heavy chain containing the amino acid sequence of SEQ ID NO: 116 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto, and a light chain containing the amino acid sequence of SEQ ID NO: 57 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto; (vii) a heavy chain containing the amino acid sequence of SEQ ID NO: 86 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto, and a light chain containing the amino acid sequence of SEQ ID NO: 57 or a sequence having at least 85%, 90%, 95% or 99% sequence identity thereto; or (viii) a heavy chain containing the amino acid sequence of SEQ ID NO: 117 or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto, and a light chain containing the amino acid sequence of SEQ ID NO: 57 or a sequence having at least 85%, 90%, 95%, or 99% sequence identity thereto; (ix) a heavy chain containing the amino acid sequence of SEQ ID NO: 46, wherein residue 451 of SEQ ID NO: 46 is K, and a light chain containing the amino acid sequence of SEQ ID NO: 57. 5. An antibody molecule that binds to human CD73, containing: (a) a heavy chain variable region (VH) comprising the amino acid sequence of heavy chain complementarity determining region 1 (VHCDR1) of SEQ ID NO: 38, the amino acid sequence of VHCDR2 of SEQ ID NO: 36, and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and a light chain variable region (VL) comprising the amino acid sequence of light chain complementarity determining region 1 (VLCDR1) of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; (b) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 35, the amino acid sequence of VHCDR2 of SEQ ID NO: 36 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; VL containing the amino acid sequence of VLCDR1 under SEQ ID NO: 48, the amino acid sequence of VLCDR2 under SEQ ID NO: 49 and the amino acid sequence of VLCDR3 under SEQ ID NO: 50; (c) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 39, the amino acid sequence of VHCDR2 of SEQ ID NO: 40 and the amino acid sequence of VHCDR3 of SEQ ID NO: 37; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 51, the amino acid sequence of VLCDR2 of SEQ ID NO: 52 and the amino acid sequence of VLCDR3 of SEQ ID NO: 53; (d) VH containing the amino acid sequence of VHCDR1 of SEQ ID NO: 41, the amino acid sequence of VHCDR2 of SEQ ID NO: 42 and the amino acid sequence of VHCDR3 of SEQ ID NO: 43; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 54, the amino acid sequence of VLCDR2 of SEQ ID NO: 52 and the amino acid sequence of VLCDR3 of SEQ ID NO: 50; or (e) VH containing the amino acid sequence VHCDR1 of SEQ ID NO: 190, amino - 311 047335 acid sequence of VHCDR2 under SEQ ID NO: 36, and amino acid sequence of VHCDR3 under SEQ ID NO: 43; and VL containing the amino acid sequence of VLCDR1 of SEQ ID NO: 48, the amino acid sequence of VLCDR2 of SEQ ID NO: 49 and VLCDR3 of SEQ ID NO: 50. 6. An antibody molecule that binds to human CD73, comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 44, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 55. 7. An antibody molecule that binds to human CD73, comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 46, wherein residue 451 of SEQ ID NO: 46 is K, and a light chain containing the amino acid sequence of SEQ ID NO: 57. 8. The antibody molecule according to any one of claims 1 to 7, wherein (i) the antibody molecule is a human antibody, full-length antibody, Fab fragment, F(ab')2, Fv or single chain Fv (scFv); (ii) the antibody molecule contains a heavy chain constant region selected from IgG1, IgG2, IgG3 and IgG4, and a light chain constant region selected from the kappa light chain or lambda chain constant regions; or (iii) the antibody molecule contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 92-103, 119 and 120, and/or a light chain constant region containing the amino acid sequence of SEQ ID NO: 104. 9. An antibody molecule according to any one of claims 1 to 8, comprising an IgG4 heavy chain constant region and a kappa light chain constant region. 10. Antibody molecule according to any one of claims 1-9, containing: a human IgG4 heavy chain constant region with a mutation at position 228 according to EU numbering, or a human IgG4 heavy chain constant region with a series mutation to proline at position 228 according to EU numbering, or a heavy chain constant region containing the amino acid sequence of SEQ ID NO: 92 or 93 . 11. Antibody molecule according to any one of claims 1 to 10, which is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following properties: (i) binds to human CD73 with a dissociation constant (K _D ) of less than 1 x 10 ^-8 M, for example, when assaying the antibody molecule as a bivalent antibody molecule using the Octet system; (ii) binds to soluble human CD73 and/or membrane-bound human CD73; (iii) does not bind to mouse CD73; (iv) inhibits or reduces the enzymatic activity of CD73 (eg, soluble human CD73 or membrane-bound human CD73), or the level of human CD73-mediated conversion of adenosine monophosphate (AMP) to adenosine; (v) inhibits the enzymatic activity of membrane-bound human CD73 by at least 60%, 70%, 80% or 90%; (vi) increases the level of proliferation of anti-CD3/anti-CD28 T cells or CD4+ T cells in the presence of adenosine monophosphate (AMP); (vii) binds to the N-terminal domain of human CD73; (viii) reduces the level of hydrogen-deuterium exchange in one or more regions of a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105, or a protein consisting of the amino acid sequence of SEQ ID NO: 171, upon binding, when wherein one or more regions are selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87-104 of SEQ ID NO: 105; (ix) upon binding to a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105, or a protein consisting of the amino acid sequence of SEQ ID NO: 171), causes a conformational change of residues 368-387 of SEQ ID NO: 105; (x) interacts with at least one, two, three or four residues within residues 158-172 of SEQ ID NO: 105; (xi) interacts with at least one, two, three, four or five residues within residues 206-215 of SEQ ID NO: 105; (xii) interacts with at least one, two, three, four or five residues within residues 368-387 of SEQ ID NO: 105 or 106; (xiii) interacts with at least one, two, three, four or five residues within residues 87-104 of SEQ ID NO: 105; (xiv) binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to - 312 047335 the first CD73 monomer, and the second antigen binding domain binds to the second CD73 monomer; (xv) binds to human CD73 in a catalytically active closed conformation with lower affinity than when the antibody molecule binds to human CD73 in a catalytically inactive open conformation; (xvi) blocks human CD73 in a catalytically inactive open conformation; or (xvii) prevents or reduces the level of conversion of human CD73 from a catalytically inactive open conformation to a catalytically active closed conformation compared to the level of conversion in the absence of the antibody molecule; or (xviii) binds to a human CD73 dimer, wherein said dimer consists of a first CD73 monomer and a second CD73 monomer, wherein if the antibody molecule contains a first antigen binding domain and a second antigen binding domain, the first antigen binding domain binds to the first CD73 monomer and the second antigen binding domain domain binds to the second monomer of CD73. 12. The combination of antibody molecules according to any one of claims 1 to 11, wherein the combination of antibody molecules binds to a human CD73 dimer, said dimer consisting of a first CD73 monomer and a second CD73 monomer, each monomer comprising the amino acid sequence of residues 27-547 of SEQ ID NO: 105, wherein each of the antibody molecules in the combination contains the same first antigen binding domain and the same second antigen binding domain, (i) at least 30%, 35% or 40% of the antibody molecules in said combination binds to a CD73 dimer to form a complex, where each of said complexes consists of one antibody molecule and one CD73 dimer; or (ii) no more than 60%, 65% or 70% of the antibody molecules in said combination bind to a CD73 dimer to form said complex, wherein each of said complexes contains two or more antibody molecules and two or more CD73 dimers. 13. Antibody molecule according to any one of claims 1-11, where: (a) the antibody molecule causes a decrease in the level of hydrogen-deuterium exchange in one or more regions of a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105 upon binding, wherein one or more regions is selected from the group consisting of residues 158-172, residues 206-215, residues 368-387 and residues 87-104 from SEQ ID NO: 105; (b) the antibody molecule, when bound to a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105, provides a decrease in the average level of hydrogen-deuterium exchange at the _XC residue(s) selected from the core C region, or residues 368-387 from SEQ ID NO: 105, to a greater extent than the residue(s) _XA selected from the core region A, or residues 158-172 from SEQ ID NO: 105, the residue(s) XB selected from the core region B , or residues 206-215 of SEQ ID NO: 105, or XD residue(s) selected from the D core region, or residues 297-309 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 or pH 7.5 and room temperature, while X _C equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or 20, X _A equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, XB equals 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and XD equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; (c) the antibody molecule, when bound to a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105, provides a decrease in the average level of hydrogen-deuterium exchange at the XA residue(s) selected from core region A, or residues 158-172 from SEQ ID NO: 105, to a greater extent than the XB residue(s) selected from the B core region, or residues 206-215 of SEQ ID NO: 105, the XC residue(s) selected from the C core region, or residues 368-387 of SEQ ID NO: 105, or XD residue(s) selected from the D core region, or residues 297-309 of SEQ ID NO: 105, for example, when examining an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 or pH 7.5 and room temperature, while X _A equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, XB equals 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and X _C equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or 20, X _D equals 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13; (d) the antibody molecule causes a decrease in the level of hydrogen-deuterium exchange in one or more regions of a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105 upon binding, wherein one or more regions is selected from the group consisting of residues 158-172, residues 206-215, residues 368-387, and residues 87-104 of SEQ ID NO: 105, wherein the region showing the greatest decrease in average hydrogen-deuterium exchange rate, from one or more of the regions, is not residues 206- 215 from SEQ - 313 047335 ID NO: 105; or (e) the antibody molecule, when bound to a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105, provides (i) a decrease in the average level of hydrogen-deuterium exchange of more than, for example, 0.02, 0. 03, 0.04, 0.05 or 0.06 Da per residue, for residues 368-387 of SEQ ID NO: 105, for example, when studying the antibody molecule as a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, carried out with exchange for 1 minute at pH 7-8 or pH 7.5 and room temperature; or (ii) a decrease in the average hydrogen-deuterium exchange rate of less than, for example, 0.05, 0.04, 0.03 or 0.02 Da per residue, for residues 206-215 of SEQ ID NO: 105, for example , in the study of an antibody molecule in the form of a bivalent antibody molecule using hydrogen-deuterium exchange mass spectrometry, carried out with an exchange for 1 minute at pH 7-8 or pH 7.5 and room temperature. 14. The antibody molecule according to any one of claims 1-11 or 13, wherein (a) the antibody molecule provides a reduction in the level of labeling using a tandem mass spectrometry (TMT) tag at residue K136 (numbered in accordance with SEQ ID NO: 105) a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105; (b) the antibody molecule provides increased TMT labeling at one or both of residues K262 and K274, numbered SEQ ID NO: 105, of the protein upon binding thereto; (c) the antibody molecule provides reduced tandem mass spectrometry (TMT) labeling at residues K206 and K214, numbered in accordance with SEQ ID NO: 105, of a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: : 105, when bound, and the reduction at residue K214 is at least 90, 80, 70, 60 or 50% of the reduction at residue K206; or (d) the antibody molecule reduces the level of tandem mass spectrometry (TMT) labeling at residue K162, numbered in accordance with SEQ ID NO: 105, of a protein containing the amino acid sequence of residues 27-547 of SEQ ID NO: 105, when bound in a TMT isotope labeling assay of an antibody molecule over a labeling time of 30 s, wherein (i) the antibody molecule does not provide a reduction in the level of TMT labeling at residue K162 in an isotope labeling assay TMT labeling performed over a 300 s labeling time, or (ii) the antibody molecule provides a reduction in the level of TMT labeling at residue K162 in a TMT isotopic labeling assay performed over a 300 s labeling time , wherein the reduction at residue K162 at a labeling time of 300 s is no more than 20, 30, 40 or 50% of the decrease at residue K162 at a labeling time of 30 s. 15. The antibody molecule according to any one of claims 1-11, 13 or 14, where (i) the antibody molecule binds to one or more residues of CD73, where one or more residues is selected from the group consisting of residues Y110, K136, L132, L157 , K162, S155 and T209, numbered in accordance with SEQ ID NO: 105; (ii) the antibody molecule binds to Y110 or K136 of CD73 numbered according to SEQ ID NO: 105; (iii) the antibody molecule binds to L132 or L157 of CD73 numbered according to SEQ ID NO: 105; (iv) the antibody molecule binds to K162 of CD73 numbered according to SEQ ID NO: 105, (v) the antibody molecule binds to S155 of CD73 numbered according to SEQ ID NO: 105; and (vi) the antibody molecule binds to T209 of CD73, numbered in accordance with SEQ ID NO: 105; (vii) the antibody molecule binds to one or more regions of CD73, wherein one or more regions is selected from the group consisting of residues 155-170, 136-138 and 209-210, numbered in accordance with SEQ ID NO: 105; (viii) the antibody molecule binds to residues 155-170 of CD73, numbered according to SEQ ID NO: 105; (ix) the antibody molecule binds to residues 136-138 of CD73 numbered according to SEQ ID NO: 105; or (x) the antibody molecule binds to residues 209-210 of CD73. 16. Antibody molecule according to claim 15, where: (i) the antibody molecule binds to residues Y110, L132 and/or K162 of CD73, numbered - 314 047335 in accordance with SEQ ID NO: 105 by electrostatic interaction; (ii) the antibody molecule binds to residues S155 and/or T209 of CD73, numbered according to SEQ ID NO: 105, via hydrogen bonding; and/or (ii) the antibody molecule binds to residues 155-170, 136-138, and/or 209-210 of CD73, numbered SEQ ID NO: 105, through shape complementarity and/or van der Waals interactions. 17. A pharmaceutical composition containing an antibody molecule according to any one of claims 1-11 or 13-16 and a pharmaceutically acceptable carrier, excipient or stabilizer. 18. Nucleic acid encoding the variable region of a heavy antibody molecule according to any one of claims 1-11 or 13-16. 19. A nucleic acid encoding the light chain variable region of an antibody molecule according to any one of claims 1-11 or 13-16. 20. The nucleic acid according to claim 18 or 19, where (i) the nucleic acid encodes a heavy chain variable region, where the nucleic acid contains the nucleotide sequence of SEQ ID NO: 45, 78, 85, 143, 152 or 160, or a nucleotide sequence, having at least 85%, 90%, 95% or 99% sequence identity to SEQ ID NO: 45, 78, 85, 143, 152 or 160; (ii) the nucleic acid encodes a heavy chain, wherein the nucleic acid contains a nucleotide sequence of SEQ ID NO: 47, 80 or 87, or a nucleotide sequence having at least 85%, 90%, 95% or 99% sequence identity with SEQ ID NO: 47, 80 or 87. (iii) the nucleic acid encodes a light chain variable region, wherein the nucleic acid contains a nucleotide sequence of SEQ ID NO: 56 or 144 or a nucleotide sequence having at least 85%, 90%, 95% or 99% sequence identity with SEQ ID NO: 56 or 144; or (iv) the nucleic acid encodes a light chain, wherein the nucleic acid contains a nucleotide sequence of SEQ ID NO: 58 or a nucleotide sequence having at least 85%, 90%, 95% or 99% sequence identity to SEQ ID NO: 58. 21. An expression vector containing a nucleic acid according to any one of claims 18-20. 22. A host cell containing a nucleic acid according to any one of claims 18 to 20 or an expression vector according to claim 21. 23. A method for producing an antibody molecule that binds to human CD73, wherein the method comprises culturing a host cell containing a nucleic acid encoding the antibody molecule of any one of claims 1-11 or 13-16 under conditions suitable for gene expression. 24. Use of an antibody molecule according to any one of claims 1-11 or 13-16 or a pharmaceutical composition according to claim 17 for the production of a medicament for stimulating an immune response in a subject. 25. Use of an antibody molecule according to any one of claims 1-11 or 13-16 or a pharmaceutical composition according to claim 17 for the production of a medicament for the treatment of cancer in a subject, where the cancer is selected from lung cancer, non-small cell lung cancer, pancreatic cancer, adenocarcinoma pancreatic duct cancer, breast cancer, triple negative breast cancer, melanoma, head and neck cancer, such as squamous cell carcinoma of the head and neck, colorectal cancer, microsatellite stability (MSS) colorectal cancer, ovarian cancer, or kidney cancer, or for example, renal cell carcinoma. 26. Use according to claim 24 or 25, where (i) the antibody molecule is used in a dose of 100 mg to 1600 mg, 100 mg to 1400 mg, 100 mg to 1200 mg, 100 mg to 1000 mg, 100 mg up to 800 mg, 100 mg to 600 mg, 100 mg to 400 mg, 100 mg to 200 mg, or 100 mg, 180 mg, or 200 mg biweekly (Q2W); (ii) the molecule is used at a dose of 5 mg to 100 mg, 100 mg to 500 mg, 500 mg to 1000 mg, 1000 mg to 1500 mg, 1500 mg to 2000 mg, 2000 mg to 2500 mg, 2500 mg to 3000 mg, from 3000 mg to 3500 mg or from 3500 mg to 4000 mg; (iii) the antibody molecule is used in combination with a PD-1 inhibitor; (iv) the antibody molecule is used in combination with an A2AR adenosine receptor antagonist; or (v) the antibody molecule is used in combination with a PD-1 inhibitor and an A2AR adenosine receptor antagonist. 27. Application according to claim 26, where: (i) the antibody molecule is used at a dose of at least 180 mg Q2W; (ii) the antibody molecule is administered intravenously; (iii) the antibody molecule is administered at a dose of 6 mg, 20 mg, 60 mg, 200 mg, 600 mg, 1200 mg, 2400 mg, 3000 mg, or 3600 mg; or (iv) the antibody is administered once weekly (QW), once every two weeks (Q2W), or once every four weeks (Q4W); - 315 047335 (v) the PD-1 inhibitor is selected from the group consisting of PDR001, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591 and AMP-224; (vi) the PD-1 inhibitor is an anti-PD-1 antibody molecule, wherein the anti-PD-1 antibody molecule is used at a dose of 250 mg to 350 mg, 350 mg to 450 mg, or 450 mg to 550 mg, 300 mg, or 400 mg; (vii) the PD-1 inhibitor is an anti-PD-1 antibody molecule, wherein the antibody molecule is administered once every three weeks (Q3W) or every four weeks (Q4W) at a dose of 300 mg Q3W or at a dose of 400 mg Q4W; (viii) the anti-CD73 antibody molecule is used at a dose of 5 mg to 100 mg, or 20 mg, Q2W, and the anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W; (ix) the anti-CD73 antibody molecule is used at a dose of 5 mg to 100 mg, 60 mg, Q2W, and the anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W; (x) the anti-CD73 antibody molecule is used at a dose of 100 mg to 500 mg, or 200 mg, Q2W, and the anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W; (xi) the anti-CD73 antibody molecule is used at a dose of 500 mg to 1000 mg, or 600 mg, Q2W, and the anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W; (xii) the anti-CD73 antibody molecule is used at a dose of 1000 mg to 1500 mg, or 1200 mg, Q2W, and the anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg or 400 mg, Q4W; (xiii) the anti-CD73 antibody molecule is used at a dose of 2000 mg to 2500 mg, or 2400 mg, Q2W, and the anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W; (xiv) the anti-CD73 antibody molecule is used at a dose of 3000 mg to 3500 mg, or 3000 mg, Q2W, and the anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W; (xv) the anti-CD73 antibody molecule is used at a dose of 3500 mg to 4000 mg, or 3600 mg, Q2W, and the anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W; (xvi) the anti-CD73 antibody molecule and the anti-PD-1 antibody molecule are administered intravenously; (xvii) the adenosine A2AR receptor antagonist is selected from the group consisting of PBF509, CPI444, AZD4635, vipadenant, GBV-2034 and AB928; (xviii) the adenosine A2AR receptor antagonist is selected from the group consisting of 5-bromo-2,6di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3 -((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2 ,3]triazolo[4,5^]pyrimidin-5-amine; ^)-7-(5-methylfuran-2yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3] triazolo[4,5^]pyrimi din-5-amine or its racemate; 7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3] triazolo[4,5^]pyrimidin-5-amine and 6-(2-chloro-6-methylpyridin-4-yl)-5-(4fluorophenyl)-1,2,4-triazin-3-amine; (xix) A2AR adenosine receptor antagonist is used in a dose of 20 mg to 60 mg, 60 mg to 100 mg, 100 mg to 140 mg, 140 mg to 180 mg, 180 mg to 220 mg, 220 mg to 260 mg, from 260 mg to 300 mg, from 300 mg to 340 mg, from 340 mg to 380 mg, from 380 mg to 480 mg, from 480 mg to 580 mg, or from 580 mg to 680 mg, 40 mg, 80 mg , 160 mg, 320 mg, 480 mg or 620 mg; (xx) the adenosine A2AR receptor antagonist is administered once daily (QD), twice daily (BID), or three times daily (TID); (xxi) the anti-CD73 antibody molecule is used at a dose of 5 mg to 100 mg, or 20 mg, Q2W, and the adenosine A2AR receptor antagonist is used at a dose of 20 mg to 60 mg, or 40 mg, BID; (xxii) the anti-CD73 antibody molecule is used at a dose of 5 mg to 100 mg, or 60 mg, Q2W, and the adenosine A2AR receptor antagonist is used at a dose of 20 mg to 60 mg, or 40 mg, BID; (xxiii) the anti-CD73 antibody molecule is used at a dose of 100 mg to 500 mg, or 200 mg, Q2W, and the adenosine A2AR receptor antagonist is used at a dose of 60 mg to 100 mg, or 80 mg, BID; (xxiv) the anti-CD73 antibody molecule is used at a dose of 100 mg to 500 mg, or 200 mg, Q2W, and the adenosine A2AR receptor antagonist is used at a dose of 140 mg to 180 mg, or 160 mg, BID; (xxv) an anti-CD73 antibody molecule is used at a dose of 500 mg to 1000 mg, or 600 mg, Q2W, and an adenosine A2AR receptor antagonist is used at a dose of 140 mg to 180 mg, or 160 mg, BID; (xxvi) an anti-CD73 antibody molecule is used at a dose of 1000 mg to 1500 mg, or 1200 mg, Q2W, and an adenosine A2AR receptor antagonist is used at a dose of 140 mg to 180 mg, or 160 mg, BID; (xxvii) the anti-CD73 antibody molecule is used at a dose of 2000 mg to 2500 mg, or 2400 mg, Q2W, and the adenosine A2AR receptor antagonist is used at a dose of 140 mg to 180 mg, or 160 mg, BID; (xxviii) the anti-CD73 antibody molecule is used at a dose of 2000 mg to 2500 mg, or 2400 mg, Q2W, and the adenosine A2AR receptor antagonist is used at a dose of 300 mg to 340 mg, or 320 mg, BID; (xxix) an anti-CD73 antibody molecule is used at a dose of 2000 mg to 2500 mg, or 2400 mg, Q2W, and an adenosine A2AR receptor antagonist is used at a dose of 480 mg to 580 mg, or 480 mg, BID; (xxx) an anti-CD73 antibody molecule is used at a dose of 2000 mg to 2500 mg, or 2400 mg, Q2W, and an adenosine A2AR receptor antagonist is used at a dose of 580 mg to 680 mg, or 620 mg, BID; (xxxi) an anti-CD73 antibody molecule is used at a dose of 3000 mg to 3500 mg, or 3000 mg, Q2W, and an adenosine A2AR receptor antagonist is used at a dose of 300 mg to 340 mg, or 320 mg, BID, (xxxii) an anti-CD73 antibody molecule is used at a dose of 300 mg to 340 mg, or 320 mg, BID, (xxxii) an anti-CD73 antibody molecule is used at a dose of 300 mg to 340 mg, or 320 mg, BID, CD73 is used at a dose of 3000 mg to 3500 mg, or 3000 mg, Q2W, and the adenosine A2AR receptor antagonist is used at a dose of 480 mg to 580 mg, or 480 mg, BID; - 316 047335 (xxxiii) an anti-CD73 antibody molecule is used at a dose of 3000 mg to 3500 mg, or 3000 mg, Q2W, and an adenosine A2AR receptor antagonist is used at a dose of 580 mg to 680 mg, or 620 mg, BID, (xxxiv ) an anti-CD73 antibody molecule is used at a dose of 3500 mg to 4000 mg, or 3600 mg, Q2W, and an adenosine A2AR receptor antagonist is used at a dose of 300 mg to 340 mg, or 320 mg, BID, (xxxv) an anti-CD73 antibody molecule is used at a dose of 3500 mg to 4000 mg, or 3600 mg, Q2W, and the adenosine A2AR receptor antagonist is used at a dose of 480 mg to 580 mg, or 480 mg, BID; (xxxvi) an anti-CD73 antibody molecule is used at a dose of 3500 mg to 4000 mg, or 3600 mg, Q2W, and an adenosine A2AR receptor antagonist is used at a dose of 580 mg to 680 mg, or 620 mg, BID; (xxxvii) the anti-CD73 antibody molecule is administered intravenously, and the adenosine receptor antagonist is administered orally; (xxxviii) an anti-CD73 antibody molecule is used at a dose of 5 mg to 100 mg, or 20 mg or 60 mg, Q2W, an anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W, and an adenosine antagonist A2AR receptor is used in a dose of 20 mg to 60 mg, or 40 mg, BID; (xxxix) an anti-CD73 antibody molecule is used at a dose of 100 mg to 500 mg, or 200 mg, Q2W, an anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W, and an adenosine receptor antagonist A2AR used in a dose of 60 mg to 100 mg, 140 mg to 180 mg, 80 mg, BID, or 160 mg, BID; (xl) an anti-CD73 antibody molecule is used at a dose of 500 mg to 1000 mg, 1000 mg to 1500 mg, 600 mg, Q2W, or 1200 mg, Q2W, an anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W, and an adenosine A2AR receptor antagonist is used at a dose of 140 mg to 180 mg, or 160 mg, BID, (xli) an anti-CD73 antibody molecule is used at a dose of 2000 mg to 2500 mg, or 2400 mg, Q2W, anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W, and the adenosine receptor antagonist A2AR is used at a dose of 140 mg to 180 mg, 300 mg to 340 mg, 160 mg, BID, or 320 mg, BID; (xlii) an anti-CD73 antibody molecule is used at a dose of 2000 mg to 2500 mg, or 2400 mg, Q2W, an anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W, and an adenosine receptor antagonist A2AR used in a dose of 480 mg to 580 mg, 580 mg to 680 mg, 480 mg, BID, or 620 mg, BID; (xliiii) an anti-CD73 antibody molecule is used at a dose of 3000 mg to 3500 mg, or 3000 mg, Q2W, an anti-PD-1 antibody molecule is used at a dose of 350 mg to 450 mg, or 400 mg, Q4W, and an adenosine receptor antagonist A2AR used in doses ranging from 300 mg to 340 mg, 480 mg to 580 mg, 580 mg to 680 mg, 320 mg BID, 480 mg BID, or 620 mg BID; (xliv) anti-CD73 antibody molecule used at a dose of 3500 mg to 4000 mg, or 3600 mg, Q2W, anti-PD-1 antibody molecule used at a dose of 350 mg to 450 mg, or 400 mg, Q4W, and adenosine receptor antagonist A2AR used in doses ranging from 300 mg to 340 mg, 480 mg to 580 mg, 580 mg to 680 mg, 320 mg BID, 480 mg BID, or 620 mg BID; or (xlv) an anti-CD73 antibody molecule is administered intravenously, an anti-PD-1 antibody molecule is administered intravenously, and an A2AR adenosine receptor antagonist is administered orally A2AR. 28. Use according to any one of claims 24-27, wherein the antibody molecule is used in combination with a second therapeutic agent, wherein the second therapeutic agent is selected from one or more of chemotherapy, targeted anticancer therapy, oncolytic drug, cytotoxic agent, immunotherapy agent, cytokine , a costimulatory molecule activator, an inhibitory molecule inhibitor, a vaccine, or a cell therapy. 29. Use according to claim 28, wherein the second therapeutic agent is (i) a PD-1 inhibitor, (ii) an adenosine A2AR antagonist, (iii) both a PD-1 inhibitor and an adenosine A2AR antagonist, (iv) a CTLA- inhibitor 4, (v) TIM-3 inhibitor, (vi) LAG-3 inhibitor, (vii) GITR agonist, (viii) multispecific anti-CD3 antibody molecule, (ix) IL-15 complexed with a soluble form of IL-15 receptor-alpha (IL-15Ra), (x) STING agonist, (xi) macrophage colony-stimulating factor (M-CSF) inhibitor, (xii) CSF-1R inhibitor, (xiii) indoleamine 2,3-dioxygenase (IDO) inhibitor and/or tryptophan 2,3-dioxygenase (TDO), (xiv) a TGF-β inhibitor, (xv) an oncolytic vaccine, (xvi) chimeric antigen receptor (CAR) T cell therapy, or (xvii) a compound listed in Table 1. 18. 30. Use according to any one of claims 24-29, wherein the antibody molecule is used in combination with a process - 317 047335 by a fool selected from a surgical procedure or a radiation treatment procedure. 31. A method for detecting CD73 in a biological sample or subject, comprising (i) contacting the sample or subject with an antibody molecule according to any one of claims 1-11 or 13-16 under conditions that allow the antibody molecule or composition to interact with CD73 and (ii) detecting the formation of a complex between the antibody molecule or composition and the sample or subject.