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CN119866349A - Antibodies specifically recognizing NKG2A and uses thereof - Google Patents

Antibodies specifically recognizing NKG2A and uses thereof Download PDF

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CN119866349A
CN119866349A CN202380065866.8A CN202380065866A CN119866349A CN 119866349 A CN119866349 A CN 119866349A CN 202380065866 A CN202380065866 A CN 202380065866A CN 119866349 A CN119866349 A CN 119866349A
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amino acid
acid sequence
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李楠
李平
李忠
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Beijing Solobio Genetechnology Co Ltd
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Beijing Solobio Genetechnology Co Ltd
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

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Abstract

涉及特异性地识别NKG2A的抗体或抗原结合片段，及其制备方法和用途。The invention relates to an antibody or antigen-binding fragment which specifically recognizes NKG2A, and a preparation method and use thereof.

Description

Antibodies specifically recognizing NKG2A and uses thereof
Cross reference to related applications
The present application claims priority from chinese patent application No. 202211127889.0, filing date 2022.09.16, entitled "antibody specifically recognizing NKG2A and use thereof", the entire contents of which are incorporated herein by reference.
Submitting sequence list in xml file
The contents of the electronic sequence Listing are incorporated herein by reference in their entirety, (NKG2A_WIPO_seq. Xml; size: 108KB; and date of creation: 2022.09.06).
Technical Field
The present invention relates to antibodies that specifically recognize NKG2A, and methods of making and using the same, including methods of treating cancer, viral diseases, autoimmune diseases, and/or inflammatory diseases therewith.
 Background
Natural killer (natural killer, NK) cells are an important component of the innate immune system and are important immunoregulatory cells for the body to combat infections and prevent malignant transformation of cells. Human NK cells account for about 10% -15% of whole blood lymphocytes. Current research considers NK cells to specifically express CD56, while lacking the T cell antigen CD3.NK cells have the functions of (1) generating direct cytotoxic activity against virus-infected cells, leukemia cells and other tumor cells, (2) secreting various immunomodulatory cytokines (e.g., IFN-. Gamma., TNF-. Alpha., GM-CSF), and (3) mediating antibody-dependent cellular cytotoxicity (ADCC) by binding of the cell membrane FcgammaRIII (CD 16) to the Fc segment of antibodies.
NK cell inhibitory receptors, consisting essentially of immunoglobulin-like receptors KIR and C-type lectin-like receptors (e.g., NKG 2A), bind to MHC class I molecules and exert their inhibitory effect. Wherein, the KIR is combined with HLA-A, HLA-B and HLA-C in MHC class I molecules to play a role in inhibiting the combination of NKG2A and HLA-E, and the sensitivity of NKG2A to down-regulation of MHC class I is higher than that of KIR, so that the NKG2A plays a more important role in regulating the function of NK cells as an NK cell surface inhibitory receptor. In addition, NKG2A can not only regulate the activation process of cd8+ T cells, but also exert the function of inhibiting cd8+ T cells in the interaction of cd8+ T cells with target cells. NKG2A is therefore critical in regulating NK and cd8+ T cell activity, particularly in eliminating tumor and virus infected cells.
NKG2A is one of the members of the natural killer cell receptor family 2 (NKG 2), which also includes NKG2B/C/D/E/F, NKG2A is an inhibitory receptor member of the NKG2 receptor family, also known as natural killer cell lectin-like receptor C1 (KILLER CELL LECTIN LIKE receptor C1, KLRC 1), which is one of the transmembrane proteins preferentially expressed on the surface of NK cells. NKG2A is expressed predominantly on NK cell surfaces, but also on part of the T cell surface. In human NK cells, the protein is combined with CD94 molecule co-expressed on the surface of NK cells to form a heterodimer complex NKG2A-CD94 by disulfide bond, and then is recognized by non-classical major histocompatibility complex I (major histocompatibility complex class I, MHC I) class I molecule HLA-E on target cells, and the N-terminal NK cell cytoplasmic domain of the NKG2A protein contains 2 immunoreceptor tyrosine inhibition motifs (immunoreceptor tyrosine-based inhibitory motifs, ITIMs), which can transmit inhibition signals into NK cells to induce cascade inhibition signals, thereby inhibiting the cytotoxic activity of NK and secretion of cytokines.
Patent application WO2008009545A1 discloses anti-NKG 2A antibodies, and related methods and materials for making and using the antibodies. WO2020102501A1 discloses antibodies that specifically bind to NKG2A proteins with high affinity and exhibit the functional properties required for therapy such as for the treatment of cancer and the like. WO2020094071A1 discloses antibodies targeting NKG2A, which have NKG2A binding affinity and anti-tumor activity. Currently Monalizumab as an antagonist drug to the NKG2A receptor has demonstrated a therapeutic effect in clinical trials of several tumor diseases, but there is still a need for therapeutic antibodies with greater activity and higher affinity that effectively inhibit or otherwise antagonize NKG2A, and related methods of treating diseases and/or disorders resulting from deregulation of NKG2A signaling pathway, such as cancer, viral diseases, autoimmune diseases, and/or inflammatory diseases.
The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein are incorporated by reference in their entirety.
Summary of the application
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising SNTMS (SEQ ID NO: 1), HC-CDR2 comprising NINTGGNTYYANWAKG (SEQ ID NO: 9), and HC-CDR3 comprising GSTIDSSGLSL (SEQ ID NO: 24), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASQNIGSDLA (SEQ ID NO: 33), LC-CDR2 comprising LASTLAS (SEQ ID NO: 43), and LC-CDR3 comprising QQX 1 WSSSNVDNV (SEQ ID NO: 66), wherein X 1 is C, S or T.
In some embodiments, an isolated anti-NKG 2A antibody comprising V H, said V H comprising HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 1 or a variant thereof comprising up to about 3 amino acid substitutions, HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 9 or a variant thereof comprising up to about 3 amino acid substitutions, and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO. 24 or a variant thereof comprising up to about 3 amino acid substitutions, and V L, said V L comprising LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 33 or a variant thereof comprising up to about 3 amino acid substitutions, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 43 or a variant thereof comprising up to about 3 amino acid substitutions, and LC-CDR3 comprising any one of the amino acid sequences shown in SEQ ID NOs 51-53 or a variant thereof comprising up to about 3 amino acid substitutions is provided.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising V H, said V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in any one of the amino acid sequences of SEQ ID NOs 68-71, and V L, said V L comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by V L as shown in any one of the amino acid sequences of SEQ ID NOs 92-95.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:68, and (ii) V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:92, LC-CDR2 and LC-CDR3, (ii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:69, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:93, LC-CDR2 and LC-CDR3, (iii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:70, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:93, LC-CDR2 and LC-CDR3, (iv) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:69, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:94, LC-CDR2 and LC-CDR3, (V) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:70, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:94, LC-CDR2 and LC-CDR3, (vi) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:71, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:95, LC-CDR2 and LC-CDR3.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, or a variant of said V H, comprising up to about 5 amino acid substitutions in the HC-CDRs; and V L comprising the amino acid sequence SEQ ID NO:33, LC-CDR2 comprising the amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:51, or variants of V L comprising up to about 5 amino acid substitutions in the LC-CDRs, (ii) V H comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, or variants of V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and (iii) V L comprising the amino acid sequence SEQ ID NO:33, LC-CDR2 comprising the amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:52, or variants of V H comprising up to about 5 amino acid substitutions in the V H, comprising the amino acid sequences SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, said V L comprising LC-CDR1 comprising the amino acid sequence SEQ ID NO:33, LC-CDR2 comprising the amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:53, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, any of the isolated anti-NKG 2A antibodies described above comprises V H comprising the amino acid sequence shown in any of SEQ ID NOs 68-71, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown in any of SEQ ID NOs 68-71, and V L comprising the amino acid sequence shown in any of SEQ ID NOs 92-95, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown in any of SEQ ID NOs 92-95.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H comprising amino acid sequence SEQ ID NO 68 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 68 and V L comprising amino acid sequence SEQ ID NO 92 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 92, (ii) V H comprising amino acid sequence SEQ ID NO 69 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 69 and V L comprising amino acid sequence SEQ ID NO 93 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 93, (iii) V H comprising amino acid sequence SEQ ID NO 70 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 70 and V L comprising amino acid sequence 69 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 93 or a variant thereof, V L comprising amino acid sequence SEQ ID NO 93 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 93, or a variant thereof comprising amino acid sequence SEQ ID NO 70 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 70, comprising the amino acid sequence SEQ ID NO. 70 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 70, and V L comprising the amino acid sequence SEQ ID NO. 94 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 94, (vi) V H comprising the amino acid sequence SEQ ID NO. 71 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 71, and V L comprising the amino acid sequence SEQ ID NO. 95 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 95.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising NYHMS (SEQ ID NO: 2), HC-CDR2 comprising YIGAAX 1X2X3 YYASWAKG (SEQ ID NO: 65), wherein X 1 is G, N or S, X 2 is N or S, X 3 is A, I or T, and HC-CDR3 comprising GVIYNNL (SEQ ID NO: 25), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASESISNYLS (SEQ ID NO: 34), LC-CDR2 comprising DASDLAS (SEQ ID NO: 44), and LC-CDR3 comprising QX 1TYGSINX2 NYGVA (SEQ ID NO: 67), wherein X 1 is A or C, X 2 is A, Q or S.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising V H, the V H comprising HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:2 or a variant thereof comprising up to about 3 amino acid substitutions, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:10-16 or a variant thereof comprising up to about 3 amino acid substitutions, and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:25 or a variant thereof comprising up to about 3 amino acid substitutions, and V L, the V L comprising LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:34 or a variant thereof comprising up to about 3 amino acid substitutions, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:44 or a variant thereof comprising up to about 3 amino acid substitutions, and LC-CDR3 comprising any one of SEQ ID NOs:54-57 or a variant thereof comprising up to about 3 amino acid substitutions.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising V H, said V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in any one of the amino acid sequences of SEQ ID NOs 72-84, and V L, said V L comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprised by V L as shown in any one of the amino acid sequences of SEQ ID NOs 96-101.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:72, and (ii) V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:96, LC-CDR2 and LC-CDR3, (ii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:73, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:97, LC-CDR2 and LC-CDR3, (iii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:74, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:97, LC-CDR2 and LC-CDR3, (iv) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:75, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:97, LC-CDR2 and LC-CDR3, (V) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:76, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:97, LC-CDR2 and LC-CDR3, (vi) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:77, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:97, LC-CDR2 and LC-CDR3, (vii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:78, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:97, LC-CDR2 and LC-CDR3, (viii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:73, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:98, LC-CDR2 and LC-CDR3, (ix) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:74, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:98, LC-CDR2 and LC-CDR3, (x) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:75, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:98, LC-CDR2 and LC-CDR3, (xi) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:76, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:98, LC-CDR2 and LC-CDR3, (xii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:77, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:98, LC-CDR2 and LC-CDR3, (xiii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:78, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:98, LC-CDR2 and LC-CDR3, (xiv) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:78, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:99, LC-CDR2 and LC-CDR3, (xv) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:78, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:100, LC-CDR2 and LC-CDR3, (xvi) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:79, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:100, LC-CDR2 and LC-CDR3, (xvii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:80, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:100, LC-CDR2 and LC-CDR3, (xviii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:81, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:99, LC-CDR2 and LC-CDR3, (xix) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:82, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:99, LC-CDR2 and LC-CDR3, (xx) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:83, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:99, LC-CDR2 and LC-CDR3, (xxi) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:84, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:99, LC-CDR2 and LC-CDR3, (xxii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:79, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:99, LC-CDR2 and LC-CDR3, (xxiii) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:80, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:99, LC-CDR2 and LC-CDR3, (xxiv) V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:78, and V L comprising LC-CDR1 comprised by V L as shown in amino acid sequence SEQ ID NO:101, LC-CDR2 and LC-CDR3.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:54, or a variant of V L comprising up to about 5 amino acid substitutions in the LC-CDRs, (ii) V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid substitutions in the V35 NO: 35, and LC 35 comprising up to about 5 amino acid substitutions in the amino acid sequence SEQ ID NO: 35, or a variant of V H comprising amino acid sequence SEQ ID NO:54, LC 35 comprising up to about 35, LC 35 comprising amino acid substitutions in the amino acid sequence SEQ ID NO: 35, or a variant of V38328 comprising up to about 35 amino acid sequence SEQ ID NO: 35, LC 35 comprising amino acid sequences SEQ ID NO: 35 and LC 35, SEQ ID NO: 35, or a variant thereof comprising up to about 5 amino acid substitutions in the amino acid sequence SEQ ID NO: 35, and LC 35 comprising amino acid sequence SEQ ID NO: 35, comprising the amino acid sequence SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 10, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs; and V L, said V L comprising LC-CDR1 comprising the amino acid sequences SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:56, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs, (iv) V H, said V H comprising HC-CDR1 comprising the amino acid sequences SEQ ID NO:2, HC-CDR2 comprising the amino acid sequences SEQ ID NO:11, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, said V L comprising LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequences SEQ ID NO:44, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:56, or said V L L Comprising up to about 5 amino acid substitutions in the LC-CDRs, (V) V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56, or a variant of V L comprising up to about 5 amino acid substitutions in the LC-CDRs, (vi) V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:2, HC-CDR3 comprising amino acid sequence SEQ ID NO: 35 and amino acid sequence SEQ ID NO: 35, and LC 35 comprising up to about 35, or a variant of V H comprising amino acid sequence SEQ ID NO: 35, LC 35, V H comprising amino acid substitutions in the amino acid sequence SEQ ID NO: 35, V H comprising amino acid sequence SEQ ID NO: 35, or a variant of V H comprising up to about 35, LC 35 comprising amino acid substitutions in the amino acid sequence SEQ ID NO: 35, V H comprising amino acid sequences comprising up to about 35, LC 35 and LC 35, comprising the amino acid sequences SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:14, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or variants of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L comprising the LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:55, or variants of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs, (viii) V H, said V H comprising HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:15, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or variants of said V H comprising up to about 5 amino acid substitutions in the LC-CDRs, and V L L Comprising an LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:55, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs; (ix) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:16, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs, (x) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO: 28, or a variant of said V3484 comprising up to about 5 amino acid substitutions in the LC-CDRs, LC-32 comprising amino acid sequence SEQ ID NO:34, LC-CDR3 comprising amino acid sequence SEQ ID NO: 28, LC-CDR3, LC-32 and LC-32, comprising amino acid sequence SEQ ID NO 55, or a variant of said V L comprising a substitution of up to about 5 amino acids in the LC-CDRs thereof, (xi) V H comprising amino acid sequence SEQ ID NO. 34, LC-CDR2 comprising amino acid sequence SEQ ID NO. 44, and LC-CDR3 comprising amino acid sequence SEQ ID NO. 12, and HC-CDR2 comprising amino acid sequence SEQ ID NO. 12, or a variant of said V H comprising a substitution of up to about 5 amino acids in the HC-CDRs, and V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO. 34, LC-CDR2 comprising amino acid sequence SEQ ID NO. 44, and LC-CDR3 comprising amino acid sequence SEQ ID NO. 55, or a variant of said V L comprising a substitution of up to about 5 amino acids in the LC-CDRs thereof, (xii) V3 comprising HC-CDR1 comprising amino acid sequence SEQ ID NO. 25, or a variant of said V H comprising a substitution of up to about 5 amino acids in the HC-CDRs, and V5262 comprising amino acid sequence SEQ ID NO. 34, LC-CDR2 comprising amino acid sequence SEQ ID NO. 44, and LC-CDR3 comprising a variant of said amino acid sequence SEQ ID NO. 55, and HC-CDR3 comprising a substitution of up to about 5 amino acid sequences of said HC-CDRs L The V L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO 34, an LC-CDR2 comprising the amino acid sequence SEQ ID NO 44, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO 57, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, any of the isolated anti-NKG 2A antibodies described above comprises V H comprising the amino acid sequence shown in any of SEQ ID NOs 72-84, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence shown in any of SEQ ID NOs 72-84, and V L comprising the amino acid sequence shown in any of SEQ ID NOs 96-101, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence shown in any of SEQ ID NOs 96-101.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H comprising amino acid sequence SEQ ID NO 72 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 72 and V L comprising amino acid sequence SEQ ID NO 96 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 96, (ii) V H comprising amino acid sequence SEQ ID NO 73 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 73 and V L comprising amino acid sequence SEQ ID NO 97 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97, (iii) V H comprising amino acid sequence SEQ ID NO 74 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 74 and V L comprising amino acid sequence SEQ ID NO 73 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97 or a variant thereof, V L comprising amino acid sequence SEQ ID NO 97 or a variant thereof having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97 or a variant thereof, comprising the amino acid sequence SEQ ID NO 76 or a variant thereof which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO 76, and V L comprising the amino acid sequence SEQ ID NO 97 or a variant thereof which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO 97, (vi) V H comprising the amino acid sequence SEQ ID NO 77 or a variant thereof which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO 77, and V L comprising the amino acid sequence SEQ ID NO 97 or a variant thereof which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO 97, (vii) V H comprising the amino acid sequence SEQ ID NO 78 or a variant thereof which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO 78, and V L comprising the amino acid sequence SEQ ID NO 97 or a variant thereof which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO 77, (vii) V5398 or a variant thereof which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO 97 or a variant thereof, V L which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO 97 or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 74, and V L comprising the amino acid sequence SEQ ID NO. 98 or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 98, (x) V H Comprising an amino acid sequence of SEQ ID NO 75 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO 75, and V L comprising an amino acid sequence of SEQ ID NO 98 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO 98, (xi) V H comprising an amino acid sequence of SEQ ID NO 76 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO 76, and V L comprising an amino acid sequence of SEQ ID NO 98 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO 98, (xii) V H comprising an amino acid sequence of SEQ ID NO 77 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO 77, and V L comprising an amino acid sequence of SEQ ID NO 98 or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO 98, (xii) V5378 comprising an amino acid sequence of at least about 80% sequence identity to the amino acid sequence of SEQ ID NO 98 or a variant thereof, or a variant thereof having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO 98 or a variant thereof, which variant has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L, which comprises the amino acid sequence SEQ ID NO:99 or a variant thereof, which variant has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:99, (xv) V H, which comprises the amino acid sequence SEQ ID NO:78 or a variant thereof, which variant has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L, which comprises the amino acid sequence SEQ ID NO:100 or a variant thereof, which variant has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:100, (xvi) V H, which comprises the amino acid sequence SEQ ID NO:79 or a variant thereof, which variant has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:79, and V L, which comprises the amino acid sequence SEQ ID NO:100 or a variant thereof, which variant has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:100, (xvi) V L, which comprises at least about 80% sequence identity to the amino acid sequence SEQ ID NO:100 or a variant thereof, which comprises at least about 80% sequence identity to the amino acid sequence SEQ ID NO:100, which variant has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:79 or a variant thereof, (xvi) V H, which comprises at least about 80% sequence identity to the amino acid sequence SEQ ID NO:79 or a variant thereof, comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99, (xix) V H Comprising the amino acid sequence SEQ ID NO. 82 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 82, and V L comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99, (xx) V H comprising the amino acid sequence SEQ ID NO. 83 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 83, and V L comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99, (xxi) V H or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 84, and V L comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 83, and (xxi) V H or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99 or a variant thereof, (xxi) V H or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO. 80, and V L, which comprises amino acid sequence SEQ ID NO. 99, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO. 99, (xxiv) V H, which comprises amino acid sequence SEQ ID NO. 78, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO. 78, and V L, which comprises amino acid sequence SEQ ID NO. 101, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO. 101.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H comprising HC-CDR1, HC-CDR2, and HC-CDR3, as represented by the amino acid sequence SEQ ID NO:68, V H, and (ii) V L comprising LC-CDR1, LC-CDR2, and LC-CDR3, as represented by the amino acid sequence SEQ ID NO:102, V L.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:35, LC-CDR2 comprising amino acid sequence SEQ ID NO:45, and LC-CDR3 comprising amino acid sequence SEQ ID NO:51, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, any one of the isolated anti-NKG 2A antibodies described above comprises V H comprising the amino acid sequence shown as SEQ ID NO. 68, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 68, and V L comprising the amino acid sequence shown as SEQ ID NO. 102, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 102.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H comprising HC-CDR1, HC-CDR2, and HC-CDR3, as represented by amino acid sequence SEQ ID NO:85, V H, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3, as represented by amino acid sequence SEQ ID NO:103, V L.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:17, and HC-CDR3 comprising amino acid sequence SEQ ID NO:26, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:36, LC-CDR2 comprising amino acid sequence SEQ ID NO:46, and LC-CDR3 comprising amino acid sequence SEQ ID NO:58, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, any one of the isolated anti-NKG 2A antibodies described above comprises V H comprising the amino acid sequence shown as SEQ ID NO:85 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO:85, and V L comprising the amino acid sequence shown as SEQ ID NO:103 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO: 103.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H comprising HC-CDR1, HC-CDR2, and HC-CDR3, as represented by the amino acid sequence SEQ ID NO:86, V H, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3, as represented by the amino acid sequence SEQ ID NO:104, V L.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising amino acid sequence SEQ ID NO:27, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:37, LC-CDR2 comprising amino acid sequence SEQ ID NO:47, and LC-CDR3 comprising amino acid sequence SEQ ID NO:59, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, any one of the isolated anti-NKG 2A antibodies described above comprises V H comprising the amino acid sequence shown as SEQ ID NO. 86, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 86, and V L comprising the amino acid sequence shown as SEQ ID NO. 104, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 104.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H comprising HC-CDR1, HC-CDR2, and HC-CDR3, as represented by amino acid sequence SEQ ID NO:87, V H, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3, as represented by amino acid sequence SEQ ID NO:105, V L.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:4, HC-CDR2 comprising amino acid sequence SEQ ID NO:19, and HC-CDR3 comprising amino acid sequence SEQ ID NO:28, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:38, LC-CDR2 comprising amino acid sequence SEQ ID NO:48, and LC-CDR3 comprising amino acid sequence SEQ ID NO:60, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, any one of the isolated anti-NKG 2A antibodies described above comprises V H comprising the amino acid sequence shown as SEQ ID NO. 87 or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 87, and V L comprising the amino acid sequence shown as SEQ ID NO. 105 or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 105.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H comprising HC-CDR1, HC-CDR2, and HC-CDR3, as represented by the amino acid sequence SEQ ID NO:88, V H, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3, as represented by the amino acid sequence SEQ ID NO:106, V L.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:5, HC-CDR2 comprising amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising amino acid sequence SEQ ID NO:29, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:39, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:61, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, any one of the isolated anti-NKG 2A antibodies described above comprises V H comprising the amino acid sequence shown as SEQ ID NO. 88, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 88, and V L comprising the amino acid sequence shown as SEQ ID NO. 106, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 106.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H comprising HC-CDR1, HC-CDR2, and HC-CDR3, as represented by the amino acid sequence SEQ ID NO:89, V H, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3, as represented by the amino acid sequence SEQ ID NO:107, V L.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:6, HC-CDR2 comprising amino acid sequence SEQ ID NO:21, and HC-CDR3 comprising amino acid sequence SEQ ID NO:30, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:40, LC-CDR2 comprising amino acid sequence SEQ ID NO:49, and LC-CDR3 comprising amino acid sequence SEQ ID NO:62, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, any one of the isolated anti-NKG 2A antibodies described above comprises V H comprising the amino acid sequence shown in SEQ ID NO. 89 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 89, and V L comprising the amino acid sequence shown in SEQ ID NO. 107 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO. 107.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H comprising HC-CDR1, HC-CDR2, and HC-CDR3, as represented by the amino acid sequence SEQ ID NO:90, V H, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3, as represented by the amino acid sequence SEQ ID NO:108, V L.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:7, HC-CDR2 comprising amino acid sequence SEQ ID NO:22, and HC-CDR3 comprising amino acid sequence SEQ ID NO:31, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:41, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:63, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, any one of the isolated anti-NKG 2A antibodies described above comprises V H comprising the amino acid sequence shown as SEQ ID NO. 90, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 90, and V L comprising the amino acid sequence shown as SEQ ID NO. 108, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 108.
In some embodiments, an isolated anti-NKG 2A antibody is provided, comprising (i) V H comprising HC-CDR1, HC-CDR2, and HC-CDR3, as represented by amino acid sequence SEQ ID NO:91, V H, and (ii) V L comprising LC-CDR1, LC-CDR2, and LC-CDR3, as represented by amino acid sequence SEQ ID NO:109, V L.
In some embodiments, an isolated anti-NKG 2A antibody is provided comprising (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:8, HC-CDR2 comprising amino acid sequence SEQ ID NO:23, and HC-CDR3 comprising amino acid sequence SEQ ID NO:32, or a variant of said V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:42, LC-CDR2 comprising amino acid sequence SEQ ID NO:50, and LC-CDR3 comprising amino acid sequence SEQ ID NO:64, or a variant of said V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, any one of the isolated anti-NKG 2A antibodies described above comprises V H comprising the amino acid sequence shown as SEQ ID NO. 91 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 91, and V L comprising the amino acid sequence shown as SEQ ID NO. 109 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 109.
In some embodiments, the Kd value of the binding of an isolated anti-NKG 2A antibody to human NKG2A is from 0.1pM to about 10nM.
In some embodiments, an isolated anti-NKG 2A antibody is provided that competes with any of the isolated anti-NKG 2A antibodies described above for specific binding to NKG 2A. In some embodiments, an isolated anti-NKG 2A antibody is provided that specifically binds to the same epitope as any of the isolated anti-NKG 2A antibodies described above.
In some embodiments, any of the isolated anti-NKG 2A antibodies described above, comprising an Fc fragment. In some embodiments, the isolated anti-NKG 2A antibody is a full-length IgG antibody. In some embodiments, the isolated anti-NKG 2A antibody is a full length IgG1, igG2, igG3, or IgG4 antibody. In some embodiments, the isolated anti-NKG 2A antibody is a chimeric, fully human or humanized antibody. In some embodiments, the isolated anti-NKG 2A antibody is an antigen-binding fragment selected from the group consisting of Fab, fab ', F (ab) ' 2, fab ' -SH, single chain Fv (scFv), fv fragment, dAb, fd, nanobody (nanobody), diabody (diabody), and linear antibody.
In some embodiments, an isolated nucleic acid molecule encoding any one of the anti-NKG 2A antibodies described above is provided. In some embodiments, a vector is provided, the vector comprising any one of the nucleic acid molecules described above. In some embodiments, a host cell is provided, comprising any of the anti-NKG 2A antibodies described above, any of the nucleic acid molecules described above, or any of the vectors described above. In some embodiments, a method of making an anti-NKG 2A antibody is provided, comprising a) culturing any one of the host cells described above under conditions effective to express the anti-NKG 2A antibody, and b) obtaining the expressed anti-NKG 2A antibody from the host cells.
In some embodiments, there is provided a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of any one of the anti-NKG 2A antibodies described above. In some embodiments, there is provided the use of any one of the anti-NKG 2A antibodies described above in the manufacture of a pharmaceutical composition for treating a disease or disorder in a subject in need thereof. In some embodiments, there is provided the use of any one of the anti-NKG 2A antibodies or a pharmaceutical composition comprising an anti-NKG 2A antibody as described above in the manufacture of a medicament for treating a disease or disorder. In some embodiments, the disease or disorder is associated with NKG2A signaling pathway, including cancer, viral disease, autoimmune disease, and/or inflammatory disease or disorder. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney cancer, bladder cancer, breast cancer, colon cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, uterine cancer, thyroid cancer, skin cancer, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid cancer, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome; viral diseases such as hepatitis A, B, C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes mellitus, uveitis, graves's disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, liver and spleen inflammation, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, meningitis, metritis, mucositis, myocarditis, myositis, tympanitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like.
Also provided are pharmaceutical compositions, kits and articles of manufacture comprising any of the anti-NKG 2A antibodies described above.
 Drawings
FIG. 1 shows the binding affinity of a rabbit full-antibody or chimeric anti-NKG 2A antibody for human NKG2A analyzed by ELISA. FIG. 1A shows the binding affinities of exemplary rabbit anti-NKG 2A antibodies ST14-R57, ST14-R58, ST14-R59, ST14-R60 to human NKG 2A. FIG. 1B shows the binding affinities of exemplary rabbit anti-NKG 2A antibodies ST14-R76, ST14-R77, ST14-R78 to human NKG 2A. FIG. 1C shows the binding affinities of exemplary chimeric anti-NKG 2A antibodies ST14-R79, ST14-R90 to human NKG 2A. FIG. 1D shows the binding affinity of an exemplary rabbit anti-NKG 2A antibody ST14-R12 to human NKG 2A. FIG. 1E shows the binding affinity of an exemplary chimeric anti-NKG 2A antibody ST14-R358 to human NKG 2A.
FIG. 2 shows the binding affinity of the ELISA-analyzed rabbit full-antibody or chimeric anti-NKG 2A-antibody to human NKG 2C. FIG. 2A shows the binding affinities of exemplary rabbit anti-NKG 2A antibodies ST14-R57, ST14-R58, ST14-R59, and ST14-R60 to human NKG 2C. FIG. 2B shows the binding affinities of exemplary rabbit anti-NKG 2A antibodies ST14-R76, ST14-R77, ST14-R78 to human NKG 2C. FIG. 2C shows the binding affinities of exemplary chimeric anti-NKG 2A antibodies ST14-R79, ST14-R90 to human NKG 2C. FIG. 2D shows the binding affinity of an exemplary rabbit anti-NKG 2A antibody ST14-R12 to human NKG 2C. FIG. 2E shows the binding affinity of an exemplary chimeric anti-NKG 2A antibody ST14-R358 to human NKG 2C.
FIG. 3 shows the activity of FACS analysis of rabbit full-antibody or chimeric anti-NKG 2A antibody blocking binding of NKL cells to HLA-E tetramers. FIG. 3A shows the activity of exemplary rabbit anti-NKG 2A antibodies ST14-R57, ST14-R58, ST14-R76, ST14-R77, ST14-R78 to block binding of NKL cells to HLA-E tetramers. FIG. 3B shows the activity of exemplary chimeric anti-NKG 2A antibodies ST14-R79, ST14-R90 to block binding of NKL cells to HLA-E tetramers. FIG. 3C shows the activity of an exemplary chimeric anti-NKG 2A antibody ST14-R358 to block binding of NKL cells to HLA-E tetramers.
FIG. 4 shows the activity of FACS analyzed rabbit anti-NKG 2A-antibodies to block NK 92-cell binding to HLA-E tetramers. FIG. 4A shows the activity of exemplary rabbit anti-NKG 2A antibodies ST14-R57, ST14-R58, ST14-R76, ST14-R77, ST14-R78 to block NK92 cell binding to HLA-E tetramers. FIG. 4B shows the activity of an exemplary rabbit anti-NKG 2A antibody ST14-R12 to block NK92 cell binding to HLA-E tetramers.
FIG. 5 shows the cross-binding activity of a rabbit full-antibody or chimeric anti-NKG 2A antibody with rhesus NKG2A analyzed by ELISA. FIG. 5A shows the cross-binding activity of exemplary rabbit anti-NKG 2A antibodies ST14-R57, ST14-R58 with rhesus NKG 2A. FIG. 5B shows the cross-binding activity of exemplary rabbit anti-NKG 2A antibodies ST14-R76, ST14-R77, ST14-R78 with rhesus NKG 2A. FIG. 5C shows the cross-binding activity of exemplary chimeric anti-NKG 2A antibodies ST14-R79, ST14-R90 with rhesus NKG 2A.
FIG. 6 shows that exemplary rabbit full-antibody or chimeric anti-NKG 2A antibodies ST14-R57, ST14-R76, ST14-R78, ST14-R358, analyzed by DELFIA EuTDA cytotoxicity, promote killing activity of NKL cells against K562-E4 cells.
FIG. 7 shows the activity of a rabbit full-antibody or chimeric anti-NKG 2A antibody to promote NKL cytotoxicity based on FACS analysis of the CD107 a-markers. FIG. 7A shows that exemplary rabbit anti-NKG 2A antibodies ST14-R57, ST14-R76, ST14-R77, ST14-R78 enhance CD107A expression in NKL cells. FIG. 7B shows that exemplary chimeric anti-NKG 2A antibodies ST14-R79, ST14-R90 enhance CD107a expression in NKL cells. FIG. 7C shows an exemplary chimeric anti-NKG 2A antibody ST14-
R358 enhances CD107a expression in NKL cells.
FIG. 8 shows the binding affinities of humanized anti-NKG 2A antibodies hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 to human NKG2A by ELISA analysis.
FIG. 9 shows the binding affinities of FACS-analyzed humanized anti-NKG 2A antibodies hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 to CHO-huNKG A cells.
FIG. 10 shows the FACS analysis of the activity of humanized anti-NKG 2A antibodies hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 to block binding of NKG cells to HLA-E tetramers.
FIG. 11A shows the cross-binding activity of humanized anti-NKG 2A antibodies hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 with rhesus NKG2A by ELISA assay. FIG. 11B shows the cross-binding activity of the humanized anti-NKG 2A antibodies hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 and CHO-rheNKG A by FACS analysis.
FIG. 12 shows that DELFIA EuTDA cytotoxicity assay of humanized anti-NKG 2A antibodies hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 promoted killing activity of NKL cells against K562-E4 cells.
FIG. 13 shows that the humanized anti-NKG 2A antibodies hum-ST14-R76-10, hum-ST14-R76-12, which were analyzed by FACS, enhanced CD107a expression in NKL cells.
FIG. 14 shows that humanized anti-NKG 2A antibodies hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12, as analyzed by the DELFIA EuTDA cytotoxicity assay, promote killing activity of primary NK cells against K562-E4 cells.
FIG. 15 shows the results of a pharmacokinetic study of exemplary anti-NKG 2A antibodies in rats.
Detailed description of the application
In one aspect, the application provides anti-NKG 2A antibody molecules. Through a combination of 293T cell display library screening, antibody humanization, affinity maturation, and appropriately designed biochemical and biological experiments, highly potent antibody molecules have been identified that are capable of binding human NKG2A and inhibiting the action of human NKG2A with its receptor. The results presented herein demonstrate that the antibodies of the application bind NKG2A compared to the known anti-NKG 2A antibody Monalizumab (NOVO NORDISK), nkg2a.9 (BRISTOL MYERS SQUIBB), M15 (shanghai-surmounting), and surprisingly demonstrate that the antibodies of the application are even more effective than Monalizumab (Mon, nkg2a.9 (A9) or M15 in various biological experiments.
Anti-NKG 2A antibodies provided herein include, for example, full-length anti-NKG 2A antibodies, anti-NKG 2A single chain antibodies (scFvs), anti-NKG 2A Fc fusion proteins, multi-specific (e.g., bispecific) anti-NKG 2A antibodies, anti-NKG 2A immunoconjugates, and the like.
In another aspect, the application provides an anti-NKG 2A antibody comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising SNTMS (SEQ ID NO: 1), HC-CDR2 comprising NINTGGNTYYANWAKG (SEQ ID NO: 9), and HC-CDR3 comprising GSTIDSSGLSL (SEQ ID NO: 24), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASQNIGSDLA (SEQ ID NO: 33), LC-CDR2 comprising LASTLAS (SEQ ID NO: 43), and LC-CDR3 comprising QQX 1 WSSSNVDNV (SEQ ID NO: 66), wherein X 1 is C, S or T.
In another aspect, the application provides an anti-NKG 2A antibody comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising NYHMS (SEQ ID NO: 2), HC-CDR2 comprising YIGAAX 1X2X3 YYASWAKG (SEQ ID NO: 65) wherein X 1 is G, N or S, X 2 is N or S, X 3 is A, I or T, and HC-CDR3 comprising GVIYNNL (SEQ ID NO: 25), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASESISNYLS (SEQ ID NO: 34), LC-CDR2 comprising DASDLAS (SEQ ID NO: 44), and LC-CDR3 comprising QX 1TYGSINX2 NYGVA (SEQ ID NO: 67) wherein X 1 is A or C, X 2 is A, Q or S.
In another aspect, the application provides an anti-NKG 2A antibody comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising SNTMS (SEQ ID NO: 1), HC-CDR2 comprising NINTGGNTYYANWAKG (SEQ ID NO: 9), and HC-CDR3 comprising GSTIDSSGLSL (SEQ ID NO: 24), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASDSIGDWLA (SEQ ID NO: 35), LC-CDR2 comprising KASILAS (SEQ ID NO: 45), and LC-CDR3 comprising QQCWSSSNVDNV (SEQ ID NO: 51).
In another aspect, the application provides an anti-NKG 2A antibody comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising GGYYMC (SEQ ID NO: 3), HC-CDR2 comprising CIGTGSGSTYYASWAKG (SEQ ID NO: 17), and HC-CDR3 comprising ESYAAYPDYGYGYNL (SEQ ID NO: 26), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASQSISSWLS (SEQ ID NO: 36), LC-CDR2 comprising QASTLAS (SEQ ID NO: 46), and LC-CDR3 comprising QANVGSDNAYVRA (SEQ ID NO: 58).
In another aspect, the application provides an anti-NKG 2A antibody comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising GGYYMC (SEQ ID NO: 3), HC-CDR2 comprising CIGTGSRSTYYASWAKG (SEQ ID NO: 18), and HC-CDR3 comprising ESYAAYPDYGDGLDL (SEQ ID NO: 27), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASQNINNWLS (SEQ ID NO: 37), LC-CDR2 comprising QASKLAS (SEQ ID NO: 47), and LC-CDR3 comprising QSNYGSTTTYVRA (SEQ ID NO: 59).
In another aspect, the application provides an anti-NKG 2A antibody comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising SYHMI (SEQ ID NO: 4), HC-CDR2 comprising GISSSGSTYYANWAKG (SEQ ID NO: 19), and HC-CDR3 comprising GYGSTFTYYDPSRLDL (SEQ ID NO: 28), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QSSQSVYDNNLLS (SEQ ID NO: 38), LC-CDR2 comprising GASKLAS (SEQ ID NO: 48), and LC-CDR3 comprising LGAYNDDGDNA (SEQ ID NO: 60).
In another aspect, the application provides an anti-NKG 2A antibody comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising SVSVT (SEQ ID NO: 5), HC-CDR2 comprising YINTGGNTGYASWVKG (SEQ ID NO: 20), and HC-CDR3 comprising GAGFSTRLGL (SEQ ID NO: 29), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASKSVAGNNELS (SEQ ID NO: 39), LC-CDR2 comprising DASDLAS (SEQ ID NO: 44), and LC-CDR3 comprising AGGYSDTSDNA (SEQ ID NO: 61).
In another aspect, the application provides an anti-NKG 2A antibody comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising DYAIN (SEQ ID NO: 6), HC-CDR2 comprising IIYDGSHNTWYASWVKG (SEQ ID NO: 21), and HC-CDR3 comprising AYAIYDGYGYLIYGMDP (SEQ ID NO: 30), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASQNIYSNLA (SEQ ID NO: 40), LC-CDR2 comprising LASTLAF (SEQ ID NO: 49), and LC-CDR3 comprising QSHDDTTAGPYGYA (SEQ ID NO: 62).
In another aspect, the application provides an anti-NKG 2A antibody comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising TYTMG (SEQ ID NO: 7), HC-CDR2 comprising TINTGGTSVYASWAKG (SEQ ID NO: 22), and HC-CDR3 comprising GIYSGWNTPFKL (SEQ ID NO: 31), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASEDIENYLA (SEQ ID NO: 41), LC-CDR2 comprising DASDLAS (SEQ ID NO: 44), and LC-CDR3 comprising QSYYYTISSFG (SEQ ID NO: 63).
In another aspect, the application provides an anti-NKG 2A antibody comprising a heavy chain variable domain (V H), said V H comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising SYDMN (SEQ ID NO: 8), HC-CDR2 comprising LMGIDGTTYYPNWAKG (SEQ ID NO: 23), and HC-CDR3 comprising NIYDDYYL (SEQ ID NO: 32), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QSSQSVYNNNALS (SEQ ID NO: 42), LC-CDR2 comprising GASTLAS (SEQ ID NO: 50), and LC-CDR3 comprising AGDYSSTSDDA (SEQ ID NO: 64).
Also provided are nucleic acids encoding anti-NKG 2A antibodies, compositions comprising anti-NKG 2A antibodies, and methods of making and using anti-NKG 2A antibodies.
Definition of the definition
As used herein, a "treatment" or "treatment" is a method of achieving a beneficial or desired result, including clinical results. For the purposes of the present application, such beneficial or desired clinical results include, but are not limited to, one or more of alleviating one or more symptoms caused by the disease, alleviating the extent of the disease, stabilizing the disease (e.g., preventing or delaying disease progression), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying disease recurrence, delaying or slowing disease progression, ameliorating the disease state, alleviating the disease (partially or wholly), reducing the dosage of one or more other drugs required to treat the disease, delaying disease progression, improving or enhancing quality of life, increasing weight, and/or prolonging survival. Meanwhile, "treatment" also includes reduction of disease pathology results (e.g., tumor volume for cancer). The methods of the present application contemplate any one or more aspects of these treatments.
The term "antibody" includes full length antibodies and antigen binding fragments thereof. Full length antibodies include two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable region in both chains typically comprises 3 hypervariable loops, known as Complementarity Determining Regions (CDRs) (light chain (LC) CDRs comprise LC-CDR1, LC-CDR2 and LC-CDR3, and Heavy Chain (HC) CDRs comprise HC-CDR1, HC-CDR2 and HC-CDR 3). CDR boundaries of antibodies or antigen binding fragments disclosed herein may be defined or identified by Kabat, chothia or Al-Lazikani conventions (Al-Lazikani 1997;Chothia 1985;Chothia 1987;Chothia 1989;Kabat 1987;Kabat 1991). The 3 CDR regions of the heavy or light chain are inserted between flanking segments called Framework Regions (FRs) which are more conserved than the CDR regions and form a scaffold supporting the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit multiple effector functions. Antibodies are classified based on the amino acid sequence of their heavy chain constant regions. The five main classes or isotypes of antibodies are IgA, igD, igE, igG and IgM, which are characterized by having alpha, delta, epsilon, gamma, and mu heavy chains, respectively. Several major antibody classes are classified into subclasses, such as IgG1 (gamma 1 heavy chain), igG2 (gamma 2 heavy chain), igG3 (gamma 3 heavy chain), igG4 (gamma 4 heavy chain), igA1 (alpha 1 heavy chain), or IgA2 (alpha 2 heavy chain).
As used herein, the term "antigen-binding fragment" includes antibody fragments, e.g., diabodies (diabodies), fab ', F (ab ') 2, fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv) 2, bispecific dsFv (dsFv-dsFv '), disulfide-stabilized diabodies (ds diabodies), single chain Fv (scFv), scFv dimers (diabodies), multispecific antibodies consisting of antibody fragments comprising one or more CDRs, single domain antibodies, nanobodies (nanobodies), domain antibodies, bivalent domain antibodies, or any other antibody fragment capable of binding an antigen but not comprising an intact antibody structure. The antigen binding fragment is capable of binding the same antigen as the parent antibody or parent antibody fragment (e.g., parent scFv). Antigen binding fragments also include fusion proteins comprising the above antibody fragments. In some embodiments, an antigen binding fragment may include one or more CDRs from a particular human antibody grafted to a framework region from one or more different human antibodies.
As used herein, the term "epitope" refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions exhibit competitive binding to an antigen, they may bind to the same epitope on the antigen.
As used herein, a first antibody "competes" with a second antibody for binding to a NKG2A target when the first antibody inhibits the second antibody from binding to the NKG2A target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) at equimolar concentrations, and vice versa. PCT publication WO 03/48731 describes a high throughput antibody "epitope categorization" method based on cross-competition.
As used herein, the term "specifically binds," "specifically recognizes," or "specific for," refers to a measurable and reproducible interaction, e.g., binding of an antibody to a target can determine the presence of the target in a heterogeneous population of molecules, including biomolecules. For example, an antibody being able to specifically recognize a target (which may be an epitope) means that the antibody binds to the target with a higher affinity, avidity, easier and/or longer lasting than other targets. In some embodiments, an antibody that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen with a binding affinity that is at least 10-fold greater than its binding affinity to other targets.
As used herein, an "isolated" anti-NKG 2A antibody refers to an anti-NKG 2A antibody that (1) is not associated with a naturally occurring protein, (2) does not contain other proteins of the same origin, (3) is expressed by cells of a different species, or (4) does not occur in nature.
As used herein, the term "isolated nucleic acid" refers to nucleic acids of genomic, cDNA, or synthetic origin, or a combination thereof. According to its origin, the term "isolated nucleic acid" means (1) not related to all or part of the polynucleotide found in nature in "isolated nucleic acid" (2) operably linked to a polynucleotide not linked thereto in nature, or (3) not present in nature as part of a longer sequence.
As used herein, the term "CDR" or "complementarity determining region" means a discontinuous antigen binding site found within the variable domains of heavy and light chain polypeptides. These particular regions have been described in literature Kabat et al.,J.Biol.Chem.252:6609-6616(1977);Kabat et al.,U.S.Dept.of Health and Human Services,"Sequences of proteins of immunological interest"(1991);Chothia et al.,J.Mol.Biol.196:901-917(1987);Al-Lazikani B.et al.,J.Mol.Biol.,273:927-948(1997);MacCallum et al.,J.Mol.Biol.262:732-745(1996);Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008);Lefranc M.P.et al.,Dev.Comp.Immunol.,27:55-77(2003); and honeygger and plackthun, j.mol.biol.,309:657-670 (2001), wherein these definitions include the coincidence or subset of amino acid residues when compared to each other. However, any definition of a CDR for an antibody or grafted antibody or variant thereof is intended to be included within the terms defined and used herein. The positions of the amino acid residues comprised by the CDRs defined by the various references cited above are listed in table 1 to illustrate the comparison. Algorithms and binding interfaces for CDR prediction are known in the art and include, for example, Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008);Ehrenmann F.et al.,Nucleic Acids Res.,38:D301-D307(2010); and Adolf-Bryfogle j.et al, nucleic Acids res, 43:d432-D438 (2015) are described. The content of the references cited in this paragraph is hereby incorporated by reference in its entirety for the purposes of the present application and possibly in one or more of the claims contained herein.
TABLE 1 CDR definition 1 Amino acid residue number refers to naming method 2 amino acid residue number in Kabat et al, refers to naming method 3 amino acid residue number in Chothia et al, refers to naming method 4 amino acid residue number in MacCallum et al, refers to naming method 5 amino acid residue number in LEFRANC ET al, refers to naming method in honeygger and Pluckthun
The term "chimeric antibody" refers to an antibody in which a portion of the heavy and/or light chain is identical or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they possess the biological activity of the application (see U.S. patent No.4,816,567; and Morrison et al, proc.Natl. Acad. Sci. USA,81:6851-6855 (1984)).
"Fv" is the smallest antibody fragment that contains the complete antigen recognition and binding site. The fragment is a dimer formed by a tight non-covalent linkage of one heavy chain variable domain and one light chain variable domain. By folding of these two domains, 6 hypervariable loops (3 loops in each of the light and heavy chains) are derived, which Gao Bianhuan provides amino acid residues for the antibody to bind antigen and confers specificity to the antibody for binding to antigen. However, even a single variable domain (or half of an Fv fragment, which contains only 3 CDRs specific for an antigen) has the ability to recognize and bind antigen, although with less affinity than the complete binding site.
"Single chain Fv", also abbreviated "sFv" or "scFv", is an antibody fragment comprising V H and V L antibody domains linked into a single polypeptide chain. In some embodiments, the scFv polypeptide further comprises a linker polypeptide between the V H and V L domains that allows the scFv to form the desired structure for antigen binding. For an overview of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies,vol.113,Rosenburg and Moore eds.,Springer-Verlag,New York,pp.269-315(1994).
The term "diabody" is a small antibody fragment prepared by constructing scFv fragments (see above) using a short linker (e.g., 5-10 residues) between the V H and V L domains, such that the variable domains pair between the chains, rather than within the chains, resulting in a bivalent fragment, i.e., a fragment having two antigen binding sites. Bispecific diabodies are heterodimers of two "crossed" scFv fragments, in which the V H and V L domains of the two antibodies are located on different polypeptide chains. Diabodies are described fully in EP404,097; WO 93/11161;Hollinger et al. Proc. Natl. Acad. Sci. USA,90:6444-6448 (1993).
The "humanized" form of a non-human (e.g., rodent) antibody is a chimeric antibody that includes minimal sequences from the non-human antibody. In most cases, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (HVR) of the recipient antibody are replaced by residues from a hypervariable region of a non-human species, such as mouse, rat, rabbit or non-human mammal, having the desired antibody specificity, affinity and properties (donor antibody). In some cases, residues in the framework region of the human immunoglobulin are replaced with corresponding non-human residues. In addition, humanized antibodies may include residues that are not present in either the recipient antibody or the donor antibody. These modifications can further improve the performance of the antibody. Typically, a humanized antibody will comprise substantially all, at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are human immunoglobulin sequences. The human antibody optionally also includes at least a portion of an immunoglobulin constant region (Fc), typically a constant region of a human immunoglobulin. For specific details, reference may be made to Jones et al, nature 321:522-525 (1986), RIECHMANN ET al, nature 332:323-329 (1988), and Presta, curr. Op. Structure. Biol.2:593-596 (1992).
"Percent (%) amino acid sequence identity" or "homology" of the polypeptide and antibody sequences identified herein is defined as the percentage of identical amino acid residues in the candidate sequence and the polypeptide sequences to be compared, when the conservative substitutions are considered to be part of the sequence identity, for comparison. The percentage of amino acid sequence identity may be determined by a variety of alignment methods within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, megalign (DNASTAR), or MUSCLE software. One skilled in the art can determine suitable parameters for measuring the alignment, including any algorithms needed to achieve maximum alignment over the full length of the compared sequences. However, for purposes herein, the percent amino acid sequence identity values are generated using the sequence alignment computer program MUSCLE(Edgar,R.C.,Nucleic Acids Research 32(5):1792-1797,2004;Edgar,R.C.,BMC Bioinformatics 5(1):113,2004).
The term "Fc receptor" or "FcR" is used to describe a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR of the application is one that binds an IgG antibody (a gamma receptor), including receptors of the fcyri, fcyrii, and fcyriii subclasses, including allelic variants and alternatively spliced forms of these receptors. Fcyrii receptors include fcyriia ("activating receptor") and fcyriib ("inhibiting receptor"), which have similar amino acid sequences, differing primarily in the cytoplasmic domain. The cytoplasmic domain of the activating receptor fcyriia contains an immune receptor tyrosine activation motif (ITAM). The cytoplasmic domain of the inhibition receptor fcyriib contains the Immunoreceptor Tyrosine Inhibitory Motif (ITIM) (see m.inAnnu.Rev.Immunol.15:203-234 (1997)). The term also includes allotypes such as FcgammaRIIIA allotype FcgammaRIIIA-Phe 158, fcgammaRIIIA-Val 158, fcgammaRIIA-R131 and/or FcgammaRIIA-H131. FcRs are described in RAVETCH AND KINET, ANNU.REV.IMMUNOL 9:457-92 (1991) and Capel et al, immunomethods 4:25-34 (1994), and de Haas et al, J.Lab. Clin. Med.126:330-41 (1995). The term FcR in the present application encompasses other types of FcRs, including FcRs identified in the future. The term FcR also includes the neonatal receptor FcRn, which is responsible for transferring the parent IgGs to the neonate (Guyer et al, J.Immunol.117:587 (1976) and Kim et al, J.Immunol.24:249 (1994)).
The term "FcRn" refers to neonatal Fc receptor (FcRn). FcRn is structurally similar to the Major Histocompatibility Complex (MHC), consisting of non-covalent binding of the alpha chain to beta 2 microglobulin. The various functions of the neonatal Fc receptor FcRn are reviewed in GHETIE AND WARD (2000) Annu. Rev. Immunol.18,739-766. FcRn plays an important role in the passive transport of immunoglobulin IgGs from the mother to neonates and in the regulation of serum IgG levels. FcRn acts as a salvage receptor that can bind and transport endocytosed IgG in intact form within and between cells and protect them from the default degradation pathway.
The "CH1 domain" of the human IgG heavy chain constant region typically extends from amino acid 118 to amino acid 215 (EU numbering system).
The "hinge region" is generally defined as extending from Glu at position 216 to Pro at position 230 of human IgG1 (Burton, molecular immunol.22:161-206 (1985)). The hinge regions of other IgG isotypes can be aligned with the IgG1 sequence by placing the first and last cysteine residues that form the inter-heavy chain disulfide bond in the same position as IgG 1.
The "CH2 domain" of the human IgG Fc region typically extends from amino acid 231 to amino acid 340. The CH2 domain is unique in that it does not mate tightly with another region, but rather inserts two N-terminally linked branched carbohydrate chains between the two CH2 domains of the intact native IgG molecule. It is speculated that carbohydrates may serve as a surrogate for domain-to-domain pairing, helping to keep the CH2 domain stable. Burton, molecular. Immunol.22:161-206 (1985).
The "CH3" domain includes the extension from the C-terminal residue to the CH2 domain (from amino acid 341 to the C-terminal end of the antibody sequence, typically amino acid 446 or 447 of IgG) within the Fc region.
The "functional Fc fragment" has the "effector function" possessed by the native Fc region sequence. Exemplary "effector functions" include C1q binding, complement Dependent Cytotoxicity (CDC), fc receptor binding, antibody dependent cell-mediated cytotoxicity (ADCC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptor; BCR), and the like. Such effector functions typically require that the Fc region bind to a binding domain (e.g., an antibody variable region) and can be assessed using a variety of experimental methods well known in the art.
Antibodies to IgG Fc variants having "altered" FcR binding affinity or ADCC activity have increased or decreased FcR binding activity and/or ADCC activity compared to the parent polypeptide or polypeptide comprising the native Fc sequence. Fc variants exhibiting "enhanced binding" to FcR have a higher binding affinity (e.g., lower apparent Kd or IC 50 values) to at least one FcR than the parent polypeptide or polypeptide comprising the native IgG Fc sequence. In some embodiments, the binding capacity is increased by a factor of 3, e.g., 5,10, 25, 50, 60, 100, 150, 200, even up to a factor of 500 or the binding capacity is increased by a factor of 25% to 1000% as compared to the parent polypeptide. Fc variants exhibiting "reduced binding" to FcR have lower affinity (e.g., higher apparent Kd or IC 50 values) for at least one FcR than the parent polypeptide. Its binding capacity is reduced by 40% or more compared to the parent polypeptide.
"Antibody-dependent cell-mediated cytotoxicity" or "ADCC" is a form of cytotoxicity that refers to the binding of secreted Ig to Fc receptors (FcRs) present on certain cytotoxic cells, such as natural killer cells (NK), neutrophils, and macrophages, enabling these cytotoxic effector cells to specifically bind antigen-bearing target cells, followed by killing of the target cells with cytotoxins. Antibodies "arm" cytotoxic cells and are necessary for such killing. In the major cell types mediating ADCC NK cells express fcyriii only, whereas monocytes express fcyri, fcyrii and fcyriii. FcR expression on hematopoietic cells is summarized in Table 3 at page 464 of RAVETCH AND KINET, ANNU.REV.IMMUNOL 9:457-92 (1991). The ADCC activity of the target molecule is assessed and an in vitro ADCC assay may be performed and is described in U.S. patent nos. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include Peripheral Blood Mononuclear Cells (PBMC) and natural killer cells (NK). Alternatively, or in addition, ADCC activity of the target molecule may also be assessed in vivo, for example as described in an animal model as disclosed in Clynes et al PNAS (USA) 95:652-656 (1998).
Polypeptides comprising an Fc region variant that are experimentally substantially the same in number as wild-type IgG Fc polypeptides (or parent polypeptides) are more effective in mediating ADCC in vitro or in vivo when they exhibit "enhanced ADCC activity" or are capable of mediating ADCC effects more effectively in the presence of human effector cells than wild-type IgG Fc polypeptides or parent polypeptides. Such variants are typically identified using any in vitro ADCC assay known in the art, such as assays or methods for identifying ADCC activity, e.g., in animal models, etc. In some embodiments, such variants mediate ADCC with a 5 to 100 fold, e.g., 25 to 50 fold increase in efficiency compared to the wild-type Fc (or parent polypeptide).
"Complement dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by binding of the first component of the complement system (C1 q) to antibodies (subclasses of appropriate structure) that bind to cognate antigens. To assess complement activation, CDC experiments can be performed as described in Gazzano-Santoro et al, J.Immunol. Methods 202:163 (1996). Polypeptide variants having altered amino acid sequences of the Fc region and increased or decreased C1q binding capacity are described in U.S. Pat. No.6,194,551B1 and WO 99/51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al J.Immunol.164:4178-4184 (2000).
Unless otherwise indicated, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and encode the same amino acid sequence. The nucleotide sequence encoding a protein or RNA may also include introns, e.g., the nucleotide sequence encoding a protein may in some forms comprise introns.
The term "operably linked" refers to a functional linkage between a regulatory sequence and a heterologous nucleotide sequence such that the latter is expressed. For example, a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence. For example, a promoter is operably linked to a coding sequence if it affects the transcription or expression of the coding sequence. Typically, operably linked DNA sequences are contiguous and, if necessary, two protein coding regions can be linked in the same reading frame.
"Homology" refers to sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same position of two compared sequences is the same base or amino acid monomer subunit, for example, the same position of both DNA molecules is adenine, then both DNA molecules are homologous at that position. The percentage of homology between two sequences refers to the function of the ratio of the number of matching or homologous positions to the total number of positions shared by the two sequences multiplied by 100. For example, if 6 of the 10 positions in two sequences are matched or homologous, the two sequences are 60% homologous. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. In general, when two sequences are aligned, alignment is performed with the aim of obtaining maximum homology.
An "effective amount" of an anti-NKG 2A antibody or composition disclosed herein refers to an amount sufficient to achieve a particular purpose. The "effective amount" may be determined empirically and by methods known in connection with the purpose.
The term "therapeutically effective amount" refers to an amount of an anti-NKG 2A antibody or composition thereof disclosed herein that is effective to treat a disease or condition in an individual. For example, in the case of cancer, a therapeutically effective amount of an anti-NKG 2A antibody or composition thereof refers to an amount that reduces the number of cancer cells, reduces the size or weight of a tumor, inhibits (i.e., slows or preferably stops to some extent) infiltration of peripheral organs by tumor cells, inhibits (i.e., slows or preferably stops to some extent) tumor metastasis, inhibits to some extent tumor growth, and/or alleviates to some extent one or more symptoms associated with cancer. The anti-NKG 2A antibodies or compositions thereof disclosed herein are capable of preventing and/or killing existing tumor cells to some extent, and may be cytostatic or cytotoxic. In some embodiments, a therapeutically effective amount refers to an amount that is capable of extending the survival of a patient. In some embodiments, a therapeutically effective amount refers to an amount that improves the progression free survival of a patient.
As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" refers to materials that are not biologically active or otherwise undesirable, e.g., that can be added to a pharmaceutical composition administered to a patient without causing significant adverse biological reactions or interacting in a deleterious manner with any of the other components of the composition in which they are contained. The pharmaceutically acceptable carrier or excipient preferably meets the desired criteria for toxicology or manufacturing testing and/or is contained in inactive ingredient guidelines established by the U.S. food and drug administration.
The embodiments of the application described herein should be understood to include embodiments that "consist of and/or" consist essentially of.
Reference herein to "about" is a numerical value or parameter, including (and describing) variations on the value or parameter itself. For example, a description relating to "about X" includes a description of "X".
As used herein, reference to a value or parameter that is "not (not)" generally means and describes "other than (other than)" a value or parameter. For example, the method cannot be used to treat type X cancers, meaning that the method is generally used to treat other types of cancers in addition to type X cancers.
As used herein and in the claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
Anti-NKG 2A antibodies
In one aspect, the application provides anti-human and/or rhesus NKG2A antibodies that specifically bind NKG2A. Such anti-NKG 2A antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibody molecules comprising heavy and/or light chain CDRs as described herein. In one aspect, the application provides an isolated antibody that binds NKG2A. Contemplated anti-NKG 2A antibodies include, for example, full-length anti-NKG 2A antibodies (e.g., full-length IgG1 or IgG 4), anti-NKG 2A single chain antibodies, anti-NKG 2A Fc fusion proteins, multi-specific (e.g., bispecific) anti-NKG 2A antibodies, anti-NKG 2A immunoconjugates, and the like. In some embodiments, the anti-NKG 2A antibody is a full length antibody (e.g., full length IgG1 or IgG 4) or an antigen-binding fragment thereof, which specifically binds NKG2A. In some embodiments, the anti-NKG 2A antibody is a Fab, fab ', F (ab) ' 2, fab ' -SH, single chain Fv (scFv), fv fragment, dAb, fd, nanobody (nanobody), diabody (diabody), or linear antibody. In some embodiments, an antibody that specifically binds NKG2A refers to an antibody that binds NKG2A with at least 10-fold greater affinity (including, for example, 10 2、103、104、105、106, or 10 7 -fold) than non-target binding affinity. In some embodiments, non-target refers to an antigen that is not NKG2A. Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence Activated Cell Sorting (FACS) analysis, or Radioimmunoassay (RIA). Kd values can be determined by methods known in the art, such as Surface Plasmon Resonance (SPR) techniques or Biological Layer Interferometry (BLI).
Although anti-NKG 2A antibodies comprising human sequences (e.g., human heavy and light chain variable domains comprising human CDR sequences) are discussed extensively herein, non-human anti-NKG 2A antibodies are also contemplated. In some embodiments, the non-human anti-NKG 2A antibody comprises a human CDR sequence and a non-human framework region sequence of an anti-NKG 2A antibody described herein, and in some embodiments, the non-human framework region sequence comprises any sequence for producing heavy and/or light chain variable domains using one or more human CDR sequences as described herein, including, for example, mammals, such as mice, rats, rabbits, pigs, cattle (e.g., cattle, bulls, buffalo), deer, sheep, goats, chickens, cats, dogs, ferrets, primates (e.g., apes, macaques), and the like. In some embodiments, the non-human anti-NKG 2A antibody comprises an anti-NKG 2A antibody produced by grafting one or more human CDR sequences described herein into a non-human framework region (e.g., a murine or chicken framework region sequence).
An exemplary human NKG2A extracellular region amino acid sequence comprises or consists of the amino acid sequence shown as SEQ ID NO: 114. An exemplary rhesus NKG2A extracellular region amino acid sequence comprises or consists of the amino acid sequence shown in SEQ ID No. 115.
In some embodiments, an anti-NKG 2A antibody described herein specifically recognizes an epitope in human NKG 2A. In some embodiments, the anti-NKG 2A antibody cross-reacts with NKG2A of a species other than human. In some embodiments, the anti-NKG 2A antibody is fully specific for human NKG2A and does not cross-react with other non-human species.
In some embodiments, the anti-NKG 2A antibody cross-reacts with at least one allelic variant of the NKG2A protein (or fragment thereof). In some embodiments, the allelic variant has up to 30 (e.g., 1,2,3, 4, 5, 6,7, 8, 9, 10, 15, 20, 25, or 30) amino acid substitutions (e.g., conservative substitutions) compared to the naturally occurring NKG2A protein (or fragment thereof). In some embodiments, the anti-NKG 2A antibody does not cross-react with any allelic variant of the NKG2A protein (or fragment thereof).
In some embodiments, the anti-NKG 2A antibody cross-reacts with at least one intervarietal variant of NKG2A protein. In some embodiments, for example, the NKG2A protein (or fragment thereof) is human NKG2A, and the intervarietal variant of the NKG2A protein (or fragment thereof) is a variant in cynomolgus monkey. In some embodiments, the anti-NKG 2A antibody does not cross-react with any of the inter-variant NKG2A proteins.
In some embodiments, any of the anti-NKG 2A antibodies as described herein, the anti-NKG 2A antibody comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the anti-NKG 2A antibody comprises an IgG 1-type heavy chain constant region. In some embodiments, the anti-NKG 2A antibody comprises an IgG 2-type heavy chain constant region. In some embodiments, the anti-NKG 2A antibody comprises an IgG 3-type heavy chain constant region. In some embodiments, the anti-NKG 2A antibody comprises an IgG 4-type heavy chain constant region. In some embodiments, the heavy chain constant region comprises (including consisting of or consisting essentially of) the amino acid sequence SEQ ID No. 110. In some embodiments, the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID No. 111. In some embodiments, the anti-NKG 2A antibody comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises (including consisting of or consisting essentially of) the amino acid sequence of SEQ ID No. 112. In some embodiments, the anti-NKG 2A antibody comprises a lambda light chain constant region. In some embodiments, the light chain constant region comprises (including consisting of or consisting essentially of) the amino acid sequence SEQ ID No. 113. In some embodiments, the anti-NKG 2A antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.
In some embodiments, the anti-NKG 2A antibody comprises a heavy chain variable domain (V H), the V H comprises a heavy chain complementarity determining region (HC-CDR) 1 comprising SNTMS (SEQ ID NO: 1), HC-CDR2 comprising NINTGGNTYYANWAKG (SEQ ID NO: 9), and HC-CDR3 comprising GSTIDSSGLSL (SEQ ID NO: 24), and a light chain variable domain (V L), the V L comprises a light chain complementarity determining region (LC-CDR) 1 comprising QASQNIGSDLA (SEQ ID NO: 43), LC-CDR2 comprising LASTLAS (SEQ ID NO: 43), and LC-CDR3 comprising QQX 1 WSSSNVDNV (SEQ ID NO: 66), wherein X 1 is C, S or T
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 1 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 9 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO. 24 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions.
In some embodiments, the anti-NKG 2A antibody comprises V H, and the V H comprises HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 1, HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 9, HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO. 24.
In some embodiments, the anti-NKG 2A antibody comprises V L, the V L comprises a LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO 33 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO 43 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, and a LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs:51-53 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions.
In some embodiments, the anti-NKG 2A antibody comprises V L, and V L comprises LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:33, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:43, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 51-53.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 1 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 9 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO. 24 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 33 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, CDR2 comprising the amino acid sequence shown in SEQ ID NO. 43 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, e.g., any one of the amino acid substitutions shown in SEQ ID NO. 43 or a variant thereof comprising up to about 3 (e.g., 1,2,3, or 3) amino acid substitutions, e.g., a variant thereof.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:24, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:33, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:43, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 51-53.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:33, LC-CDR2 comprising the amino acid sequence SEQ ID NO:43, LC-CDR3 comprising the amino acid sequence SEQ ID NO:51, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:33, LC-CDR2 comprising amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising amino acid sequence SEQ ID NO:51.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:33, LC-CDR2 comprising the amino acid sequence SEQ ID NO:43, LC-CDR3 comprising the amino acid sequence SEQ ID NO:52, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:33, LC-CDR2 comprising amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising amino acid sequence SEQ ID NO:52.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:33, LC-CDR2 comprising the amino acid sequence SEQ ID NO:43, LC-CDR3 comprising the amino acid sequence SEQ ID NO:53, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:33, LC-CDR2 comprising amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising amino acid sequence SEQ ID NO:53.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in any one of the amino acid sequences of SEQ ID NOs:68-71, and V L, the V L comprises LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in any one of the amino acid sequences of SEQ ID NOs: 92-95.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:68, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 92.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:69, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 93.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:70, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 93.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:69, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 94.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:70, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 94.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:71, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 95.
In some embodiments, the anti-NKG 2A antibody comprises V H, said V H comprises the amino acid sequence shown in any one of SEQ ID NOs 68-71 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence shown in any one of SEQ ID NOs 68-71, and V L, said V L comprises the amino acid sequence shown in any one of SEQ ID NOs 92-95 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence shown in any one of SEQ ID NOs 92-95. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence shown in any one of SEQ ID NOs:68-71, and V L, the V L comprises the amino acid sequence shown in any one of SEQ ID NOs: 92-95.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:68 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:68, and V L, which V L comprises amino acid sequence SEQ ID NO:92 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:92. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 68, and V L, the V L comprises the amino acid sequence SEQ ID No. 92.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:69, or a variant thereof, which has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:69, and V L, which V L comprises amino acid sequence SEQ ID NO:93, or a variant thereof, which has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:93. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 69, and V L, the V L comprises the amino acid sequence SEQ ID No. 93.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 70 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 70, and V L, which V L comprises amino acid sequence SEQ ID NO 93 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 93. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 70, and V L, the V L comprises the amino acid sequence SEQ ID No. 93.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:69, or a variant thereof, which has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:69, and V L, which V L comprises amino acid sequence SEQ ID NO:94, or a variant thereof, which has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:94. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 69, and V L, the V L comprises the amino acid sequence SEQ ID No. 94.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 70 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 70, and V L, which V L comprises amino acid sequence SEQ ID NO 94 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 94. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 70, and V L, the V L comprises the amino acid sequence SEQ ID No. 94.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:71 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:71, and V L, which V L comprises amino acid sequence SEQ ID NO:95 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:95. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 71, and V L, the V L comprises the amino acid sequence SEQ ID No. 95.
In some embodiments, the anti-NKG 2A antibody comprises a heavy chain variable domain (V H), the V H comprises a heavy chain complementarity determining region (HC-CDR) 1 comprising NYHMS (SEQ ID NO: 2), HC-CDR2 comprising YIGAAX 1X2X3 YYASWAKG (SEQ ID NO: 65) wherein X 1 is G, N or S, X 2 is N or S, X 3 is A, I or T, and HC-CDR3 comprising GVIYNNL (SEQ ID NO: 25), and a light chain variable domain (V L), the V L comprises a light chain complementarity determining region (LC-CDR) 1 comprising QASESISNYLS (SEQ ID NO: 34), LC-CDR2 comprising DASDLAS (SEQ ID NO: 44), and LC-CDR3 comprising QX 1TYGSINX2 NYGVA (SEQ ID NO: 67) wherein X 1 is A or C, X 2 is A, Q or S
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:2 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 10-16 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:25 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions.
In some embodiments, the anti-NKG 2A antibody comprises V H, and the V H comprises HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 2, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 10-16, HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO. 25.
In some embodiments, the anti-NKG 2A antibody comprises V L, the V L comprises a LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO 34 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO 44 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions, and a LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs 54-57 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions.
In some embodiments, the anti-NKG 2A antibody comprises V L, and V L comprises LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:44, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 54-57.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:2 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) substitutions of amino acids, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 10-16 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) substitutions of amino acids, and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:25 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) substitutions of amino acids, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:34 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) substitutions of amino acids, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:44 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) substitutions of amino acid sequence shown in SEQ ID NO:44 or a variant thereof, e.g., up to about 3 (e.g., 1,2, or 3) amino acid substitutions of any one of amino acid sequence shown in SEQ ID NO: 34.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 10-16, and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:25, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:44, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs 54-57.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:10, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:54, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:54.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:10, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:10, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:56, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:11, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:56, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:12, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:56, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:13, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:13, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:14, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:14, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:15, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:15, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:16, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:16, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:11, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:12, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence SEQ ID NO:10, HC-CDR3 comprising the amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:57, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:57.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in any one of the amino acid sequences of SEQ ID NOs 72-84, and V L, the V L comprises LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in any one of the amino acid sequences of SEQ ID NOs 96-101.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:72, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 96.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:73, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 97.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:74, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 97.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:75, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 97.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:76, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 97.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:77, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 97.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:78, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 97.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:73, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 98.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:74, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 98.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:75, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 98.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:76, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 98.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:77, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 98.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:78, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 98.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:78, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 99.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:78, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 100.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:79, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 100.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:80, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 100.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:81, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 99.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:82, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 99.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:83, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 99.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:84, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 99.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:79, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 99.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:80, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 99.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:78, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 101.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises an amino acid sequence shown in any one of SEQ ID NOs 72-84, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence shown in any one of SEQ ID NOs 72-84, and V L, the V L comprises an amino acid sequence shown in any one of SEQ ID NOs 96-101, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence shown in any one of SEQ ID NOs 96-101. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence shown in any one of SEQ ID NOs 72-84, and V L, the V L comprises the amino acid sequence shown in any one of SEQ ID NOs 96-101.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:72 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:72, and V L, which V L comprises amino acid sequence SEQ ID NO:96 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:96. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 72, and V L, the V L comprises the amino acid sequence SEQ ID No. 96.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:73 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:73, and V L, which V L comprises amino acid sequence SEQ ID NO:97 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:97. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 73, and V L, the V L comprises the amino acid sequence SEQ ID No. 97.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 74 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 74, and V L, which V L comprises amino acid sequence SEQ ID NO 97 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 74, and V L, the V L comprises the amino acid sequence SEQ ID No. 97.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 75 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 75, and V L, which V L comprises amino acid sequence SEQ ID NO 97 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 75, and V L, the V L comprises the amino acid sequence SEQ ID No. 97.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 76 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 76, and V L, which V L comprises amino acid sequence SEQ ID NO 97 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 76, and V L, the V L comprises the amino acid sequence SEQ ID No. 97.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 77 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 77, and V L, which V L comprises amino acid sequence SEQ ID NO 97 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 77, and V L, the V L comprises the amino acid sequence SEQ ID No. 97.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:78 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:78, and V L, which V L comprises amino acid sequence SEQ ID NO:97 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:97. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 78, and V L, the V L comprises the amino acid sequence SEQ ID No. 97.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:73 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:73, and V L, which V L comprises amino acid sequence SEQ ID NO:98 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:98. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 73, and V L, the V L comprises the amino acid sequence SEQ ID No. 98.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:74 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:74, and V L, which V L comprises amino acid sequence SEQ ID NO:98 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:98. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 74, and V L, the V L comprises the amino acid sequence SEQ ID No. 98.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 75 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 75, and V L, which V L comprises amino acid sequence SEQ ID NO 98 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 98. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 75, and V L, the V L comprises the amino acid sequence SEQ ID No. 98.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 76 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 76, and V L, which V L comprises amino acid sequence SEQ ID NO 98 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 98. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 76, and V L, the V L comprises the amino acid sequence SEQ ID No. 98.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:77 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:77, and V L, which V L comprises amino acid sequence SEQ ID NO:98 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:98. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 77, and V L, the V L comprises the amino acid sequence SEQ ID No. 98.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:78 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:78, and V L, which V L comprises amino acid sequence SEQ ID NO:98 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:98. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 78, and V L, the V L comprises the amino acid sequence SEQ ID No. 98.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:78 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:78, and V L, which V L comprises amino acid sequence SEQ ID NO:99 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:99. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 78, and V L, the V L comprises the amino acid sequence SEQ ID No. 99.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:78 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:78, and V L, which V L comprises amino acid sequence SEQ ID NO:100 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:100. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 78, and V L, the V L comprises the amino acid sequence SEQ ID No. 100.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:79 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:79, and V L, which V L comprises amino acid sequence SEQ ID NO:100 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:100. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 79, and V L, the V L comprises the amino acid sequence SEQ ID No. 100.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:80 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:80, and V L, which V L comprises amino acid sequence SEQ ID NO:100 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:100. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 80, and V L, the V L comprises the amino acid sequence SEQ ID No. 100.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:81 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:81, and V L, which V L comprises amino acid sequence SEQ ID NO:99 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:99. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 81, and V L, the V L comprises the amino acid sequence SEQ ID No. 99.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:82 or a variant thereof that has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:82, and V L, which V L comprises amino acid sequence SEQ ID NO:99 or a variant thereof that has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:99. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 82, and V L, the V L comprises the amino acid sequence SEQ ID No. 99.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 83 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 83, and V L, which V L comprises amino acid sequence SEQ ID NO 99 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 99. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 83, and V L, the V L comprises the amino acid sequence SEQ ID No. 99.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 84 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 84, and V L, which V L comprises amino acid sequence SEQ ID NO 99 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 99. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 84, and V L, the V L comprises the amino acid sequence SEQ ID No. 99.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:79 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:79, and V L, which V L comprises amino acid sequence SEQ ID NO:99 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:99. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 79, and V L, the V L comprises the amino acid sequence SEQ ID No. 99.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:80 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:80, and V L, which V L comprises amino acid sequence SEQ ID NO:99 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:99. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 80, and V L, the V L comprises the amino acid sequence SEQ ID No. 99.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:78 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:78, and V L, which V L comprises amino acid sequence SEQ ID NO:101 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:101. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 78, and V L, the V L comprises the amino acid sequence SEQ ID No. 101.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:35, LC-CDR2 comprising the amino acid sequence SEQ ID NO:45, LC-CDR3 comprising the amino acid sequence SEQ ID NO:51, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:35, LC-CDR2 comprising amino acid sequence SEQ ID NO:45, and LC-CDR3 comprising amino acid sequence SEQ ID NO:51.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:68, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 102.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:68 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:68, and V L, which V L comprises amino acid sequence SEQ ID NO:102 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:102. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID NO:68, and V L, the V L comprises the amino acid sequence SEQ ID NO:102.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:3, HC-CDR2 comprising the amino acid sequence SEQ ID NO:17, HC-CDR3 comprising the amino acid sequence SEQ ID NO:26, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:36, LC-CDR2 comprising the amino acid sequence SEQ ID NO:46, LC-CDR3 comprising the amino acid sequence SEQ ID NO:58, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:17, and HC-CDR3 comprising amino acid sequence SEQ ID NO:26, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:36, LC-CDR2 comprising amino acid sequence SEQ ID NO:46, and LC-CDR3 comprising amino acid sequence SEQ ID NO:58.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:85, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 103.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:85 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:85, and V L, which V L comprises amino acid sequence SEQ ID NO:103 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:103. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 85, and V L, the V L comprises the amino acid sequence SEQ ID No. 103.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:18, HC-CDR3 comprising amino acid sequence SEQ ID NO:27, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:37, LC-CDR2 comprising amino acid sequence SEQ ID NO:47, LC-CDR3 comprising amino acid sequence SEQ ID NO:59, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising amino acid sequence SEQ ID NO:27, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:37, LC-CDR2 comprising amino acid sequence SEQ ID NO:47, and LC-CDR3 comprising amino acid sequence SEQ ID NO:59.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:86, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 104.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 86 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 86, and V L, which V L comprises amino acid sequence SEQ ID NO 104 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 104. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 86, and V L, the V L comprises the amino acid sequence SEQ ID No. 104.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:4, HC-CDR2 comprising amino acid sequence SEQ ID NO:19, HC-CDR3 comprising amino acid sequence SEQ ID NO:28, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:38, LC-CDR2 comprising amino acid sequence SEQ ID NO:48, LC-CDR3 comprising amino acid sequence SEQ ID NO:60, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:4, HC-CDR2 comprising amino acid sequence SEQ ID NO:19, and HC-CDR3 comprising amino acid sequence SEQ ID NO:28, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:38, LC-CDR2 comprising amino acid sequence SEQ ID NO:48, and LC-CDR3 comprising amino acid sequence SEQ ID NO:60.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:87, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 105.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 87 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 87, and V L, which V L comprises amino acid sequence SEQ ID NO 105 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 105. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 87, and V L, the V L comprises the amino acid sequence SEQ ID No. 105.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, HC-CDR3 comprising the amino acid sequence SEQ ID NO:29, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:39, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, LC-CDR3 comprising the amino acid sequence SEQ ID NO:61, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:5, HC-CDR2 comprising amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising amino acid sequence SEQ ID NO:29, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:39, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:61.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:88, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 106.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:88 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:88, and V L, which V L comprises amino acid sequence SEQ ID NO:106 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:106. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 88, and V L, the V L comprises the amino acid sequence SEQ ID No. 106.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:6, HC-CDR2 comprising amino acid sequence SEQ ID NO:21, HC-CDR3 comprising amino acid sequence SEQ ID NO:30, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:40, LC-CDR2 comprising amino acid sequence SEQ ID NO:49, LC-CDR3 comprising amino acid sequence SEQ ID NO:62, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:6, HC-CDR2 comprising amino acid sequence SEQ ID NO:21, and HC-CDR3 comprising amino acid sequence SEQ ID NO:30, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:40, LC-CDR2 comprising amino acid sequence SEQ ID NO:49, and LC-CDR3 comprising amino acid sequence SEQ ID NO:62.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:89, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 107.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO:89 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:89, and V L, which V L comprises amino acid sequence SEQ ID NO:107 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO:107. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 89, and V L, the V L comprises the amino acid sequence SEQ ID No. 107.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:7, HC-CDR2 comprising amino acid sequence SEQ ID NO:22, HC-CDR3 comprising amino acid sequence SEQ ID NO:31, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:41, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, LC-CDR3 comprising amino acid sequence SEQ ID NO:63, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:7, HC-CDR2 comprising amino acid sequence SEQ ID NO:22, and HC-CDR3 comprising amino acid sequence SEQ ID NO:31, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:41, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:63.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:90, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 108.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 90 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 90, and V L, which V L comprises amino acid sequence SEQ ID NO 108 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 108. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID No. 90, and V L, the V L comprises the amino acid sequence SEQ ID No. 108.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:8, HC-CDR2 comprising amino acid sequence SEQ ID NO:23, HC-CDR3 comprising amino acid sequence SEQ ID NO:32, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:42, LC-CDR2 comprising amino acid sequence SEQ ID NO:50, LC-CDR3 comprising amino acid sequence SEQ ID NO:64, or a variant of the V L comprising up to about 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:8, HC-CDR2 comprising amino acid sequence SEQ ID NO:23, and HC-CDR3 comprising amino acid sequence SEQ ID NO:32, and the V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:42, LC-CDR2 comprising amino acid sequence SEQ ID NO:50, and LC-CDR3 comprising amino acid sequence SEQ ID NO:64.
In some embodiments, the anti-NKG 2A antibody comprises V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 comprised by V H as shown in amino acid sequence SEQ ID NO:91, and V L comprising LC-CDR1, LC-CDR2, and LC-CDR3 comprised by V L as shown in amino acid sequence SEQ ID NO: 109.
In some embodiments, the anti-NKG 2A antibody comprises V H, which V H comprises amino acid sequence SEQ ID NO 91 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 91, and V L, which V L comprises amino acid sequence SEQ ID NO 109 or a variant thereof, which variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 109. In some embodiments, the anti-NKG 2A antibody comprises V H, the V H comprises the amino acid sequence SEQ ID NO:91, and V L, the V L comprises the amino acid sequence SEQ ID NO:109.
In some embodiments, the amino acid substitutions described above are limited to the "exemplary substitutions" shown in table 4 herein. In some embodiments, amino acid substitutions are limited to the "preferred substitutions" shown in table 4 herein.
In some embodiments, the functional epitope can be resolved by combining alanine scanning methods. In this process, combinatorial alanine scanning techniques can be used to identify amino acids in the NKG2A protein that are necessary for interaction with anti-NKG 2A antibodies. In some embodiments, the epitope is conformational, and the crystal structure of an anti-NKG 2A antibody that binds to the NKG2A protein may be employed to identify the epitope.
In some embodiments, the application provides antibodies that compete with any of the anti-NKG 2A antibodies described herein for binding to NKG 2A. In some embodiments, antibodies are provided that are capable of competitively binding to an epitope on NKG2A with any of the anti-NKG 2A antibodies described herein. In some embodiments, anti-NKG 2A antibodies are provided that bind to the same epitope as an anti-NKG 2A antibody molecule comprising V H and V L, wherein said V H comprises the amino acid sequence set forth in any one of SEQ ID NOs:68-91, and said V L comprises the amino acid sequence set forth in any one of SEQ ID NOs: 92-109. In some embodiments, anti-NKG 2A antibodies are provided that competitively bind to NKG2A with anti-NKG 2A antibodies comprising V H and V L, wherein said V H comprises the amino acid sequence set forth in any one of SEQ ID NOs 68-91 and said V L comprises the amino acid sequence set forth in any one of SEQ ID NOs 92-109.
In some embodiments, competition experiments may be used to identify monoclonal antibodies that competitively bind to NKG2A with the anti-NKG 2A antibodies described herein. Competition experiments can determine whether two antibodies bind to the same epitope by recognizing the same or spatially overlapping epitopes or by one antibody competitively inhibiting the binding of the other antibody to the antigen. In certain embodiments, such a competing antibody binds to the same epitope as the antibodies described herein. Some exemplary competition experiments include, but are not limited to, routine experiments as mentioned in Harlow and Lane(1988)Antibodies:A Laboratory Manual ch.14(Cold Spring Harbor Laboratory,Cold Spring Harbor,N.Y.). A detailed exemplary method for resolving epitopes to which antibodies bind is described in Morris(1996)"Epitope Mapping Protocols,"in Methods in Molecular Biology vol.66(Humana Press,Totowa,N.J.). In some embodiments, each antibody is said to bind to the same epitope if it blocks 50% or more of the binding of the other antibody. In some embodiments, the antibody that competes with an anti-NKG 2A antibody described herein is a chimeric, humanized, or fully human antibody.
Exemplary anti-NKG 2A antibody sequences are shown in tables 2,3, with CDR numbering according to Kabat definition. Those skilled in the art will recognize that there are a variety of known algorithms to predict CDR positions and define antibody light and heavy chain variable regions. Antibodies comprising CDRs, V H, and/or V L sequences of antibodies as described herein, but based on predictive algorithms other than those exemplified in the tables below, are also within the scope of the application.
TABLE 2 exemplary anti-NKG 2A antibody CDR sequences
Table 3 exemplary sequences
NKG2A
NK cells are an indigenous lymphocyte that plays an important role as an immune whistle in combating "non-autologous" invasion of target cells. Peripheral blood NK cells account for about 10% -15% of all circulating lymphocytes, but they can also be isolated in different tissues including spleen, liver, lung and bone marrow. In adults, NK cells develop primarily from CD34 hematopoietic stem cells in the bone marrow, which interact with stromal cells in a cytokine-and growth factor-rich microenvironment, supporting NK cell development and maturation. NK cells migrate rapidly from the blood to inflamed tissues or secondary lymphoid organs for immune surveillance of pathogens and tumors. Unlike T and B cells, activation of NK cells does not require antigen sensitization, as NK cell effector function is controlled by limited NK cell activation receptors (aNKRs) and NK cell inhibition receptors (iNKRs). NK cells also produce and secrete chemokines and cytokines upon activation, which play a key role in promoting inflammatory responses and in initiating other cells in the immune system, such as dendritic cells or macrophages, linking innate immunity with adaptive immunity (Elisa Zaghi et al, 2018,J Leukoc Biol).
Activation of NK cells relies on the ability to distinguish "autologous" from "non-autologous" by recognition of Major Histocompatibility Complex (MHC) class I molecules by iNKRs family members. Indeed, the interaction of these receptors with haploid Human Leukocyte Antigen (HLA) class I molecules specific for the target cell surface is critical in determining NK cell's alloreactivity against "non-self". Currently, there are two classes of receptors that mediate mainly the recognition of "self," KIRs and lectin type C receptors. The C-lectin HLA-I specific receptor is represented by a CD94/NKG2 heterodimer, wherein CD94/NKG2A is an inhibitory receptor and contains an ITIM in the cytoplasmic domain, while CD94/NKG2C is an activating receptor and lacks an ITIM in the cytoplasmic domain and binds to the DAP-12 ligand. These receptors interact with non-classical HLA-E molecules. Although NKG2A and NKG2C recognize overlapping HLA-E molecules, inhibitory receptors exhibit higher binding affinity for their ligands, overcoming NK cell activation signals.
The NKG2A protein is encoded by the NKG2A gene in humans. NKG2A is also known as CD159 antigen-like family member A, NK cell receptor A, NKG a-activated NK receptor, NKG 2A/B-activated NK receptor, killer lectin-like receptor C1 (CD 159 a), and NKG2A/NKG2B type II integral membrane protein. NKG2A belongs to a member of the lectin receptor family, which also contains NKG2C, NKG D and NKG2E. NKG2A, NKG C and NKG2E have a high degree of homology in the amino acid sequences of their extracellular domains, whereas NKG2A is a functionally different type of receptor. NKG2A forms a heterodimer with CD94, of which NKG2/CD94 heterodimer, NKG2A/CD94 is the only receptor with inhibitory function, and NKG2C/CD94, and NKG2E/CD94 are activating receptors. NKG2D is also an activating receptor, but does not form a heterodimer with CD94, nor does NKG2D bind HLA-E.
NKG2A is expressed in natural killer cells (NK), effector/memory CD8, NKT cells, γδ T cells. About 50% of peripheral blood NK cells express NKG2A (Andre' et al, 1999; mahaptra et al, 2017; manser and Uhrberg, 2016), whose expression on NK cells can be up-regulated under stimulation by cytokines such as interleukin-15 (IL-15) (Brady et al, 2004; mori et al, 1998). In healthy humans, approximately 5% of human peripheral blood CD8+ T cells express cell surface NKG2A, but chronic antigen stimulation can up-regulate it (Bertone et al, 1999; mcMahon et al, 2002; mingari et al, 1998; shea et al, 2005).
The NKG2/CD94 receptor recognizes non-classical Major Histocompatibility (MHC) class I molecules, human leukocyte antigen-E (HLA-E) in humans and Qa-1 in mice. NKG2A/CD94 binds HLA-E with about 6-fold stronger affinity than NKG2C/CD 94. After binding to NKG2A, HLA-E molecule expressed on target cell has inhibiting effect on NK cell killing function. The N-terminal NK cell cytoplasmic domain of NKG2A protein contains 2 immunoreceptor tyrosine inhibition motifs (immunoreceptor tyrosine-based inhibitory motifs, ITIMs) which can transmit inhibition signals into NK cells and induce cascade inhibition signals, thereby inhibiting the effector functions of T cells and NK cells.
Studies have reported that blocking inhibitory NKG2A receptors can promote effector functions of NK cells and cd8+ T cells, thereby enhancing tumor immunity in mice and humans. Monalizumab is a humanized anti-NKG 2A antibody, which enhances the activity of NK cells against various tumor cells under the combined action of PD-x axis blocking and saves the functions of CD8+ T cells. Thus, targeting NKG2A is a novel checkpoint inhibition mechanism that promotes anti-tumor immunity by enhancing T-cell and NK cell activity.
NKG2A ligand HLA-E
The ligand of the heterodimer receptor NKG2A/CD94 is human HLA-E and its mouse homolog Qa-1b. These non-classical MHC class Ib molecules are conserved across the population and present signal peptides of classical MHC class I molecules (45). Polymorphic classical HLA class I molecules present antigenic peptide epitopes to TCRs on the surface of CD8T cells. In contrast, HLA-E is a single-state, non-classical HLA class I molecule that presents a limited set of conserved signal peptides. These signal peptides are derived from the leader sequence of classical HLA class I molecules. Both NKG2A and NKG2C form heterodimeric receptors with CD94 and target the same HLA-E tetramer complex, however NKG2A/CD94 induces an inhibitory signal for NKG2A upon binding to HLA-E and NKG2C/CD94 induces an activating signal for NKG2C upon binding to HLA-E. Importantly, the NKG2A/CD94 receptor has a strong signal peptide specificity, i.e.NKG 2A/CD94 preferentially binds HLA-E comprising signal peptides, especially HLA-E comprising conserved leader polypeptides, but not when these polypeptides are absent. Most HLA class I molecules share a common amino acid sequence VMAPRTLLL in the signal peptide region. Wherein positions 7 and 8 are varied between leucine and valine without affecting binding affinity.
Although basal cell surface levels of most tissues are low, HLA-E is highly expressed in immune-free regions of the body, including trophoblasts of placenta and ductal epithelial cells of testis and epididymis, suggesting that HLA-E has an effect against potential attack of CD8T cells and NK cells on partially HLA-mismatched fetal and haploid germ cells. In addition, expression of HLA-E or its mouse homologous gene Qa-1b protects tissue integrity during viral clearance and limits excessive activation and apoptosis of CD8T cells.
One of the strategies for tumor-transformed cells to evade NK cell immune surveillance is to down-regulate HLA, a mechanism also used by some viruses to evade lymphocyte cytotoxicity. However, certain types of cancers include renal cancer, acute Myeloid Leukemia (AML), and hepatocellular carcinoma, and are not completely devoid of HLA-I, even non-classical up-regulation of HLA-E and HLA-G expression. One possible explanation is that expression of HLA-I self molecules on tumor cells disrupts NK cell alloreactivity, thereby rendering cancer cells resistant to NK lysis. Experimental evidence supporting this hypothesis suggests that kidney cancer cells express HLA-E on the cell surface and are able to inhibit the effector function of tumor infiltrating NK cells by upregulating CD94/NKG2A heterodimers on NK cells. NK cells from AML patients have also been reported to exhibit reduced expression of the activation receptor NKp46, accompanied by increased NKG2A expression and impaired effector function. These phenotypes and dysfunctions may be mediated directly by tumor cells that express not only HLA-E on their surface, but also release soluble molecules that regulate NKRs (Elisa Zaghi et al, 2018,J Leukoc Biol).
Full-length anti-NKG 2A antibodies
In some embodiments, the anti-NKG 2A antibody is a full-length anti-NKG 2A antibody. In some embodiments, the full-length anti-NKG 2A antibody is IgA, igD, igE, igG or IgM. In some embodiments, the full length anti-NKG 2A antibody comprises an IgG constant region, e.g., a constant region of IgG1, igG2, igG3, igG4, or a variant thereof. In some embodiments, the full length anti-NKG 2A antibody comprises a lambda light chain constant region. In some embodiments, the full length anti-NKG 2A antibody comprises a kappa light chain constant region. In some embodiments, the full length anti-NKG 2A antibody is a full length human anti-NKG 2A antibody. In some embodiments, the full length anti-NKG 2A antibody comprises a mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-NKG 2A antibody comprises an Fc sequence that has been altered or otherwise altered such that it has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effector functions.
Thus, for example, in some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, which anti-NKG 2A antibody specifically binds NKG 2A. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG2 constant region is provided, which anti-NKG 2A antibody specifically binds NKG 2A. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG3 constant region is provided, which anti-NKG 2A antibody specifically binds NKG 2A. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, which anti-NKG 2A antibody specifically binds NKG 2A. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acids, a variant comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acids, a HC-CDR2 comprising an amino acid sequence of any of SEQ ID NOs 9-23, or a variant thereof, said variant comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acids, and a HC-CDR3 comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acids, a variant thereof, said variant comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acids, a substitution of any of at most about 3 (e.g., 1,2, or 3) amino acids, a variant thereof, a light chain variable domain comprising a substitution of LC-CDR1 comprising a substitution of at most about 42 (e.g., 1,2, or 3) amino acid, a substitution of any of at most about 3 (e.g., 1,2, or 3) amino acid, a variant thereof, comprising a substitution of any of amino acid sequence of at most about 3 (e.g., 1,2,3, or a variant thereof, amino acid, a sequence of any of amino acid comprising at most about 43). In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG2 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs 1-8 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 9-23 or a variant thereof comprising up to about 3 (e.g., 1,2 or 3) amino acid substitutions, and HC-CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 24-32 or a variant thereof comprising up to about 3 (e.g., 1,2 or 3) amino acid substitutions, and b) a light chain variable domain comprising LC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 33-42 or a variant thereof comprising up to about 3 (e.g., 1,2 or 3) amino acid substitutions, LC-CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 43-50 or a variant thereof comprising up to about 3 (e.g., 1,2 or 3) amino acid substitutions, and LC-CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 33-42 or a variant thereof comprising up to about 3 (e.g., 1,2 or a variant thereof). In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG3 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acids, a variant comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acids, a HC-CDR2 comprising an amino acid sequence of any of SEQ ID NOs 9-23, or a variant thereof, said variant comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acids, and a HC-CDR3 comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acids, a variant thereof, said variant comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acids, a substitution of any of at most about 3 (e.g., 1,2, or 3) amino acids, a variant thereof, a light chain variable domain comprising a substitution of LC-CDR1 comprising a substitution of at most about 3 (e.g., 1,2, or 3) amino acid, a substitution of any of at most about 3 (e.g., 1,2, or 3) amino acid, a variant thereof, comprising a substitution of any of at most about 3 (e.g., 1,2,3, or a variant thereof, amino acid, a sequence of amino acid, e.g., at most about 43, or a variant thereof). In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs 1-8 or a variant thereof comprising up to about 3 (e.g., 1,2, or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 9-23 or a variant thereof comprising up to about 3 (e.g., 1,2 or 3) amino acid substitutions, and HC-CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 24-32 or a variant thereof comprising up to about 3 (e.g., 1,2 or 3) amino acid substitutions, and b) a light chain variable domain comprising LC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 33-42 or a variant thereof comprising up to about 3 (e.g., 1,2 or 3) amino acid substitutions, LC-CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 43-50 or a variant thereof comprising up to about 3 (e.g., 1,2 or 3) amino acid substitutions, and LC-CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 33-42 or a variant thereof comprising up to about 3 (e.g., 1,2 or a variant thereof). In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising a substitution of up to about 5 (e.g., 1,2,3,4, or 5) amino acids in the HC-CDR sequence comprising an amino acid sequence as set forth in any one of SEQ ID NOs 1-8, HC-CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 9-23, and HC-CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 24-32, or a variant of the heavy chain variable domain comprising a substitution of up to about 5 (e.g., 1,2,3,4, or 5) amino acids in the HC-CDR sequence, and b) a light chain variable domain comprising an LC-CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 43-23, and an LC-CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs 43-23, and a variant of up to about 51, e.g., a substitution of up to about 5 amino acids in the amino acid sequence as set forth in any one of SEQ ID NOs 4-42, or a variant thereof. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising a substitution of up to about 5 (e.g., 1,2,3,4, or 5) amino acids in the HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs 1-8, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 9-23, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs 24-32, or a variant of the heavy chain variable domain comprising a substitution of up to about 5 (e.g., 1,2,3,4, or 5) amino acids in the HC-CDR sequence, and b) a light chain variable domain comprising LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs 33-42, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 43-50, and up to about 64, or a variant of amino acid sequence comprising up to about 51, e.g., 4, or a variant of amino acid sequence comprising up to about 51, e.g., 1, 4, or a variant of amino acid sequence. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs:1-8, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:9-23, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs:24-32, and b) a light chain variable domain comprising LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs:33-42, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:43-50, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 51-64. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs:1-8, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:9-23, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs:24-32, and b) a light chain variable domain comprising LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs:33-42, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:43-50, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 51-64. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, and b) a light chain variable domain comprising the amino acid sequence LC-CDR1 comprising the amino acid sequence SEQ ID NO:43, LC-CDR2 comprising the amino acid sequence SEQ ID NO:51. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, and b) a light chain variable domain comprising the amino acid sequence LC-CDR1 comprising the amino acid sequence SEQ ID NO:43, LC-CDR2 comprising the amino acid sequence SEQ ID NO:52. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, and b) a light chain variable domain comprising the amino acid sequence LC-CDR1 comprising the amino acid sequence SEQ ID NO:43, LC-CDR2 comprising the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:54. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:13, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:14, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:15, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:16, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:57. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:35, LC-CDR2 comprising amino acid sequence SEQ ID NO:45, and LC-CDR3 comprising amino acid sequence SEQ ID NO:51. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:17, and HC-CDR3 comprising amino acid sequence SEQ ID NO:26, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:36, LC-CDR2 comprising amino acid sequence SEQ ID NO:46, and LC-CDR3 comprising amino acid sequence SEQ ID NO:58. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising amino acid sequence SEQ ID NO:27, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:37, LC-CDR2 comprising amino acid sequence SEQ ID NO:47, and LC-CDR3 comprising amino acid sequence SEQ ID NO:59. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:4, HC-CDR2 comprising amino acid sequence SEQ ID NO:19, and HC-CDR3 comprising amino acid sequence SEQ ID NO:28, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:38, LC-CDR2 comprising amino acid sequence SEQ ID NO:48, and LC-CDR3 comprising amino acid sequence SEQ ID NO:60. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:5, HC-CDR2 comprising amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising amino acid sequence SEQ ID NO:29, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:39, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:61. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:6, HC-CDR2 comprising amino acid sequence SEQ ID NO:21, and HC-CDR3 comprising amino acid sequence SEQ ID NO:30, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:40, LC-CDR2 comprising amino acid sequence SEQ ID NO:49, and LC-CDR3 comprising amino acid sequence SEQ ID NO:62. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:7, HC-CDR2 comprising amino acid sequence SEQ ID NO:22, and HC-CDR3 comprising amino acid sequence SEQ ID NO:31, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:41, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:63. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:8, HC-CDR2 comprising amino acid sequence SEQ ID NO:23, and HC-CDR3 comprising amino acid sequence SEQ ID NO:32, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:42, LC-CDR2 comprising amino acid sequence SEQ ID NO:50, and LC-CDR3 comprising amino acid sequence SEQ ID NO:64. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, and b) a light chain variable domain comprising the amino acid sequence LC-CDR1 comprising the amino acid sequence SEQ ID NO:43, LC-CDR2 comprising the amino acid sequence SEQ ID NO:51. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, and b) a light chain variable domain comprising the amino acid sequence LC-CDR1 comprising the amino acid sequence SEQ ID NO:43, LC-CDR2 comprising the amino acid sequence SEQ ID NO:52. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, and b) a light chain variable domain comprising the amino acid sequence LC-CDR1 comprising the amino acid sequence SEQ ID NO:43, LC-CDR2 comprising the amino acid sequence SEQ ID NO:53. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:54. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:13, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:14, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:15, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:16, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:57. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:35, LC-CDR2 comprising amino acid sequence SEQ ID NO:45, and LC-CDR3 comprising amino acid sequence SEQ ID NO:51. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:17, and HC-CDR3 comprising amino acid sequence SEQ ID NO:26, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:36, LC-CDR2 comprising amino acid sequence SEQ ID NO:46, and LC-CDR3 comprising amino acid sequence SEQ ID NO:58. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising amino acid sequence SEQ ID NO:27, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:37, LC-CDR2 comprising amino acid sequence SEQ ID NO:47, and LC-CDR3 comprising amino acid sequence SEQ ID NO:59. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:4, HC-CDR2 comprising amino acid sequence SEQ ID NO:19, and HC-CDR3 comprising amino acid sequence SEQ ID NO:28, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:38, LC-CDR2 comprising amino acid sequence SEQ ID NO:48, and LC-CDR3 comprising amino acid sequence SEQ ID NO:60. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:5, HC-CDR2 comprising amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising amino acid sequence SEQ ID NO:29, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:39, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:61. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:6, HC-CDR2 comprising amino acid sequence SEQ ID NO:21, and HC-CDR3 comprising amino acid sequence SEQ ID NO:30, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:40, LC-CDR2 comprising amino acid sequence SEQ ID NO:49, and LC-CDR3 comprising amino acid sequence SEQ ID NO:62. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:7, HC-CDR2 comprising amino acid sequence SEQ ID NO:22, and HC-CDR3 comprising amino acid sequence SEQ ID NO:31, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:41, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:63. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a) a heavy chain variable domain comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:8, HC-CDR2 comprising amino acid sequence SEQ ID NO:23, and HC-CDR3 comprising amino acid sequence SEQ ID NO:32, and b) a light chain variable domain comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:42, LC-CDR2 comprising amino acid sequence SEQ ID NO:50, and LC-CDR3 comprising amino acid sequence SEQ ID NO:64. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a heavy chain variable domain (V H) comprising an amino acid sequence set forth in any one of SEQ ID NOs:68-91, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs:68-91, and a light chain variable domain (V L) comprising an amino acid sequence set forth in any one of SEQ ID NOs:92-109, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 92-109. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG2 constant region is provided, wherein the anti-NKG 2A antibody comprises a heavy chain variable domain (V H) comprising an amino acid sequence set forth in any one of SEQ ID NOs:68-91, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs:68-91, and a light chain variable domain (V L) comprising an amino acid sequence set forth in any one of SEQ ID NOs:92-109, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 92-109. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG3 constant region is provided, wherein the anti-NKG 2A antibody comprises a heavy chain variable domain (V H) comprising an amino acid sequence set forth in any one of SEQ ID NOs:68-91, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs:68-91, and a light chain variable domain (V L) comprising an amino acid sequence set forth in any one of SEQ ID NOs:92-109, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 92-109. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a heavy chain variable domain (V H) comprising an amino acid sequence set forth in any one of SEQ ID NOs:68-91, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs:68-91, and a light chain variable domain (V L) comprising an amino acid sequence set forth in any one of SEQ ID NOs:92-109, or a variant thereof, having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 92-109. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises a heavy chain variable domain (V H), said V H comprising the amino acid sequence set forth in any one of SEQ ID NOs:68-91, and a light chain variable domain (V L), said V L comprising the amino acid sequence set forth in any one of SEQ ID NOs: 92-109. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises a heavy chain variable domain (V H), said V H comprising the amino acid sequence set forth in any one of SEQ ID NOs:68-91, and a light chain variable domain (V L), said V L comprising the amino acid sequence set forth in any one of SEQ ID NOs: 92-109. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:68, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:68, and V L comprising the amino acid sequence SEQ ID NO:92, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 92. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO:69, or a variant thereof, that has at least about 80% sequence identity to amino acid sequence SEQ ID NO:69, and V L comprising amino acid sequence SEQ ID NO:93, or a variant thereof, that has at least about 80% sequence identity to amino acid sequence SEQ ID NO: 93. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 70, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 70, and V L comprising the amino acid sequence SEQ ID NO 93, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 93. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:69, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO:69, and V L comprising the amino acid sequence SEQ ID NO:94, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 94. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 70, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 70, and V L comprising the amino acid sequence SEQ ID NO 94, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 94. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO 71 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 71, and V L comprising amino acid sequence SEQ ID NO 95 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 95. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:72, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:72, and V L comprising the amino acid sequence SEQ ID NO:96, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 96. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO:73 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:73, and V L comprising amino acid sequence SEQ ID NO:97 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 97. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 74, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO 74, and V L comprising the amino acid sequence SEQ ID NO 97, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 75, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 75, and V L comprising the amino acid sequence SEQ ID NO 97, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 76, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 76, and V L comprising the amino acid sequence SEQ ID NO 97, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 77 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 77, and V L comprising the amino acid sequence SEQ ID NO 97 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:78 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L comprising the amino acid sequence SEQ ID NO:97 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 97. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO:73 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:73, and V L comprising amino acid sequence SEQ ID NO:98 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 98. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 74, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO 74, and V L comprising the amino acid sequence SEQ ID NO 98, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO 98. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 75, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 75, and V L comprising the amino acid sequence SEQ ID NO 98, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 98. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:76, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO:76, and V L comprising the amino acid sequence SEQ ID NO:98, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 98. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:77 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:77, and V L comprising the amino acid sequence SEQ ID NO:98 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 98. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:78, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L comprising the amino acid sequence SEQ ID NO:98, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 98. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:78 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L comprising the amino acid sequence SEQ ID NO:99 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 99. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:78, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L comprising the amino acid sequence SEQ ID NO:100, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 100. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:79 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:79, and V L comprising the amino acid sequence SEQ ID NO:100 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 100. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 80, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 80, and V L comprising the amino acid sequence SEQ ID NO 100, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 100. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:81 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:81, and V L comprising the amino acid sequence SEQ ID NO:99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 99. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:82 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:82, and V L comprising the amino acid sequence SEQ ID NO:99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 99. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO 83 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 83, and V L comprising amino acid sequence SEQ ID NO 99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 99. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 84, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 84, and V L comprising the amino acid sequence SEQ ID NO 99, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 99. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:79 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:79, and V L comprising the amino acid sequence SEQ ID NO:99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 99. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 80, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 80, and V L comprising the amino acid sequence SEQ ID NO 99, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 99. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:78 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L comprising the amino acid sequence SEQ ID NO:101 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 101. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:68, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:68, and V L comprising the amino acid sequence SEQ ID NO:102, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 102. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:85, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO:85, and V L comprising the amino acid sequence SEQ ID NO:103, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 103. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 86 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 86, and V L comprising the amino acid sequence SEQ ID NO 104 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 104. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO 87 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 87, and V L comprising amino acid sequence SEQ ID NO 105 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 105. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 88 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 88, and V L comprising the amino acid sequence SEQ ID NO 106 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 106. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:89 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:89, and V L comprising the amino acid sequence SEQ ID NO:107 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 107. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 90, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 90, and V L comprising the amino acid sequence SEQ ID NO 108, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 108. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG1 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO 91 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 91, and V L comprising amino acid sequence SEQ ID NO 109 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 109. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:68, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:68, and V L comprising the amino acid sequence SEQ ID NO:92, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 92. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO:69, or a variant thereof, that has at least about 80% sequence identity to amino acid sequence SEQ ID NO:69, and V L comprising amino acid sequence SEQ ID NO:93, or a variant thereof, that has at least about 80% sequence identity to amino acid sequence SEQ ID NO: 93. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 70, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 70, and V L comprising the amino acid sequence SEQ ID NO 93, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 93. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO:69, or a variant thereof, that has at least about 80% sequence identity to amino acid sequence SEQ ID NO:69, and V L comprising amino acid sequence SEQ ID NO:94, or a variant thereof, that has at least about 80% sequence identity to amino acid sequence SEQ ID NO: 94. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 70, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 70, and V L comprising the amino acid sequence SEQ ID NO 94, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 94. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO 71 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 71, and V L comprising amino acid sequence SEQ ID NO 95 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 95. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:72, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:72, and V L comprising the amino acid sequence SEQ ID NO:96, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 96. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO:73 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:73, and V L comprising amino acid sequence SEQ ID NO:97 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 97. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 74, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO 74, and V L comprising the amino acid sequence SEQ ID NO 97, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 75, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 75, and V L comprising the amino acid sequence SEQ ID NO 97, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 76, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 76, and V L comprising the amino acid sequence SEQ ID NO 97, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 77 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 77, and V L comprising the amino acid sequence SEQ ID NO 97 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:78 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L comprising the amino acid sequence SEQ ID NO:97 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 97. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO:73 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:73, and V L comprising amino acid sequence SEQ ID NO:98 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 98. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 74, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO 74, and V L comprising the amino acid sequence SEQ ID NO 98, or a variant thereof, which has at least about 80% sequence identity to amino acid sequence SEQ ID NO 98. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 75, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 75, and V L comprising the amino acid sequence SEQ ID NO 98, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 98. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:76, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO:76, and V L comprising the amino acid sequence SEQ ID NO:98, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 98. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:77 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:77, and V L comprising the amino acid sequence SEQ ID NO:98 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 98. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:78, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L comprising the amino acid sequence SEQ ID NO:98, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 98. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:78 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L comprising the amino acid sequence SEQ ID NO:99 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:78, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L comprising the amino acid sequence SEQ ID NO:100, or a variant thereof, which has at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 100. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:79 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:79, and V L comprising the amino acid sequence SEQ ID NO:100 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 100. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 80, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 80, and V L comprising the amino acid sequence SEQ ID NO 100, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 100. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:81 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:81, and V L comprising the amino acid sequence SEQ ID NO:99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:82 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:82, and V L comprising the amino acid sequence SEQ ID NO:99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO 83 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 83, and V L comprising amino acid sequence SEQ ID NO 99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 84, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 84, and V L comprising the amino acid sequence SEQ ID NO 99, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:79 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:79, and V L comprising the amino acid sequence SEQ ID NO:99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 80, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 80, and V L comprising the amino acid sequence SEQ ID NO 99, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:78 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:78, and V L comprising the amino acid sequence SEQ ID NO:101 or a variant thereof, said variant having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 101. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:68, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:68, and V L comprising the amino acid sequence SEQ ID NO:102, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence SEQ ID NO: 102. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:85, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO:85, and V L comprising the amino acid sequence SEQ ID NO:103, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 103. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 86, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 86, and V L comprising the amino acid sequence SEQ ID NO 104, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 104. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO 87 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 87, and V L comprising amino acid sequence SEQ ID NO 105 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 105. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 88, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 88, and V L comprising the amino acid sequence SEQ ID NO 106, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 106. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO:89 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:89, and V L comprising the amino acid sequence SEQ ID NO:107 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 107. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising the amino acid sequence SEQ ID NO 90, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 90, and V L comprising the amino acid sequence SEQ ID NO 108, or a variant thereof, having at least about 80% sequence identity to amino acid sequence SEQ ID NO 108. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
In some embodiments, a full length anti-NKG 2A antibody comprising an IgG4 constant region is provided, wherein the anti-NKG 2A antibody comprises V H comprising amino acid sequence SEQ ID NO 91 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 91, and V L comprising amino acid sequence SEQ ID NO 109 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 109. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 112. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:111 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 113.
Binding affinity
Binding affinity is expressed in Kd, koff, kon or Ka. As used herein, the term Koff refers to the rate constant of dissociation of an antibody from an antigen/antibody complex, as determined by a kinetic selection device. The term Kon refers to the binding rate constant of an antibody to an antigen to form an antigen/antibody complex. The equilibrium dissociation constant Kd as used herein refers to the dissociation constant at which a particular antibody antigen interacts, meaning that in a solution of an antibody molecule, the antigen occupies half of all antibody binding sites and the concentration of antigen required to reach equilibrium is equal to Koff/Kon. Determination of Kd assumes that all binding molecules are in solution. In the case of antibody attachment to the cell wall, for example in yeast expression systems, the corresponding equilibrium dissociation rate constant is expressed in EC 50, which is a good approximation of Kd. The affinity binding constant Ka is the inverse of the dissociation constant Kd.
The dissociation constant (Kd) can be used as an indicator of the affinity of the reactive antibody moiety for the antigen. For example, the interactions between biomolecules can be analyzed by Scatchard method using antibodies labeled with various markers, and Biacore instrument (manufactured by Amersham Biosciences) according to user manual or attached kit, by surface plasmon resonance. The Kd values obtained using these methods are expressed in units M. Antibodies that specifically bind to a target may have, for example, kd values of 10 - 7M、≤10-8M、≤10-9M、≤10-10M、≤10-11M、≤10-12 M or 10 -13 M.
The binding specificity of an antibody can be determined experimentally by methods known in the art. These methods include, but are not limited to, western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore assays, peptide scans, and the like.
In some embodiments, the anti-NKG 2A antibody specifically binds to the NKG2A target with a Kd value of 10 -7 M to 10 - 13 M (e.g., 10 -7 M to 10 -13M、10-8 M to 10 -13M、10-9 M to 10 -13 M or 10 -10 M to 10 -12 M). Thus, in some embodiments, the Kd value of the binding between an anti-NKG 2A antibody and NKG2A is 10 -7 M to 10 -13M、1×10- 7 M to 5×10 -13M、10-7 M to 10 -12M、10-7 M to 10 -11M、10-7 M to 10 -10M、10-7 M to 10 -9M、10-8 M to 10 -13M、1×10-8 M to 5×10 -13M、10-8 M to 10 -12M、10-8 M to 10 -11M、10-8 M to 10 - 10M、10-8 M to 10 -9M、5×10-9 M to 1×10 -13M、5×10-9 M to 1×10 -12M、5×10-9 M to 1×10 - 11M、5×10-9 M to 1×10 -10M、10-9 M to 10 -13M、10-9 M to 10 -12M、10-9 M to 10 -11M、10-9 M to 10 -10M、5×10-10 M to 1×10 -13M、5×10-10 M to 1×10 -12M、5×10-10 M to 1×10 -11M、10-10 M to 10 -13M、1×10-10 M to 5×10 -13M、1×10-10 M to 1×10 -12M、1×10-10 M to 5×10 -12M、1×10-10 M to 1×10 -11M、10-11 M to 10 -13M、1×10-11 M to 5×10 -13M、10-11 M to 10 -12M、10-12 M to 10 - 13 M. In some embodiments, the Kd value of the binding between an anti-NKG 2A antibody and NKG2A is 10 -7 M to 10 -13 M.
In some embodiments, the Kd value of binding between an anti-NKG 2A antibody and a non-target is higher than the Kd value of the anti-NKG 2A antibody to the target, and in some embodiments cited herein, the binding affinity of the anti-NKG 2A antibody to the target (e.g., NKG 2A) is higher than the binding affinity of the anti-NKG 2A antibody to the non-target. In some embodiments, non-target refers to an antigen other than NKG 2A. In some embodiments, the anti-NKG 2A antibody (against NKG 2A) differs by at least a factor of 10, e.g., 10-100, 100-1000, 10 3-104, 10 4-105, 10 5-106, 10 6-107, 10 7-108, 10 8-109, 10 9-1010, 10 10-1011, 10 11-1012, between Kd values for binding to a non-NKG 2A target.
In some embodiments, the anti-NKG 2A antibody binds to a non-target with a Kd value of 10 -1 M to 10 -6 M (e.g., 10 - 1 M to 10 -6M、10-1 M to 10 -5M、10-2 M to 10 -4 M). in some embodiments, the non-target refers to an antigen other than NKG 2A. Thus, in some embodiments, the Kd value of binding between an anti-NKG 2A antibody and a non-NKG 2A target is 10 -1 M to 10 -6M、1×10-1 M to 5×10 -6M、10-1 M to 10 -5M、1×10-1 M to 5×10 -5M、10-1 M to 10 -4M、1×10-1 M to 5×10 -4M、10-1 M to 10 -3M、1×10-1 M to 5×10 -3M、10-1 M to 10 -2M、10-2 M to 10 -6M、1×10-2 M to 5×10 -6M、10-2 M to 10 -5M、1×10-2 M to 5×10 -5M、10-2 M to 10 -4M、1×10-2 M to 5×10 -4M、10-2 M to 10 -3M、10-3 M to 10 -6M、1×10-3 M to 5×10 -6M、10-3 M to 10 -5M、1×10-3 M to 5×10 -5M、10-3 M to 10 -4M、10-4 M to 10 -6M、1×10-4 M to 5×10 -6M、10-4 M to 10 -5M、10-5 M to 10 -6 M.
In some embodiments, when referring to an anti-NKG 2A antibody specifically recognizing an NKG2A target with high binding affinity and binding to a non-target with low binding affinity, the anti-NKG 2A antibody binds to the NKG2A target with a Kd value of 10 -7 M to 10 -13 M (e.g., 10 -7 M to 10 -13M、10-8 M to 10 -13M、10-9 M to 10 -13M、10-10 M to 10 -12 M) and with a Kd value of 10 -1 M to 10 -6 M (e.g., 10 -1 M to 10 -6M、10-1 M to 10 -5M、10-2 M to 10 -4 M).
In some embodiments, when referring to an anti-NKG 2A antibody specifically recognizing NKG2A, the binding affinity of the anti-NKG 2A antibody is compared to the binding affinity of a control anti-NKG 2A antibody (e.g., monalizumab). In some embodiments, the Kd value of the binding between a control anti-NKG 2A antibody and NKG2A may be at least 2-fold, e.g., 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 100-1000-fold, 10- 3-104 -fold, of the Kd value of the binding between an anti-NKG 2A antibody and NKG2A described herein.
Nucleic acid
Nucleic acid molecules encoding anti-NKG 2A antibodies are also contemplated. In some embodiments, a nucleic acid (or set of nucleic acids) encoding a full-length anti-NKG 2A antibody is provided, including any of the full-length anti-NKG 2A antibodies described herein. In some embodiments, a nucleic acid (or a set of nucleic acids) of an anti-NKG 2A antibody described herein may also include a nucleic acid sequence encoding a polypeptide tag (e.g., a protein purification tag, his tag, HA tag).
Also contemplated herein are isolated host cells comprising an anti-NKG 2A antibody, isolated nucleic acids encoding an anti-NKG 2A antibody polypeptide component, or vectors comprising nucleic acids encoding an anti-NKG 2A antibody polypeptide component described herein.
The application also includes variants of these nucleic acid sequences. For example, variants include nucleotide sequences that hybridize under at least moderately stringent hybridization conditions to nucleic acid sequences encoding an anti-NKG 2A antibody of the application.
The application also provides vectors into which the nucleic acid sequences of the application can be inserted.
Briefly, a natural or synthetic nucleic acid encoding an anti-NKG 2A antibody may be inserted into a suitable expression vector such that the nucleic acid is operably linked to 5' and 3' regulatory elements, including, for example, promoters (e.g., lymphocyte-specific promoters) and 3' untranslated regions (UTRs), to express the anti-NKG 2A antibody (e.g., full-length anti-NKG 2A antibody). The vectors may be suitable for replication and integration in eukaryotic host cells. Typical cloning and expression vectors contain transcriptional and translational terminators, initiation sequences, and promoters that regulate the expression of a nucleic acid sequence of interest.
The nucleic acids of the application can also be used for nucleic acid immunization and gene therapy by using standard gene delivery protocols. Nucleic acid delivery methods are known in the art. See, for example, U.S. Pat. nos.5,399,346, 5,580,859, 5,589,466, the entire contents of which are incorporated herein by reference. In some embodiments, the application also provides gene therapy vectors.
Nucleic acids can be cloned into many types of vectors. For example, the nucleic acid may be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe-generating vectors and sequencing vectors.
In addition, the expression vector may be provided to the cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Green and Sambrook(2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York), and other virology or molecular biology manuals. Viruses that may be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses. In general, suitable vectors include an origin of replication, promoter sequences, convenient restriction enzyme sites, and one or more selectable markers that function in at least one organism (see, e.g., WO 01/96584; WO 01/29058; and U.S. Pat.No.6,326,193).
Many virus-based systems have been developed for transferring genes into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. The selected gene may be inserted into a vector and packaged into retroviral particles using techniques known in the art. The recombinant virus is then isolated and delivered to cells of the subject in vivo or in vitro. Many retroviral systems are known in the art. In some embodiments, an adenovirus vector is used. Many adenoviral vectors are known in the art. In some embodiments, lentiviral vectors are used. Retroviral-derived vectors, such as lentiviruses, are suitable tools for achieving long-term gene transfer, as they allow for long-term stable integration of the transgene and propagation in daughter cells. Lentiviral vectors have additional advantages over retroviruses derived from tumors, such as the mouse leukemia virus, in that they can transduce non-dividing cells, such as hepatocytes. At the same time, it has the additional advantage of low immunogenicity.
Other promoter elements, e.g., enhancers, regulate the transcription initiation frequency. Typically they are located 30-110bp upstream of the start site, although many promoters have recently been found to contain functional elements downstream of the start site as well. The spacing between promoter elements is generally flexible so that the function of the promoter is maintained when the elements are interchanged or moved in position relative to each other. In the thymidine kinase (tk) promoter, the increase in the spacing between promoter elements to 50bp activity begins to decrease.
One example of a suitable promoter is the immediate early Cytomegalovirus (CMV) promoter sequence. The promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operably linked thereto. Another example of a suitable promoter is the elongation factor 1 alpha (EF-1 alpha) promoter. However, other constitutive promoters may also be used, including but not limited to simian virus 40 (SV 40) early promoter, mouse Mammary Tumor Virus (MMTV), human immunodeficiency virus long terminal repeat (HIV-LTR) promoter, moMuLV promoter, avian leukemia virus promoter, epstein-Barr virus immediate early promoter, rous sarcoma virus promoter, and human gene promoters including, for example, but not limited to, actin promoter, myosin promoter, hemoglobin promoter, and creatine kinase promoter. Furthermore, the application should not be limited to the use of constitutive promoters alone, and inducible promoters are also contemplated by the application. The use of an inducible promoter provides a molecular switch that enables expression of the polynucleotide sequence to which it is operably linked when such expression is desired and turns off expression when not desired. Inducible promoters include, but are not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.
In some embodiments, expression of the anti-NKG 2A antibody is inducible. In some embodiments, the nucleic acid sequence encoding an anti-NKG 2A antibody is operably linked to an inducible promoter, including any of the inducible promoters described herein.
Inducible promoter
The use of an inducible promoter provides a molecular switch that can initiate expression of a polynucleotide sequence operably linked thereto when expression is desired and which can shut down expression when expression is not desired. Exemplary inducible promoters suitable for use in eukaryotic cells include, but are not limited to, hormone regulatory elements (see, e.g., mader, s.and White, j.h. (1993) proc.Natl.Acad.Sci.USA 90:5603-5607), synthetic ligand regulatory elements (see, spencer, d.m.et al (1993) Science 262:1019-1024), and ionizing radiation regulatory elements (see, Manome,Y.et al.(1993)Biochemistry 32:10607-10613;Datta,R.et al.(1992)Proc.Natl.Acad.Sci.USA 89:1014-10153). other exemplary inducible promoters suitable for use in mammalian systems in vivo or in vitro see GINGRICH ET al. (1998) Annual rev.neurosci 21:377-405. In some embodiments, the inducible promoter system for expression of anti-NKG 2A antibodies is the Tet system, in some embodiments, the inducible promoter system for expression of anti-NKG 2A antibodies is the E.coli inhibition system.
One exemplary inducible promoter system employed in the present application is the Tet system. The system is based on the Tet system described by golden et al (1993). In one exemplary embodiment, the target polynucleotide is controlled by a promoter comprising one or more Tet operator (TetO) sites. In the inactive state, the Tet repressor (TetR) binds to the TetO site and inhibits transcription of the promoter. In the activated state, for example, in the presence of an inducer such as tetracycline (Tc), anhydrous tetracycline, doxycycline (Dox), or an active analog thereof, the inducer will release TetR from TetO, resulting in transcription. Doxycycline is a member of the tetracycline antibiotic family under the chemical name 1-dimethylamino-2, 4a,5, 7-pentahydroxy-11-methyl-4, 6-dioxo-1, 4a,11 a,12 a-hexahydrotetraene-3-carboxamide.
In one embodiment, tetR is codon optimized for expression in mammalian cells, such as mouse or human cells. Because of the degeneracy of the genetic code, most amino acids are encoded by more than one codon, such that the sequence of a given nucleic acid has a large number of variants without any change in the amino acid sequence encoded thereby. However, many organisms differ in codon usage, also known as "codon preference" (i.e., the preference of a given amino acid to use a particular codon). Codon preference is generally related to the presence of dominant tRNA species for a particular codon, which in turn increases the efficiency of mRNA translation. Coding sequences derived from a particular species (e.g., prokaryotes) can thus be tailored by codon optimization to enhance their expression in a different species (e.g., eukaryotes).
Other specific variations of the Tet system include the following "Tet-Off" and "Tet-On" systems. In the Tet-off system, transcription is inactive in the presence of Tc or Dox. In this system, the tetracycline-regulated transcriptional activator protein (tTA), consisting of TetR fused to the strong transcriptional activation domain of the herpes simplex virus VP16, regulates expression of the target nucleic acid under the transcriptional control of the tetracycline responsive promoter element (TRE). The TRE element consists of a TetO sequence tandem fused to a promoter (typically the smallest promoter sequence derived from the human cytomegalovirus immediate early promoter). In the absence of Tc or Dox, tTA binds to TRE and activates transcription of the target gene. In the presence of Tc or Dox, tTA cannot bind to TRE and the target gene cannot be expressed.
In contrast, in the Tet-On system, transcription is active in the presence of Tc or Dox. The Tet-On system is based On the reverse tetracycline regulated transcriptional activator rtTA. Like tTA, rtTA is a fusion protein consisting of the TetR repressor and VP16 transcriptional activation domain. However, a 4 amino acid change in the DNA binding region of TetR alters the binding properties of rtTA such that it recognizes only the tetO sequence on the target transgenic TRE in the presence of Dox. Therefore in the Tet-On system rtTA activates the transcription of the target gene regulated by TRE only in the presence of Dox.
Another inducible promoter system is the E.coli lac repressor system (see Brown et al, cell 49:603-612 (1987)). The Lac repressor system functions by regulating transcription of a polynucleotide of interest operably linked to a promoter comprising the Lac operator (lacO). The Lac repressor (lacR) binds to LacO and thereby prevents transcription of the target polynucleotide. Expression of the polynucleotide of interest is induced by a suitable inducer, for example isopropyl- β -D thiogalactopyranoside (IPTG).
To assess the expression of the polypeptide or portion thereof, the expression vector to be introduced into the cell may further comprise a selectable marker gene or a reporter gene or both to facilitate identification and selection of the expressing cell from a population of cells transfected or infected with the viral vector. In other aspects, the selectable marker may be carried on separate DNA fragments and used in a co-transfection experiment. Either the selectable marker gene or the reporter gene may be flanked by appropriate regulatory sequences to enable expression in the host cell. Useful selectable markers include, for example, antibiotic resistance genes, such as neo and the like.
Reporter genes can be used to identify potentially transfected cells and evaluate the function of regulatory sequences. Typically, a reporter gene is a gene that is not present in or expressed by a recipient organism or tissue, and encodes a polypeptide whose expression is manifested by some readily detectable property, such as enzymatic activity. After the DNA is introduced into the recipient cell, the expression of the reporter gene is detected at an appropriate time. Suitable reporter genes may include genes encoding luciferases, beta-galactosidases, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or green fluorescent protein (see Ui-Tel et al, 2000 FEBS Letters 479:79-82). Suitable expression systems are well known and may be prepared by known techniques or obtained commercially. In general, constructs that display the smallest 5' flanking region of the highest expression level of the reporter gene are considered promoters. Such promoter regions may be linked to reporter genes and used to assess the ability of certain substances to regulate promoter-driven transcription.
In some embodiments, nucleic acids encoding any of the full-length anti-NKG 2A antibodies described herein are provided. In some embodiments, the nucleic acid comprises one or more nucleic acid sequences encoding the heavy and light chains of a full length anti-NKG 2A antibody. In some embodiments, each of the one or more nucleic acid sequences is contained in a separate vector. In some embodiments, at least some of the nucleic acid sequences are contained in the same vector. In some embodiments, all nucleic acid sequences are contained in the same vector. The vector may be selected from, for example, mammalian expression vectors and viral vectors (such as vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses and lentiviruses).
Methods for introducing and expressing genes into cells are known in the art. In the context of expression vectors, the vector may be readily introduced into a host cell, such as a mammalian cell, bacterial, yeast or insect cell, by any method known in the art. For example, the expression vector may be introduced into the host cell by physical, chemical or biological means.
Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, lipofection, gene gun methods, microinjection, electroporation, and the like. Methods for preparing cells comprising vectors and/or exogenous nucleic acids are well known in the art. See, e.g., Green and Sambrook(2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York). in some embodiments, the polynucleotide is introduced into the host cell by calcium phosphate transfection.
Biological methods for introducing polynucleotides of interest into host cells include the use of DNA and RNA vectors. Viral vectors, particularly retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells. Other viral vectors may be derived from lentiviruses, poxviruses, herpes simplex virus type 1, adenoviruses, adeno-associated viruses, and the like. See, e.g., U.S. Pat. nos.5,350,674 and 5,585,362.
Chemical methods for introducing polynucleotides into host cells include colloidal dispersion systems, such as macromolecular complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system used as a delivery vehicle in vivo and in vitro is a liposome (e.g., an artificial membrane vesicle).
In the case of non-viral delivery systems, an exemplary delivery vehicle is a liposome. The use of lipid formulations to introduce nucleic acids into host cells (in vitro, ex vivo or in vivo) is contemplated. In another aspect, the nucleic acid may be conjugated to a lipid. The lipid-bound nucleic acid may be entrapped within the aqueous interior of the liposome, dispersed within the lipid bilayer of the liposome, linked to the liposome by a linking molecule that binds to the liposome and the oligonucleotide, entrapped in the liposome, formed a complex with the liposome, dispersed in a solution containing the lipid, mixed with the lipid, bound to the lipid, suspended in the lipid, contained in or mixed with the micelle, or otherwise bound to the lipid. The lipid, lipid/DNA or lipid/expression vector-related composition is not limited to any particular structure in solution. For example, they may exist in a bilayer structure, in micelles, or in a "collapsed" structure. They may also be simply dispersed in solution, possibly forming aggregates of non-uniform size or shape. Lipids are fatty substances, which may be naturally occurring or synthetic. For example, lipids include fat droplets naturally occurring in the cytoplasm, as well as a class of compounds containing long chain aliphatic hydrocarbons and derivatives thereof, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.
Regardless of the method used to introduce exogenous nucleic acid into a host cell or otherwise expose the cell to the inhibitors of the application, various experiments can be performed in order to confirm the presence of the recombinant DNA sequence in the host cell. Such assays include, for example, "molecular biology" assays well known to those of skill in the art. Such as Southern and Northern blotting, RT-PCR and PCR, and "biochemical" experiments, such as detecting the presence or absence of a particular polypeptide, such as by immunological methods (ELISAs and Western blots) or by the experiments described herein, are within the scope of the application.
Preparation of anti-NKG 2A antibody
In some embodiments, the anti-NKG 2A antibody is a monoclonal antibody or is derived from a monoclonal antibody. In some embodiments, the anti-NKG 2A antibody comprises V H and V L, or variants thereof, from a monoclonal antibody. In some embodiments, the anti-NKG 2A antibody further comprises CH1 and CL regions from a monoclonal antibody, or a variant thereof. Monoclonal antibodies can be prepared using methods known in the art, including hybridoma cell methods, phage display methods, or using recombinant DNA methods, for example. Furthermore, exemplary phage display methods are described herein and in the examples below.
In hybridoma cell methods, hamsters, mice, or other suitable host animals are typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Or lymphocytes may be immunized in vitro. The immunizing agent may include a polypeptide or fusion protein of the protein of interest. Typically, peripheral Blood Lymphocytes (PBLs) are used if human cells are desired, whereas spleen cells or lymph node cells are used if non-human mammalian cells are desired. Lymphocytes are fused with an immortalized cell line, such as polyethylene glycol, using an appropriate fusion agent to form a hybridoma cell. Immortalized cell lines are typically transformed mammalian cells, especially myeloma cells of rodent, bovine and human origin. Rat or mouse myeloma cell lines are typically employed. The hybridoma cells may be cultured in a suitable medium, which preferably contains one or more substances that inhibit the growth or survival of the unfused immortalized cells. For example, if the parent cell lacks hypoxanthine-guanine phosphoribosyl transferase (HGPRT or HPRT), the hybridoma cell culture medium typically includes hypoxanthine, aminopterin, and thymidine (HAT medium), which prevents HGPRT-deficient cells from growing.
In some embodiments, the immortalized cell lines fuse efficiently, ensure high levels of stable expression of antibodies by the antibody-producing cell of choice, and are sensitive to certain media, such as HAT media. In some embodiments, the immortal cell line is a mouse myeloma cell line, available from, for example, the sork cell collection in san diego, california and the american type culture collection in ma, virginia. Human myeloma and murine-human hybrid myeloma cell lines are also described for use in the production of humanized monoclonal antibodies.
The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the polypeptide. The binding specificity of monoclonal antibodies produced by hybridoma cells can be determined by immunoprecipitation or in vitro binding assays, such as Radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art. The binding affinity of a monoclonal antibody can be determined by, for example, the Scatchard (Scatchard) assay described in Munson and Pollard, anal. Biochem.,107:220 (1980).
After the desired hybridoma cells are identified, the target clone may be subcloned by limiting dilution and cultured by standard methods. Suitable media for this purpose include, for example, modified Eagle Medium (DMEM) and RPMI-1640 medium. Alternatively, the hybridoma cells may be grown as ascites in a mammal.
Monoclonal antibodies secreted by subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification methods, such as protein A-sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
In some embodiments, according to any of the anti-NKG 2A antibodies described herein, the anti-NKG 2A antibody comprises a sequence selected from the group consisting of clones of an antibody library (e.g., a phage library displaying scFv or Fab fragments). The clones may be identified by screening combinatorial libraries of antibody fragments having the desired activity. For example, a variety of methods are known in the art for generating phage display libraries and screening these libraries to obtain antibodies of the desired binding characteristics. These methods are reviewed in Hoogenboom et al.,Methods in Molecular Biology 178:1-37(O'Brien et al.,ed.,Human Press,Totowa,N.J.,2001), for example, and further described in McCafferty et al.,Nature 348:552-554;Clackson et al.,Nature 352:624-628(1991);Marks et al.,J.Mol.Biol.222:581-597(1992);Marks and Bradbury,Methods in Molecular Biology 248:161-175(Lo,ed.,Human Press,Totowa,N.J.,2003);Sidhu et al.,J.Mol.Biol.338(2):299-310(2004);Lee et al.,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004);and Lee et al.,J.Immunol.Methods 284(1-2):119-132(2004), for example.
In some phage display methods, all components of the V H and V L genes are cloned separately by Polymerase Chain Reaction (PCR) and randomly recombined in a phage library, followed by screening for phage capable of binding to antigen, as described in Winter et al, ann.Rev.Immunol.,12:433-455 (1994). Phage typically display antibody fragments as scFv fragments or as Fab fragments. The immune-derived library phage provides high affinity antibodies to the immunogen without the need to construct hybridoma cells. Alternatively, a natural repertoire (e.g., from a human) can be cloned to provide a single antibody source against multiple non-self and self-antigens without any immunization, as described in GRIFFITHS ET al, EMBO J,12:725-734 (1993). Finally, natural libraries can also be prepared by cloning non-rearranged V-gene fragments from stem cells and encoding CDR3 hypervariable regions using PCR primers comprising random sequences and completing the rearrangement in vitro, as described in Hoogenboom AND WINTER, J.mol.biol.,227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Pat. nos. 5,750,373 and US Patent Publication Nos.2005/0079574、2005/0119455、2005/0266000、2007/0117126、2007/0160598、2007/0237764、2007/0292936 and 2009/0002360.
The anti-NKG 2A antibodies are prepared by phage display screening of the portion of the library of anti-NKG 2A antibodies that specifically bind to the target NKG 2A. The library may be a human scFv phage display library, having at least 1 x 10 9 (e.g., at least 1×109、2.5×109、5×109、7.5×109、1×1010、2.5×1010、5×1010、7.5×1010 or 1 x 10 11) diversity of unique human antibody fragments. In some embodiments, the library is a human natural library constructed from DNA extracted from PMBCs and spleen of healthy subjects, comprising all human heavy and light chain subfamilies. In some embodiments, the library is a human natural library constructed from DNA extracted from PMBCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients, and patients with infectious diseases. In some embodiments, the library is a semi-synthetic human library in which the heavy chain CDR3 is entirely random, with all amino acids (except cysteine) present at any given position with the same probability. (see, e.g., hoet, R.M. et al, nat. Biotechnol.23 (3): 344-348, 2005). In some embodiments, the heavy chain CDR3 of the semi-synthetic human library is between 5 and 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) amino acids in length. In some embodiments, the library is a fully synthetic phage display library. In some embodiments, the library is a non-human phage display library.
Phage clones with high affinity for target NKG2A may be screened by iterative binding of phage to target NKG2A, which target NKG2A is bound to a solid support (e.g. beads for solution panning or mammalian cells for cell panning), followed by removal of unbound phage and elution of specifically bound phage. The bound phage clones are then eluted and used to infect appropriate host cells, e.g., E.coli XL1-Blue, for expression and purification. Phage clones that specifically bind NKG2A can be enriched by multiple rounds of panning (e.g., 2,3,4, 5,6 or more rounds), such as solution panning, cell panning, or both. Specific binding of the enriched phage clones to the target NKG2A can be detected by any method known in the art, including, for example, ELISA and FACS.
Another method of screening antibody libraries is to display proteins on the surface of yeast cells. Wittrup et al (U.S. Pat. Nos. 6,699,658 and 6,696,251) developed a method for displaying libraries of yeast cells. In this yeast display system, one component comprises a yeast lectin protein (Aga 1) anchored to the yeast cell wall, and the other component comprises a second subunit of lectin protein Aga2, which subunit can bind to the Aga1 protein via disulfide bonds and thus be displayed on the yeast cell surface. The Aga1 protein is expressed by integrating the Aga1 gene into the yeast chromosome. A library of single-chain variable fragments (scFv) was fused to the Aga2 gene in a yeast display plasmid, and after transformation, the library was retained in the yeast due to the presence of additional nutritional markers. Both the Aga1 and Aga2 proteins are expressed under the control of a galactose-inducible promoter.
The human antibody V gene library (fragments V H and V K) was obtained by PCR using a degenerate set of primers (Sblattero, D.and Bradbury, A.immunotechnology 3,271-278 1998). PCR templates were derived from commercially available RNA or cDNA, including PBMC, spleen, lymph nodes, bone marrow and tonsils. Independent V H and V K PCR libraries were pooled and assembled into scFv forms by overlap extension PCR (Sheets, M.D.et al, proc.Natl. Acad.Sci. USA 95,6157-6162 1998). To construct a yeast scFv display library, the resulting scFv PCR product is cloned into a yeast display plasmid in yeast by homologous recombination .(Chao,G,et al,Nat Protoc.2006;1(2):755-68.Miller KD,et al.Current Protocols in Cytometry 4.7.1-4.7.30,2008).
Anti-NKG 2A antibodies can be screened using a mammalian cell display system, wherein the antibody portion is displayed on the cell surface and antibodies specifically targeting NKG2A are isolated by antigen-directed screening methods (as described in U.S. patent No.7,732,195B2). A Chinese Hamster Ovary (CHO) cell library displaying a large number of human IgG antibody genes can be established and used to discover clones expressing high affinity antibody genes. Another display system has been developed that allows the same protein to be displayed and secreted simultaneously on the cell surface by alternative splicing, wherein the displayed protein phenotype remains genotype-dependent, allowing the secreted soluble antibody to be characterized simultaneously in biophysical and cell function-based assays. This method overcomes many of the limitations previously exhibited by mammalian cells and enables direct screening and maturation of antibodies in the form of full-length, glycosylated IgGs (Peter M.Bowers, et al Methods 2014, 65:44-56). Transient expression systems are suitable for single round antigen selection prior to antibody gene recovery and are therefore most useful for selecting antibodies from smaller libraries. Stable exon vectors offer an attractive option. The exon vectors can be transfected efficiently and stably maintained at low copy numbers, allowing multiple rounds of panning and resolution of more complex antibody libraries.
The IgG library was constructed based on ligation of germline sequence V gene segments isolated from a population of human donors with rearranged (D) J regions. RNA collected from 2000 human blood samples was reverse transcribed into cDNA, and V H and V K fragments were amplified using V H and V K specific primers and purified by gel extraction. The V H and V K fragments were subcloned into a display vector comprising an IgG1 or K constant region, respectively, and then electroporated or transduced 293T into cells to prepare an IgG library. To prepare the scFv antibody display library, V H and V K were linked to generate scFv, which were then subcloned into display vectors and electroporated or transduced 293T cells. It is well known that IgG libraries are constructed based on germline sequence V gene segments and rearranged (D) J regions isolated from a population of donors, which may be mice, rats, rabbits or monkeys.
Monoclonal antibodies can also be prepared by recombinant DNA methods, for example as described in U.S. patent No.4,816,567. The DNA encoding the monoclonal antibodies of the application can be readily isolated and sequenced by conventional methods, such as by oligonucleotide probes that specifically bind to the light and heavy chain genes encoding murine antibodies. Hybridoma cells as described above or NKG 2A-specific phage clones of the application may be used as a source of such DNA. After isolation, the DNA may be placed in an expression vector, which is then transfected into a host cell, such as simian COS cells, chinese hamster ovary Cancer (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain monoclonal antibodies synthesized in the recombinant host cell. The DNA may also be modified, for example by replacing the human heavy and light chain constant regions with coding sequences and/or by replacing homologous non-human sequences with framework regions (U.S. patent No.4,816,567; morrison et al, supra), or by covalently joining all or part of the coding sequence of an immunoglobulin to the coding sequence of a non-immunoglobulin polypeptide. Such non-immunoglobulin polypeptides may replace the constant regions of the antibodies of the application, or may replace an antigen binding site in the variable domains of the antibodies of the application, to form chimeric bivalent antibodies.
The antibody may be a monovalent antibody. Methods of making monovalent antibodies are known in the art. For example, a recombinant expression method involving an immunoglobulin light chain and a modified heavy chain. Heavy chains are typically truncated at any position in the Fc region to prevent heavy chains from cross-linking with each other. Or the relevant cysteine residues are substituted with other amino acid residues or deleted to prevent cross-linking.
In vitro methods are also suitable for the preparation of monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, may be accomplished using any method known in the art.
The antibody variable domain having the desired binding specificity (antibody-antigen binding site) may be fused to an immunoglobulin constant region. Preferably fusion with an immunoglobulin heavy chain constant region, which comprises at least part of the hinge, CH2 and CH3 regions. In some embodiments, the first heavy chain constant region (CH 1) comprising the necessary site for light chain binding is present in at least one fusion. The DNA encoding the immunoglobulin heavy chain fusion, and if desired, the immunoglobulin light chain, is inserted into a separate expression vector and co-transfected into a suitable host organism.
Fully human and humanized antibodies
The anti-NKG 2A antibody (e.g., full length anti-NKG 2A antibody) may be a fully human antibody or a humanized antibody. Humanized forms of non-human (e.g., mouse) antibody portions are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (e.g., fv, fab, fab ', F (ab') 2, scFv or other antigen-binding subsequences of antibodies) that typically include minimal sequences derived from non-human immunoglobulins. Humanized antibodies include human immunoglobulins, immunoglobulin chains or fragments thereof (recipient antibodies) in which residues from a recipient CDR are replaced by non-human (donor antibody) CDR residues having the desired specificity, affinity and properties, such as mouse, rat or rabbit CDRs. In some embodiments, the human immunoglobulin Fv framework region residues are replaced by corresponding non-human residues. Humanized antibodies may also comprise amino acid residues that are neither of the recipient antibody nor in the introduced CDR or framework sequences. Typically, a humanized antibody comprises at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are human immunoglobulin consensus sequences.
Typically, humanized antibodies contain one or more amino acid residues introduced from a non-human source. Those non-human amino acid residues are often referred to as "import" residues, typically from "import" variable domains. According to some embodiments, humanization may be performed substantially as described below by Winter and colleagues (Jones et al.,Nature,321:522-525(1986);Riechmann et al.,Nature,332:323-327(1988);Verhoeyen et al.,Science,239:1534-1536(1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Thus, this "humanized" antibody portion (U.S. patent No.4,816,567), which is substantially less than a fully human antibody, has its variable domains replaced by corresponding sequences from a non-human source. In practice, humanized antibody portions are typical human antibody portions in which some CDR residues and possibly some framework region residues are replaced with residues from similar sites in rodent antibodies.
Fully human antibodies are an alternative to humanization. For example, transgenic animals (e.g., mice) that are capable of producing a complete fully human antibody library after immunization without endogenous immunoglobulin production can now be prepared. For example, homozygous deletion of the antibody heavy chain Junction (JH) gene in chimeric and germ-line mutant mice has been reported to completely suppress endogenous antibody production. Transfer of an array of human germline immunoglobulin genes into such germline mutant mice can result in the production of human antibodies under antigenic stimulation, see, e.g., akobovits et al.,PNAS USA,90:2551(1993);Jakobovits et al.,Nature,362:255-258(1993);Bruggemann et al.,Year in Immunol.,7:33(1993);U.S.Patent Nos.5,545,806,5,569,825,5,591,669,5,545,807; and WO 97/17852. Alternatively, fully human antibodies can be prepared by introducing a human immunoglobulin locus into a transgenic animal (e.g., a mouse in which endogenous immunoglobulin genes have been partially or fully silenced). Upon antigen stimulation, the production of fully human antibodies can be found to be very similar in all respects to their production in humans, including gene rearrangement, assembly and antibody libraries. Such a method is described, for example, in U.S.Patent Nos.5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;and 5,661,016,and Marks et al.,Bio/Technology,10:779-783(1992);Lonberg et al.,Nature,368:856-859(1994);Morrison,Nature,368:812-813(1994);Fishwild et al.,Nature Biotechnology,14:845-851(1996);Neuberger,Nature Biotechnology,14:826(1996);Lonberg and Huszar,Intern.Rev.Immunol.,13:65-93(1995).
Fully human antibodies are also produced by in vitro activation of B cells (see U.S. patents 5,567,610and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom AND WINTER, J.mol. Biol.,227:381 (1991); marks et al, J.mol. Biol.,222:581 (1991); cole et al, and Boerner et al, techniques that can also be used to prepare fully human monoclonal antibodies. See Cole et al.,Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,p.77(1985)and Boerner et al.,J.Immunol.,147(1):86-95(1991).
Anti-NKG 2A antibody variants
In some embodiments, the amino acid sequences of anti-NKG 2A antibody variants provided herein (e.g., full length anti-NKG 2A antibodies) are also contemplated. For example, it may be desirable to improve the binding affinity and/or other biological activity of antibodies. The amino acid sequence of an antibody variant may be prepared by introducing appropriate modifications in the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the amino acid sequence of the antibody. The final construction can be accomplished by any combination of amino acid residue deletions, insertions, and substitutions to impart the desired characteristics. For example, antigen binding.
In some embodiments, anti-NKG 2A antibody variants having one or more amino acid substitutions are provided. Target sites for substitution mutations include hypervariable regions (HVRs) and Framework Regions (FRs). Amino acid substitutions may be introduced into the antibody of interest to screen for products of a desired activity, e.g., improved biological activity, retention/improvement of antigen binding capacity, reduced immunogenicity, or improved ADCC or CDC.
Conservative substitutions are shown in table 4 below.
TABLE 4 conservative substitutions
Amino acids are classified into different classes according to the nature of the side chain:
a. Hydrophobic amino acids such as norleucine Norleucine, methionine Met, alanine Ala, valine Val, leucine Leu, and isoleucine Ile;
b. neutral hydrophilic amino acids such as cysteine Cys, serine Ser, threonine Thr, asparagine Asn and glutamine Gln;
c. acidic amino acid, aspartic acid Asp, glutamic acid Glu;
d. Basic amino acids including histidine His, lysine Lys and arginine Arg;
e. Contains amino acids affecting the chain direction, glycine Gly, proline Pro;
f. aromatic amino acids Trp, tyr, phe.
Substitutions of non-conservative amino acids include substitution of one of the above classes into another class.
One exemplary substitution variant is an affinity matured antibody, conveniently produced using, for example, phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated, the variant antibody portion displayed on a phage, and variants are screened for a particular biological activity (e.g., NK cell killing activity assay based on DELFIA EuTDA cytotoxicity or binding affinity). Alterations (e.g., substitutions) can be made in the HVRs region to obtain improved NK cell killing activity assays or binding affinity biological activity based on DELFIA EuTDA cytotoxicity. The binding affinities of the resulting variants V H and V L can be tested for changes in the "hot spot" of the HVR, i.e., codon-encoded residues that undergo high frequency mutations during somatic maturation (see, e.g., chowdhury, methods mol. Biol.207:179-196 (2008)), and/or at Specific Determinant Residues (SDRs). Methods for constructing and reselecting affinity maturation from secondary libraries have been described in some literature, for example ,Hoogenboom et al.in Methods in Molecular Biology 178:1-37(O'Brien et al.,ed.,Human Press,Totowa,NJ,(2001)).
In some affinity maturation embodiments, diversity is introduced into the selected variable genes for affinity maturation by any of a variety of methods (e.g., error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is screened to identify antibody variants with the desired affinity. Another approach to introducing diversity involves HVR-mediated approaches in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically recognized, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 regions are generally particularly important targets.
In some embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, provided that such changes do not substantially reduce the ability of the antibody to bind to an antigen. For example, conservative changes (e.g., conservative substitutions provided herein) may be made in HVRs that do not substantially reduce binding affinity. These changes may occur outside the HVR "hot spot" or SDRs region. In some embodiments the variant V H and V L sequences provided above, each HVR is either unchanged or comprises no more than 1,2, or 3 amino acid substitutions.
One useful method by which amino acid residues or regions of an antibody that can be targeted for mutation can be identified is known as "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085. In this method, one or a group of target residues (e.g., charged residues such as arginine, aspartic acid, histidine, lysine, and glutamic acid) are substituted with neutral or negatively charged amino acids (e.g., alanine or glutamic acid) to determine whether the interaction of the antibody with the antigen is affected. Substitutions may be further introduced at the amino acid position to demonstrate functional sensitivity of the position to the initial substitution. Alternatively or additionally, the contact site between the antibody and the antigen is identified by the crystal structure of the antigen-antibody complex. These contact site residues and adjacent residues may be targeted or eliminated as substitution candidates. Variants are screened to determine if they have the desired properties.
Insertion of amino acid sequences, including fusion at the amino and/or carboxy terminus, ranges in length from 1 residue to polypeptides comprising 100 or more residues, and also includes insertion of 1 or more amino acid residues within the sequence. Examples of terminal insertions include antibodies having a methionyl residue at the N-terminus. Other insertional variants of antibody molecules include polypeptides that fuse an enzyme (e.g., ADEPT) or increase the serum half-life of an antibody at the N-or C-terminus of the antibody molecule.
Variant Fc region
In some embodiments, one or more amino acid modifications are introduced into the Fc region of an antibody described herein (e.g., a full length anti-NKG 2A antibody or an anti-NKG 2A antibody fusion protein), thereby producing an Fc region variant. In some embodiments, the Fc region variant has enhanced ADCC potency, typically associated with Fc-binding receptors (FcRs). In some embodiments, the Fc region variant has reduced ADCC potency. There are many examples of alterations or mutations in Fc sequences affecting their potency, for example, WO 00/42072 and SHIELDS ET al J biol. Chem.9 (2): 6591-6604 (2001) describe antibody variants with increased or decreased binding to FcRs. The contents of these publications are incorporated herein by reference.
Antibody-dependent cell-mediated cytotoxicity (ADCC) is the mechanism of action of therapeutic antibodies against tumor cells. ADCC is a cell-mediated immune defense in which effector cells of the immune system actively lyse target cells (e.g., cancer cells) when antigens on the surface of the target cell membrane are bound by specific antibodies (e.g., anti-NKG 2A antibodies). Typically ADCC effects involve NK cells activated by antibodies. NK cells express the Fc receptor CD16. The receptor recognizes and binds to the Fc portion of an antibody molecule that binds to the surface of a target cell. The most common Fc receptor on the surface of NK cells is CD16 or fcyriii. Binding of the Fc receptor to the Fc region of the antibody results in activation of NK cells, releasing the cell lysis particles, followed by apoptosis of the target cells. The killing of tumor cells by ADCC can be determined by experiments specific for NK-92 cells transfected with high affinity FcR. The results were compared with wild-type NK-92 which did not express FcR.
In some embodiments, the application also provides an anti-NKG 2A antibody variant (e.g., a full length anti-NKG 2A antibody variant) comprising an Fc region having a portion, but not all, effector functions such that it has an extended half-life in vivo, whereas a particular effector function (e.g., CDC or ADCC) is not necessary or detrimental, such an anti-NKG 2A antibody being a desirable candidate for the application. Reduction/elimination of CDC and/or ADCC activity is confirmed by cytotoxicity assays in vitro and/or in vivo. For example, antibodies were confirmed to lack fcγr binding capacity (and thus potentially ADCC activity) by an Fc receptor (FcR) binding assay but still retain FcRn binding capacity. Among the major cells mediating ADCC, NK cells express fcyriii only, whereas monocytes express fcyri, fcyrii and fcyriii. The expression of FcR on hematopoietic cells is summarized in Table 3 at page 464 of RAVETCH AND KINET Annu. Rev. Immunol.9:457-492 (1991). Non-limiting examples of in vitro evaluation of ADCC activity of a target molecule are described in U.S. Pat. No.5,500,362 (see, e.g., Hellstrom,I.et al.Proc.Nat'l Acad.Sci.USA 83:7059-7063(1986)and Hellstrom,I et al.,Proc.Nat'l Acad.Sci.USA 82:1499-1502(1985);U.S.Pat.No.5,821,337(see Bruggemann,M.et al.,J.Exp.Med.166:1351-1361(1987)). or non-radioactive detection methods can be employed (see, e.g., ACTI TM flow cytometry non-radioactive cytotoxicity assay (CellTechnology, inc.Mountain View, calif.) and CYTOTOX 96 TM non-radioactive cytotoxicity assay (Promega, madison, wis.). Effector cells employed in such assay experiments include Peripheral Blood Mononuclear Cells (PBMCs) and natural killer cells (NK). Or in addition, ADCC activity of the target molecule is detected in vivo, for example, in an animal model, as described in Clynes et al Proc.Nat' l Acad.Sci.USA 95:652-656 (1998). Also, a C1q binding assay may be performed to confirm that the antibody is unable to bind to C1q, thereby lacking CDC activity. See, e.g., C1q and C3C binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, CDC assays can be performed (see, e.g., gazzano-Santoro et al, J.Immunol. Methods 202:163 (1996); cragg, M.S. et al, blood 101:1045-1052 (2003); and Cragg, M.S. and M.J. Glennie, blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life are determined using methods known in the art (see, e.g., petkova, s.b. et al, int' l.immunol.18 (12): 1759-1769 (2006)).
Antibodies with reduced effector function comprising substitution of one or more residues at residues 238, 265, 269, 270, 297, 327 and 329 of the Fc region (u.s.pat.no. 6,737,056). These Fc variants include Fc variants with substitution of two or more residues at positions 265, 269, 270, 297 and 327, including Fc variants known as "DANA" with substitution of alanine at residues 265 and 297 (u.s.pat. No.7,332, 581).
Such antibody variants with increased or decreased binding to FcRs have been described (see, e.g., U.S. Pat.No.6,737,056; WO 2004/056312, and SHIELDS ET al, J.biol.chem.9 (2): 6591-6604 (2001)).
In some embodiments, an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody) variant is provided that comprises an Fc region variant having one or more amino acid substitutions capable of enhancing ADCC effect. In some embodiments, the Fc region variant comprises one or more amino substitutions at positions 298, 333, and/or 334 (EU residue numbering) of the Fc region that are capable of enhancing ADCC effects. In some embodiments, the anti-NKG 2A antibody (e.g., full length anti-NKG 2A antibody) variant comprises amino acid substitutions at positions S298A, E333A, and K334A of the Fc region.
In some embodiments, the change in the Fc region results in a change (i.e., an increase or decrease) in C1q binding and/or Complement Dependent Cytotoxicity (CDC), as described in U.S.Pat.No.6,194,551, WO/51642, and Idusogie et al, J.Immunol.164:4178-4184 (2000).
In some embodiments, an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody) variant is provided that comprises an Fc region variant having one or more amino acid substitutions that is capable of extending half-life or enhancing binding to an Fc receptor (FcRn). Antibodies with extended half-life and improved FcRn binding are described in US 2005/0014934A1 (hiton et al). These antibody Fc regions comprise one or more amino acid substitutions that enhance the binding of the Fc region to FcRn. These Fc variants comprise one or more substitutions in residues 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434 in the Fc region, for example a substitution in residue 434 in the Fc region (u.s.pat. No.7,371,826).
See also Duncan & Winter, nature 322:738-40 (1988), U.S. Pat.No.5,648,260, U.S. Pat.No.5,624,821 and WO 94/29351 for examples of other Fc region variants.
The application contemplates anti-NKG 2A antibodies (e.g., full-length anti-NKG 2A antibodies) comprising any one or a combination of the Fc variants described herein.
Glycosylation variants
In some embodiments, an anti-NKG 2A antibody provided herein (e.g., a full-length anti-NKG 2A antibody) is altered to increase or decrease the degree of glycosylation of the anti-NGF antibody. The addition or deletion of glycosylation sites on an anti-NKG 2A antibody may be conveniently accomplished by altering the amino acid sequence of the anti-NGF antibody or polypeptide portion thereof to thereby add or remove one or more glycosylation sites.
Wherein the anti-NKG 2A antibody comprises an Fc region, to which a saccharide may be linked. Natural antibodies produced by mammalian cells typically comprise branched double-antennary oligosaccharides, which are typically linked to the Fc region CH2 domain Asn297 via an N-linkage, see, e.g., wright et al, TIBTECH 15:26-32 (1997). The oligosaccharides may comprise a variety of sugars, such as mannose, N-acetylglucosaminide (GlcNAc), galactose and sialic acid, as well as trehalose attached to the GlcNAc of the "stem" of the double-antennary oligosaccharide structure. In some embodiments, the anti-NKG 2A antibodies of the application may be oligosaccharide modified to produce anti-NKG 2A antibody variants with certain improved properties.
N-glycans attached to the CH2 domain of the Fc region are heterogeneous. Antibodies or Fc fusion proteins produced in CHO cells are fucosylated by fucosyltransferase activity, see Shoji-Hosaka et al, J.biochem.2006,140:777-83. Typically, a small fraction of naturally occurring nonfucosylated IgGs can be detected in human serum. N-glycosylation of the Fc region is important for its binding to fcγr, whereas non-fucosylated N-glycans enhance the binding capacity of Fc to fcγriiia. Enhanced binding to FcRIIIa results in enhanced ADCC effect, which is advantageous in certain antibody therapeutic applications requiring cytotoxicity.
In some embodiments, enhanced effector function may be detrimental when Fc-mediated cellular cytotoxicity is not required. In some embodiments, the Fc fragment or CH2 domain is non-glycosylated. In some embodiments, glycosylation is prevented by mutating the N-glycosylation site in the CH2 domain.
In some embodiments, anti-NKG 2A antibody (e.g., full length anti-NKG 2A antibody) variants are provided that comprise an Fc region, wherein the saccharide structure linked to the Fc region has reduced fucose or lacks fucose, which may enhance ADCC function. In particular, provided herein are anti-NKG 2A antibodies having reduced fucose relative to the same anti-NKG 2A antibodies produced by wild-type CHO cells. That is, they are characterized by having a smaller amount of fucose than antibodies produced by natural CHO cells (e.g., CHO cells producing a naturally glycosylated form, CHO cells containing the natural FUT8 gene). In some embodiments, the N-linked glycans of the anti-NKG 2A antibody have less than 50%, 40%, 30%, 20%, 10% or 5% fucose. For example, the anti-NKG 2A antibody may have a fucose content of 1% -80%, 1% -65%, 5% -65% or 20% -40%. In some embodiments, the N-linked glycans of the anti-NKG 2A antibody do not comprise fucose, i.e., wherein the anti-NKG 2A antibody is completely free of fucose, or is free of fucose or is defucosylated. The fucose content is determined by calculating the average fucose content in the sugar chains attached to Asn297 relative to the total amount of all sugar structures attached to Asn297 (e.g. complex, hybrid or mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546. asn297 refers to the asparagine residue at position 297 of the Fc region (EU Fc region residue numbering system). However, asn297 may also be located upstream or downstream of position 297 by ±3 amino acids, i.e. between positions 294 and 300, due to minor sequence variations of the antibody. These fucosylated variants may have enhanced ADCC function. See, for example, US Patent Publication nos. US 2003/0157108 (Presta, l.), US 2004/0093621 (Kyowa Hakko Kogyo co., ltd). Examples of publications related to antibody variants that are "defragmented" or "deficient in fucose" include ,US 2003/0157108;WO 2000/61739;WO 2001/29246;US 2003/0115614;US 2002/0164328;US 2004/0093621;US 2004/0132140;US 2004/0110704;US 2004/0110282;US 2004/0109865;WO 2003/085119;WO 2003/084570;WO 2005/035586;WO 2005/035778;WO 2005/053742;WO 2002/031140;Okazaki et al.J.Mol.Biol.336:1239-1249(2004);Yamane-Ohnuki et al.Biotech.Bioeng.87:614(2004). cell lines capable of producing defragmented antibodies including Lec13CHO cells lacking the fucosylation function of the protein (Ripka et al. Arch. Biochem. Biophys.249:533-545 (1986); US Pat Appl No US 2003/0157108a1, presta, l; and WO 2004/056312A1,Adams et al, especially example 11), and knockout cell lines such as the α -1, 6-fucosyltransferase gene, FUT8 knockout CHO cells (see Yamane-Ohnuki et al.Biotech.Bioeng.87:614(2004);Kanda,Y.et al.,Biotechnol.Bioeng.,94(4):680-688(2006); and WO 2003/085107).
Variants of anti-NKG 2A antibodies (e.g., full length anti-NKG 2A antibodies) further provide bisecting oligosaccharides, e.g., wherein a double antennary oligosaccharide linked to the Fc region of an anti-NKG 2A antibody is bisected by GlcNAc. Such anti-NKG 2A antibody (e.g., full-length anti-NKG 2A antibody) variants may have reduced fucosylation and/or enhanced ADCC function. Examples of such antibody variants are described in WO 2003/011878(Jean-Mairet et al.);U.S.Pat.No.6,602,684(Umana et al.);US 2005/0123546(Umana et al.), and FERRARA ET al, biotechnology and Bioengineering,93 (5): 851-861 (2006). Also provided are variants of anti-NKG 2A antibodies (e.g., full length anti-NKG 2A antibodies) having at least one galactose residue in the oligosaccharide linked to the Fc region. Such anti-NKG 2A antibody variants may have enhanced CDC function. Such variants are described, for example, in WO 1997/30087 (Patel et al), WO 1998/58964 (Raju, S.), and WO 1999/22764 (Raju, S.).
In some embodiments, the anti-NKG 2A antibody (e.g., full length anti-NKG 2A antibody) variant comprises an Fc region capable of binding to fcyriii. In some embodiments, the variant of the anti-NKG 2A antibody (e.g., a full-length anti-NKG 2A antibody) comprising an Fc region has ADCC activity in the presence of human effector cells (e.g., T cells) or has enhanced ADCC activity in the presence of human effector cells compared to an otherwise identical anti-NKG 2A antibody (e.g., a full-length anti-NKG 2A antibody) having a human wild-type IgG1Fc region.
Cysteine engineered variants
In some embodiments, it is desirable to prepare cysteine engineered anti-NKG 2A antibodies (e.g., full length anti-NKG 2A antibodies) in which one or more amino acid residues are substituted with cysteine residues. In some embodiments, the substitution residue occurs at an accessible site of the anti-NKG 2A antibody. By substituting those residues with cysteines, active sulfhydryl groups located at accessible sites of anti-NKG 2A antibodies can be used to couple the anti-NKG 2A antibodies with other moieties, such as drug moieties or linker-drug moieties, to prepare anti-NKG 2A immunoconjugates as further described herein. Cysteine engineered anti-NKG 2A antibodies (e.g., full length anti-NKG 2A antibodies) may be prepared as described, for example, in u.s.pat. No.7,521,541.
Derivatives and their use as inhibitors of viral infection
In some embodiments, an anti-NKG 2A antibody provided herein (e.g., a full length anti-NKG 2A antibody) may be further modified to include other non-protein portions known and readily available in the art. Moieties suitable for derivatizing anti-NKG 2A antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene/maleic anhydride copolymers, polyaminoacids (homo-or random copolymers), dextran or poly (n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymers, propylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde has advantages in manufacturing due to its stability in water. The polymer may have any molecular weight and may be branched or unbranched. The number of polymers attached to an anti-NKG 2A antibody may vary, and if more than one polymer is attached, they may be the same or different molecules. In general, the amount and/or type of polymer used for derivatization may be determined based on considerations including, but not limited to, the need to improve the properties or function of the anti-NKG 2A antibody, whether the anti-NKG 2A antibody derivative is used for treatment under specific conditions, and the like.
Pharmaceutical composition
Also provided herein are compositions (e.g., pharmaceutical compositions, also referred to herein as formulations) comprising any of the anti-NKG 2A antibodies (e.g., full length anti-NKG 2A antibodies), nucleic acids encoding the antibodies, vectors comprising nucleic acids encoding the antibodies, or host cells comprising the nucleic acids or vectors described herein. In some embodiments, a pharmaceutical composition is provided comprising any of the anti-NKG 2A antibodies described herein and a pharmaceutically acceptable carrier.
Suitable anti-NKG 2A antibody formulations may be prepared in lyophilized or liquid formulation form by mixing an anti-NKG 2A antibody of the desired purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences 16th edition,Osol,A.Ed (1980)). Acceptable carriers, excipients or stabilizers are non-toxic to the recipient at the dosages and concentrations employed, including buffers such as phosphate, citric acid and other organic acids, antioxidants including ascorbic acid and methionine, preservatives (e.g., octadecyldimethylbenzyl ammonium chloride, hexamethyl ammonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butanol or benzyl alcohol, alkyl p-hydroxybenzoates such as methyl or propyl p-hydroxybenzoate, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol), low molecular weight (less than 10 residues) polypeptides, proteins such as serum albumin, gelatin or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine, monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrin, chelating agents such as EDTA, sugars such as sucrose, mannitol, trehalose or sorbitol, salt forming counterions such as sodium, metal complexes such as zinc-protein complexes, and/or non-ionic complexes such as een 35 or polyethylene glycol as PEG TM,PLURONICSTM and formulations as those described herein are specifically cited. Lyophilized formulations suitable for subcutaneous administration are described in WO 97/04801. Such lyophilized formulations can be reconstituted into high protein concentration formulations by means of a suitable diluent and the reconstituted formulations can be administered to the individual to be treated herein by means of subcutaneous administration. Cationic liposomes or liposomes can be used to deliver the anti-NKG 2A antibodies of the application to cells.
The formulations described herein may contain, in addition to an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody), one or more other active agents necessary to treat a particular disorder, preferably agents that are complementary in activity and do not adversely react with each other. For example, it may be desirable to further include, in addition to an anti-NKG 2A antibody, an anti-cancer agent (e.g., a chemotherapeutic agent, a hormonal agent, an anti-angiogenic agent, an anti-metastatic agent, an anti-cancer antibody such as an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, and/or Rituximab, an antibody directed against an inhibitor KIR molecule, a growth factor inhibitor, an apoptosis-promoting compound), an immunomodulatory compound (e.g., a cytokine). These molecules are present in combination in amounts effective for the intended purpose. The effective amount of the other substances depends on the amount of anti-NKG 2A antibody in the formulation, the type of disease or disorder or treatment, and other factors as described above. These drugs are typically used at the same dosages and routes of administration as described herein, or at 1% to 99% of the presently employed dosages.
The anti-NKG 2A antibodies (e.g., full-length anti-NKG 2A antibodies) may also be embedded in microcapsules prepared, for example, by coacervation techniques and interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly (methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Can be prepared into sustained release preparation.
Sustained release formulations of anti-NKG 2A antibodies (e.g., full length anti-NKG 2A antibodies) may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody (or fragments thereof), which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactic acid (U.S. Pat. No.3,773,919), L-glutamic acid and L-ethyl glutamate copolymers, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON deptatm (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprorelin acetate), and poly-D (-) -3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic-glycolic acid can allow release of molecules for more than 100 days, certain hydrogels can release proteins in a shorter time. When encapsulated antibodies stay in the body for a long period of time, they may denature or aggregate as a result of exposure to a humid environment at 37 ℃, potentially resulting in loss of biological activity or altered immunogenicity. anti-NKG 2A antibodies can be stabilized according to a corresponding mechanism, rationally designed strategy. For example, if the aggregation mechanism is found to be the formation of intermolecular S-S bonds through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing in acidic solutions, controlling water content, using appropriate additives, and developing specific polymer matrix compositions.
In some embodiments, the anti-NKG 2A antibody (e.g., full length anti-NKG 2A antibody) is formulated in a buffer containing citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 (tween 80), or any combination thereof.
Formulations for in vivo administration must be sterile. This can be easily achieved by, for example, filtration using sterile filtration membranes.
Methods of treatment using anti-NKG 2A antibodies
Anti-NKG 2A antibodies (e.g., full length anti-NKG 2A antibodies) and/or compositions of the application may be administered to an individual (e.g., mammal, such as a human) to treat diseases and/or disorders resulting from deregulation of NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease), including, but not limited to, cancers such as kidney cancer, bladder cancer, breast cancer, colon cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, uterine cancer, thyroid cancer, skin cancer, melanoma, colored stem skin disease, keratoacanthoma, seminoma, thyroid follicular cancer, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome; viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases, such as hemolytic anemia, pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, liver splenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis, meningitis, metritis, mucositis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenositis, peritonitis, pharyngitis, phlebitis, etc. Accordingly, in some embodiments, the application provides a method of treating a disease and/or disorder resulting from deregulation of NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) comprising administering to an individual an effective amount of a composition (e.g., a pharmaceutical composition) comprising an anti-NKG 2A antibody (e.g., a full-length anti-NKG 2A antibody), such as any of the anti-NKG 2A antibodies described herein (e.g., a full-length anti-NKG 2A antibody), in some embodiments, the individual is a human.
For example, in some embodiments, a method for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the individual an effective amount of a pharmaceutical composition comprising an NKG2A antibody (e.g., a full length anti-NKG 2A antibody) that specifically binds an epitope on human NKG2A, wherein the epitope comprises an amino acid residue at position of human NKG2A. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney cancer, bladder cancer, breast cancer, colon cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, uterine cancer, thyroid cancer, skin cancer, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid cancer, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome; viral diseases such as hepatitis A, B, C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes mellitus, uveitis, graves's disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, liver and spleen inflammation, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, meningitis, metritis, mucositis, myocarditis, myositis, tympanitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. In some embodiments, the individual is a human.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease), comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-NKG 2A antibody (e.g., a full-length anti-NKG 2A antibody), wherein the antibody comprises a heavy chain variable domain (V H), the V H comprises a heavy chain complementarity determining region (HC-CDR) 1 comprising SNTMS (SEQ ID NO: 1), a HC-CDR2 comprising NINTGGNTYYANWAKG (SEQ ID NO: 9), and a HC-CDR3 comprising GSTIDSSGLSL (SEQ ID NO: 24), and a light chain variable domain (V L), the V L comprises a light chain complementarity determining region (LC-CDR) 1 comprising QASQNIGSDLA (SEQ ID NO: 33), a LC-CDR2 comprising LASTLAS (SEQ ID NO: 43) and a LC-CDR3 comprising QQX 1 WSSSNVDNV, wherein C 1 is C 1 S or T. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, Multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, Pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, Meningitis, metritis, mucositis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. in some embodiments, the individual is a human.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:24, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:33, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:43, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NO: 51-53, or a variant of the V L comprising up to about 5 amino acid substitutions thereof.
In some embodiments, there is provided a method for treating a subject having a disease associated with an NKG2A signaling pathway (e.g., cancer, a viral disease, an autoimmune disease, and/or an inflammatory disease), comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises the amino acid sequence set forth in any one of SEQ ID NOs 68-71, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs 68-71, and V L, the V L comprises the amino acid sequence set forth in any one of SEQ ID NOs 92-95, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs 92-95.
In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:33, LC-CDR2 comprising amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising amino acid sequence SEQ ID NO:51, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO. 68, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 68, and V L, said V L comprising amino acid sequence SEQ ID NO. 92, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 92. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:33, LC-CDR2 comprising amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising amino acid sequence SEQ ID NO:52, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:69, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:69, and V L, said V L comprising amino acid sequence SEQ ID NO:93, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 93. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 70, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 70, and V L, said V L comprising amino acid sequence SEQ ID NO 93, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 93. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:33, LC-CDR2 comprising amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising amino acid sequence SEQ ID NO:53, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:69, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:69, and V L, said V L comprising amino acid sequence SEQ ID NO:94, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 94. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 70, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 70, and V L, said V L comprising amino acid sequence SEQ ID NO 94, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 94. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:71 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:71, and V L, said V L comprising amino acid sequence SEQ ID NO:95 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 95. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease), comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-NKG 2A antibody (e.g., a full-length anti-NKG 2A antibody), wherein the antibody comprises a heavy chain variable domain (V H), the V H comprises a heavy chain complementarity determining region (HC-CDR) 1 comprising NYHMS (SEQ ID NO: 2), HC-CDR2 comprising YIGAAX 1X2X3 YYASWAKG (SEQ ID NO: 65), wherein X 1 is G, N or S, X 2 is N or S, X 3 is A, I or T, and HC-CDR3 comprising GVIYNNL (SEQ ID NO: 25), and a light chain variable domain (V L), said V L comprising a light chain complementarity determining region (LC-CDR) 1 comprising QASESISNYLS (SEQ ID NO: 34), LC-CDR2 comprising DASDLAS (SEQ ID NO: 44), and LC-CDR3 comprising QX 1TYGSINX2 NYGVA (SEQ ID NO: 67), wherein X 1 is A or C, X 2 is A, Q or S. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, Multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, Pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, Meningitis, metritis, mucositis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. in some embodiments, the individual is a human.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:2, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs 10-16, and HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L comprising LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:44, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs 54-57, or up to about 35 of the amino acid substitutions in the variant thereof.
In some embodiments, there is provided a method for treating a subject having a disease associated with an NKG2A signaling pathway (e.g., cancer, a viral disease, an autoimmune disease, and/or an inflammatory disease), comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises the amino acid sequence shown in any one of SEQ ID NOs 72-84, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence shown in any one of SEQ ID NOs 72-84, and V L, the V L comprises the amino acid sequence shown in any one of SEQ ID NOs 96-101, or a variant thereof, having at least about 80% sequence identity to the amino acid sequence shown in any one of SEQ ID NOs 96-101.
In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:54, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:72, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:72, and V L, said V L comprising amino acid sequence SEQ ID NO:96, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 96. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:73, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:73, and V L, said V L comprising amino acid sequence SEQ ID NO:97, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 97. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 74, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 74, and V L, said V L comprising amino acid sequence SEQ ID NO 97, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 75, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 75, and V L, said V L comprising amino acid sequence SEQ ID NO 97, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 76, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 76, and V L, said V L comprising amino acid sequence SEQ ID NO 97, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 77 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 77, and V L, said V L comprising amino acid sequence SEQ ID NO 97 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 97. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:78, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:78, and V L, said V L comprising amino acid sequence SEQ ID NO:97, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 97. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:73, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:73, and V L, said V L comprising amino acid sequence SEQ ID NO:98, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 98. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 74, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 74, and V L, said V L comprising amino acid sequence SEQ ID NO 98, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 98. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 75, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 75, and V L, said V L comprising amino acid sequence SEQ ID NO 98, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 98. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 76, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 76, and V L, said V L comprising amino acid sequence SEQ ID NO 98, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 98. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:77 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:77, and V L, said V L comprising amino acid sequence SEQ ID NO:98 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 98. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:78, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:78, and V L, said V L comprising amino acid sequence SEQ ID NO:98, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 98. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:78, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:78, and V L, said V L comprising amino acid sequence SEQ ID NO:99, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 99. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:78, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:78, and V L, said V L comprising amino acid sequence SEQ ID NO:100, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 100. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:79 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:79, and V L, said V L comprising amino acid sequence SEQ ID NO:100 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 100. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO. 80, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 80, and V L, said V L comprising amino acid sequence SEQ ID NO. 100, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 100. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:13, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO. 81 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 81, and V L, said V L comprising amino acid sequence SEQ ID NO. 99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 99. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:14, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO. 82 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 82, and V L, said V L comprising amino acid sequence SEQ ID NO. 99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 99. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:15, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 83, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 83, and V L, said V L comprising amino acid sequence SEQ ID NO 99, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 99. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:16, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO 84, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 84, and V L, said V L comprising amino acid sequence SEQ ID NO 99, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO 99. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:79 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:79, and V L, said V L comprising amino acid sequence SEQ ID NO:99 or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 99. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO. 80, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 80, and V L, said V L comprising amino acid sequence SEQ ID NO. 99, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO. 99. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) is provided, comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and V L, the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:57, or a variant of the V L comprising up to about 5 amino acid substitutions.
In some embodiments, an anti-NKG 2A antibody described herein comprises V H, said V H comprising amino acid sequence SEQ ID NO:78, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO:78, and V L, said V L comprising amino acid sequence SEQ ID NO:101, or a variant thereof, said variant having at least about 80% sequence identity to amino acid sequence SEQ ID NO: 101. In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody), wherein the antibody comprises a heavy chain variable domain (V H), the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and a light chain variable domain (V L), the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:35, LC-CDR2 comprising amino acid sequence SEQ ID NO:45, and amino acid sequence SEQ ID NO:3, and LC-CDR3 comprising up to about 5 amino acid substitutions in the variant thereof. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, Multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, Pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, Meningitis, metritis, mucositis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. in some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual having a disease associated with a NKG2A signaling pathway (e.g., cancer, a viral disease, an autoimmune disease, and/or an inflammatory disease), comprising administering to the individual an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises the amino acid sequence shown as SEQ ID NO:68 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO:68, and V L, the V L comprises the amino acid sequence shown as SEQ ID NO:102 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO: 102.
In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody), wherein the antibody comprises a heavy chain variable domain (V H), the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:17, and HC-CDR3 comprising amino acid sequence SEQ ID NO:26, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and a light chain variable domain (V L), the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:36, LC-CDR2 comprising amino acid sequence SEQ ID NO:46, and amino acid sequence SEQ ID NO:3, and LC-CDR3 comprising up to about 5 amino acid substitutions in the variant thereof. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, Multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, Pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, Meningitis, metritis, mucositis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. in some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating a subject having a disease associated with a NKG2A signaling pathway (e.g., cancer, a viral disease, an autoimmune disease, and/or an inflammatory disease), comprising administering to the subject an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises the amino acid sequence shown as SEQ ID NO:85 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO:85, and V L, the V L comprises the amino acid sequence shown as SEQ ID NO:103 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO: 103.
In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody), wherein the antibody comprises a heavy chain variable domain (V H), the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising amino acid sequence SEQ ID NO:27, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and a light chain variable domain (V L), the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:37, LC-CDR2 comprising amino acid sequence SEQ ID NO:47, and 3, and up to about 35 amino acid substitutions in the amino acid sequence SEQ ID NO:35 or a variant thereof. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, Multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, Pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, Meningitis, metritis, mucositis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. in some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual having a disease associated with a NKG2A signaling pathway (e.g., cancer, a viral disease, an autoimmune disease, and/or an inflammatory disease), comprising administering to the individual an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises the amino acid sequence shown as SEQ ID NO:86 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO:86, and V L, the V L comprises the amino acid sequence shown as SEQ ID NO:104 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO: 104.
In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody), wherein the antibody comprises a heavy chain variable domain (V H), the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:4, HC-CDR2 comprising amino acid sequence SEQ ID NO:19, and HC-CDR3 comprising amino acid sequence SEQ ID NO:28, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and a light chain variable domain (V L), the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:38, LC-CDR2 comprising amino acid sequence CDR NO:48, and amino acid sequence SEQ ID NO:3, and LC-CDR3 comprising up to about 5 amino acid substitutions in the variant thereof. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, Multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, Pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, Meningitis, metritis, mucositis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. in some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual having a disease associated with a NKG2A signaling pathway (e.g., cancer, a viral disease, an autoimmune disease, and/or an inflammatory disease), comprising administering to the individual an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises the amino acid sequence shown in SEQ ID No. 87 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID No. 87, and V L, the V L comprises the amino acid sequence shown in SEQ ID No. 105 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID No. 105.
In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody), wherein the antibody comprises a heavy chain variable domain (V H), the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:5, HC-CDR2 comprising amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising amino acid sequence SEQ ID NO:29, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and a light chain variable domain (V L), the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:39, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:35, or a variant thereof comprising up to about 5 amino acid substitutions in the amino acid sequence SEQ ID NO:35 or a variant thereof. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, Multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, Pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, Meningitis, metritis, mucositis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. in some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual having a disease associated with a NKG2A signaling pathway (e.g., cancer, a viral disease, an autoimmune disease, and/or an inflammatory disease), comprising administering to the individual an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises the amino acid sequence shown as SEQ ID NO:88 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO:88, and V L, the V L comprises the amino acid sequence shown as SEQ ID NO:106 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO: 106.
In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody), wherein the antibody comprises a heavy chain variable domain (V H), the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:6, HC-CDR2 comprising amino acid sequence SEQ ID NO:21, and HC-CDR3 comprising amino acid sequence SEQ ID NO:30, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and a light chain variable domain (V L), the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:40, LC-CDR2 comprising amino acid sequence SEQ ID NO:49, and HC-CDR3 comprising amino acid sequence SEQ ID NO:62, or a variant thereof comprising up to about 5 amino acid substitutions in the amino acid sequence of SEQ ID No. 35. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, Multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, Pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, Meningitis, metritis, mucositis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. in some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual having a disease associated with a NKG2A signaling pathway (e.g., cancer, a viral disease, an autoimmune disease, and/or an inflammatory disease), comprising administering to the individual an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises the amino acid sequence shown in SEQ ID NO:89 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO:89, and V L, the V L comprises the amino acid sequence shown in SEQ ID NO:107 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown in SEQ ID NO: 107.
In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody), wherein the antibody comprises a heavy chain variable domain (V H), the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:7, HC-CDR2 comprising amino acid sequence SEQ ID NO:22, and HC-CDR3 comprising amino acid sequence SEQ ID NO:31, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and a light chain variable domain (V L), the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:41, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and amino acid sequence HC-CDR3 comprising amino acid sequence SEQ ID NO: 63-35, or a variant thereof comprising up to about 5 amino acid substitutions in the amino acid sequence SEQ ID NO: 63-3. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, Multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, Pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, Meningitis, metritis, mucositis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. in some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual having a disease associated with a NKG2A signaling pathway (e.g., cancer, a viral disease, an autoimmune disease, and/or an inflammatory disease), comprising administering to the individual an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises the amino acid sequence shown as SEQ ID NO:90 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO:90, and V L, the V L comprises the amino acid sequence shown as SEQ ID NO:108 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO: 108.
In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with an NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody), wherein the antibody comprises a heavy chain variable domain (V H), the V H comprises HC-CDR1 comprising amino acid sequence SEQ ID NO:8, HC-CDR2 comprising amino acid sequence SEQ ID NO:23, and HC-CDR3 comprising amino acid sequence SEQ ID NO:32, or a variant of the V H comprising up to about 5 amino acid substitutions in the HC-CDRs, and a light chain variable domain (V L), the V L comprises LC-CDR1 comprising amino acid sequence SEQ ID NO:42, LC-CDR2 comprising amino acid sequence SEQ ID NO:50, and amino acid sequence HC-CDR3 comprising amino acid sequence SEQ ID NO:35, or a variant comprising up to about 35 amino acid substitutions in the amino acid sequence SEQ ID NO:35 or a variant comprising up to about 35 amino acid substitutions. In some embodiments, the anti-NKG 2A antibody is a full-length antibody. In some embodiments, the full length anti-NKG 2A antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, Multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, viral diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, Pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, endophthalmitis, laryngitis, lymphangitis, mastitis, otitis media, Meningitis, metritis, mucositis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like. in some embodiments, the individual is a human.
In some embodiments, there is provided a method for treating an individual having a disease associated with a NKG2A signaling pathway (e.g., cancer, a viral disease, an autoimmune disease, and/or an inflammatory disease), comprising administering to the individual an effective amount of a composition comprising an anti-NKG 2A antibody, wherein the antibody comprises V H, the V H comprises the amino acid sequence shown as SEQ ID NO:91 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO:91, and V L, the V L comprises the amino acid sequence shown as SEQ ID NO:109 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO: 109.
In some embodiments, an anti-NKG 2A antibody described herein is a full-length anti-NKG 2A antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 111. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 112. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 113.
In some embodiments, the individual is a mammal (e.g., human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.). In some embodiments, the individual is a human. In some embodiments, the individual is a clinical patient, a clinical trial volunteer, a laboratory animal, or the like. In some embodiments, the individual is less than 60 years old (including, for example, less than 50, 40, 30, 25, 20, 15, or 10 years old). In some embodiments, the individual is older than 60 years (including, for example, older than 70, 80, 90, or 100 years). In some embodiments, the individual is diagnosed with or genetically predisposed to one or more of the diseases or disorders described herein (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease). In some embodiments, the individual has one or more risk factors associated with one or more diseases or disorders described herein.
In some embodiments, the application provides a method of delivering an anti-NKG 2A antibody (e.g., any of the anti-NKG 2A antibodies described herein, e.g., an isolated anti-NKG 2A antibody) to a cell expressing NKG2A on its surface in an individual, the method comprising administering to the individual a composition comprising an anti-NKG 2A antibody.
Many diagnostic methods for cancer, viral diseases, autoimmune and/or inflammatory diseases or any other disease exhibiting abnormal expression of NKG2A and clinical descriptions of these diseases are known in the art. Such methods include, but are not limited to, for example, immunohistochemistry, PCR, and Fluorescence In Situ Hybridization (FISH).
In some embodiments, the anti-NKG 2A antibodies (e.g., full length anti-NKG 2A antibodies) and/or compositions of the application are used in combination with a second, third, or fourth agent (including, e.g., an anti-cancer agent (e.g., a chemotherapeutic agent, a hormonal agent, an anti-angiogenic agent, an anti-metastatic agent, an anti-cancer antibody such as an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, and/or Rituximab, an antibody directed against an inhibitor KIR molecule, a growth factor inhibitor, an apoptosis-promoting compound), an immunomodulatory compound such as a cytokine) to treat a disease associated with NKG2A signaling pathway.
Cancer treatment is assessed using, for example, tumor regression, reduction in tumor weight or size, time to progression, survival, progression free survival, overall response rate, response duration, quality of life, protein expression, and/or activity. Methods of determining the effect of treatment may be employed, including, for example, detecting whether or not to respond by radiological imaging.
In some embodiments, the effect of treatment is assessed as percent tumor growth inhibition (%tgi), calculated using equation 100- (T/C x 100), where T is the relative average tumor volume of the treated tumor and C is the relative average tumor volume of the untreated tumor. In some embodiments, the% TGI is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95% or more than 95%. In some embodiments, the therapeutic effect is assessed by a change in granulocyte morphology and/or an increase in the number of granulocytes surviving. In some embodiments, the therapeutic effect is assessed by an increase in the secretion of cytokines by monocytes.
Dosage and method of administration of anti-NKG 2A antibody
The dosage of an anti-NKG 2A antibody (e.g., an isolated anti-NKG 2A antibody) composition administered to an individual (e.g., a human) may vary depending on the particular composition, mode of administration, and type of disease being treated. In some embodiments, the amount of the composition (e.g., a composition comprising an anti-NKG 2A antibody) may be effective to produce an objective response (e.g., a partial response or a complete response) in the treatment of cancer, viral disease, autoimmune disease, and/or inflammatory disease. In some embodiments, the amount of the anti-NKG 2A antibody composition is sufficient to produce a complete response in the individual. In some embodiments, the amount of the anti-NKG 2A antibody composition is sufficient to produce a partial response in the individual. In some embodiments, the amount of the anti-NKG 2A antibody composition administered (e.g., when administered alone) is sufficient to produce a total response rate of greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85% or 90% in a population of individuals treated with the anti-NKG 2A antibody composition. The response of an individual to a method of treatment described herein can be determined, for example, by the level of RECIST.
In some embodiments, the amount of the composition (e.g., the composition comprising an isolated anti-NKG 2A antibody) is sufficient to extend the progression free survival of the individual. In some embodiments, the amount of the composition is sufficient to extend the overall survival of the individual. In some embodiments, the amount of the composition (e.g., when administered alone) is sufficient to produce a clinical benefit of greater than 50%, 60%, 70%, or 77% in a population of individuals treated with an anti-NKG 2A antibody composition.
In some embodiments, the amount of a composition (e.g., a composition comprising an isolated anti-NKG 2A antibody), alone or in combination with a second, third, and/or fourth agent, is an amount sufficient to control symptoms and reduce the risk of exacerbations prior to treatment or as compared to the corresponding activity in other subjects not receiving treatment. The magnitude of the therapeutic effect can be measured using standard methods, such as in vitro assays for purified enzymes, cell-based assays, animal models, or human trials.
In some embodiments, when the composition is administered to an individual, the amount of anti-NKG 2A antibody (e.g., full length anti-NKG 2A antibody) in the composition is below a level that causes a toxic effect (i.e., an effect above a clinically acceptable toxicity level), or at a level where potential side effects can be controlled or tolerated.
In some embodiments, the amount of the composition approaches the Maximum Tolerated Dose (MTD) of the composition following the same dosing regimen. In some embodiments, the amount of the composition is greater than 80%, 90%, 95% or 98% of the MTD.
In some embodiments, the amount of anti-NKG 2A antibody (e.g., full length anti-NKG 2A antibody) in the composition is in the range of 0.001 μg to 1000 μg.
In any of the embodiments described above, the effective amount of anti-NKG 2A antibody (e.g., full length anti-NKG 2A antibody) in the composition is in the range of 0.1 μg/kg to 100mg/kg as calculated at body weight.
The anti-NKG 2A antibody composition may be administered to an individual (e.g., a human) by a variety of routes including, for example, intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, inhalational, intravascular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal, mucosal or transdermal. In some embodiments, a slow release formulation of the composition is used. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered through an artery. In some embodiments, the composition is administered intraperitoneally. In some embodiments, the composition is administered intrahepatially. In some embodiments, the composition is administered by hepatic arterial infusion. In some embodiments, the composition is applied to a site remote from the first lesion.
Product and kit
In some embodiments of the application, an article of manufacture is provided comprising a substance that is capable of being used to treat a disease associated with NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease), or to deliver an anti-NKG 2A antibody (e.g., a full-length anti-NKG 2A antibody) to cells that surface express NKG 2A. The article of manufacture may comprise a container and a label or package insert attached to or associated with the container. Suitable containers include, for example, bottles, vials, syringes, and the like. The container may be made of a variety of materials, such as glass or plastic. Typically, the container contains a composition effective to treat the diseases or conditions described herein and has a sterile port (e.g., the container may be an iv bag or a vial with a pierceable cap of a hypodermic injection needle). At least one active substance in the composition is the anti-NKG 2A antibody of the application. The label or package insert identifies the particular condition for which the composition may be used. The label or package insert further comprises instructions for administering the anti-NKG 2A antibody composition to the patient. Articles of manufacture and kits comprising combination therapies are within the contemplation herein.
Package insert refers to instructions that are typically contained within the commercial package of therapeutic products, including indications, usage, dosage, administration, contraindications, and/or warning information regarding the use of such therapeutic products. In some embodiments, the package insert indicates that the composition may be used to treat a disease associated with NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease). In some embodiments, the package insert indicates that the composition can be used to treat a disease including cancer, such as kidney cancer, bladder cancer, breast cancer, colon cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, uterine cancer, thyroid cancer, skin cancer, melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, follicular thyroid cancer, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome; viral diseases such as hepatitis A, B, C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes mellitus, uveitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, liver splenitis, keratitis, inner ear inflammation, laryngitis, lymphangitis, mastitis, otitis media, meningitis, metritis, mucositis, myocarditis, myositis, tympanitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like.
In addition, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffer, grignard solution, or dextrose solution. Other materials may be included as desired from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
Also, kits useful for various purposes, e.g., for treating diseases associated with NKG2A signaling pathways (e.g., cancer, viral diseases, autoimmune diseases, and/or inflammatory diseases), or for delivering anti-NKG 2A antibodies (e.g., full-length anti-NKG 2A antibodies) to cells that surface express NKG2A, optionally in combination with a preparation. Kits of the application include one or more containers comprising an anti-NKG 2A antibody composition (or single dose form and/or article of manufacture), and in some embodiments, further comprising another agent (e.g., an agent described herein) and/or instructions for use consistent with any of the methods described herein. The kit may further comprise a description of the selection of suitable individuals for treatment. The instructions for use attached to the kits of the application are typically written instructions on labels or packaging instructions (e.g., paper sheets contained within the kit), and machine-readable instructions (e.g., instructions on a magnetic or optical storage disc) are also acceptable.
For example, in some embodiments, the kit comprises a composition comprising an anti-NKG 2A antibody (e.g., a full length anti-NKG 2A antibody). In some embodiments, the kit comprises a) a composition comprising any of the anti-NKG 2A antibodies described herein, and b) at least one additional agent in an amount effective to enhance the effect (e.g., therapeutic effect, detection effect) of the anti-NKG 2A antibody. In some embodiments, the kit comprises a) a composition comprising any of the anti-NKG 2A antibodies described herein, and b) instructions for administering the anti-NKG 2A antibody composition to an individual for treating a disease associated with NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease). In some embodiments, the kit comprises a) a composition comprising any of the anti-NKG 2A antibodies described herein, and b) at least one additional agent in an amount effective to enhance the effect (e.g., therapeutic effect, detection effect) of the anti-NKG 2A antibody, and c) instructions for administering the anti-NKG 2A antibody composition and additional substances to an individual for treating a disease associated with the NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease). The anti-NKG 2A antibody and the other substance may be present in separate containers or in the same container. For example, the kit may comprise one specific composition or two or more compositions, wherein one composition comprises an anti-NKG 2A antibody and the other composition comprises another agent.
In some embodiments, the kit comprises a nucleic acid (or a set of nucleic acids) encoding an anti-NKG 2A antibody (e.g., a full-length anti-NKG 2A antibody). In some embodiments, the kit comprises a) a nucleic acid (or a set of nucleic acids) encoding an anti-NKG 2A antibody (e.g., a full-length anti-NKG 2A antibody), and b) a host cell expressing the nucleic acid (or the set of nucleic acids). In some embodiments, the kit comprises a) one (or a set of) nucleic acids encoding an anti-NKG 2A antibody (e.g., a full-length anti-NKG 2A antibody), and b) instructions for use, suitable for i) expressing the anti-NKG 2A antibody in a host cell, ii) preparing a composition comprising the anti-NKG 2A antibody, and iii) administering the composition comprising the anti-NKG 2A antibody to an individual to treat a disease associated with the NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease). In some embodiments, the kit comprises a) a nucleic acid (or set of nucleic acids) encoding an anti-NKG 2A antibody (e.g., a full-length anti-NKG 2A antibody), b) a host cell expressing the nucleic acid (or set of nucleic acids), and c) instructions for use, i) expressing the anti-NKG 2A antibody in the host cell, ii) preparing a composition comprising the anti-NKG 2A antibody, and iii) administering the composition comprising the anti-NKG 2A antibody to an individual to treat a disease associated with the NKG2A signaling pathway (e.g., cancer, viral disease, autoimmune disease, and/or inflammatory disease).
The kit of the application is packaged in a suitable form. Suitable packages include, but are not limited to, vials, bottles, jars, flexible packages (e.g., sealed mylar or plastic bags), and the like. The kit may optionally provide additional components, such as buffers and instructional information. Thus, the present application also provides articles, including vials, bottles, jars, flexible packages (e.g., sealed mylar or plastic bags), and the like.
Instructions for use of an anti-NKG 2A antibody composition typically include information such as dosage, period of administration, route of administration, and the like. The container may be unit dose, large package (e.g., multi-dose package) or subunit dose. For example, a kit comprising a sufficient dose of an anti-NKG 2A antibody as described herein (e.g., a full length anti-NKG 2A antibody) is provided for long term effective treatment of an individual, e.g., one week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. The kit may also comprise multiple unit doses of an anti-NKG 2A antibody, pharmaceutical compositions, and instructions for use, and be packaged in amounts sufficient for storage and use in a pharmacy, e.g., a hospital pharmacy and a compound pharmacy.
Those skilled in the art will recognize several embodiments that are possible within the scope and spirit of the application. The application will now be described in more detail by reference to the following non-limiting examples. The following examples further illustrate the application but should not be construed as in any way limiting its scope.
Detailed Description
Example 1 preparation of recombinant NKG2A antigen and screening for anti-NKG 2A antibody
Preparation of recombinant NKG2A antigen
Nucleic acid sequences encoding the extracellular region (94 aa-233aa,SEQ ID NO:114) of the human NKG2A (huNKG A) protein, the extracellular region (94 aa-233aa,SEQ ID NO:115) of the rhesus NKG2A (rheNKG A) protein, the extracellular region (32 aa-179aa,SEQ ID NO:117) of the human CD94 (huCD 94) protein, and the extracellular region (94 aa-231aa,SEQ ID NO:116) of the human NKG2C (huNKG C) protein were respectively constructed into expression vectors with human IgG Fc (huFc) or mouse IgG Fc (musFc) by subcloning, and the above expression vector plasmids were prepared according to established standard molecular biology methods.
The protein is expressed. Briefly, the huNKG A-Fc, huNKG2C-Fc, rheNKG2A-Fc fusion protein expression vector plasmids described above were co-transfected with huCD94-Fc expression vector plasmids, respectively, HEK293F cells, and the cells were cultured at 37℃under conditions of 5% CO 2 at 120rpm for 5 days, followed by harvesting the cell culture broth to obtain culture supernatants comprising huNKG A-huCD94-Fc heterodimer protein, huNKG C-huCD94-Fc protein heterodimer protein, or rheNKG A-huCD94-Fc heterodimer protein, respectively.
Recombinant proteins with Fc tags were purified using MabCap At FF pre-cartridge according to manufacturer's instructions. The specific procedure was as follows, protein purification was performed using MabCap At FF protein a resin (cat No. SA023C 15) from everlasting and biotechnology limited. The protein A column was first equilibrated with 6 column volumes of PBS buffer at a flow rate of 5ml/min. The pH of the culture supernatant was adjusted to 7.2, and the sample was applied at room temperature at a flow rate of 5ml/min. Subsequently, the column was again equilibrated with 6-10 column volumes of PBS buffer at a flow rate of 5ml/min. After complete equilibration, the target protein was collected and the pH was adjusted to neutral by adding 1M Tris (pH 9.0) and eluting with 6 column volumes of eluent (0.1M Gly,150mM NaCl,pH3.2). Ultrafiltering the solution into PBS solution with ultrafilter tube, and concentrating to a certain concentration.
Immunization and screening for anti-NKG 2A antibodies
New Zealand rabbits were immunized with huNKG A-huCD94-Fc heterodimer antigen, the immunized rabbit serum was collected, and the total IgG titer in the serum was detected by ELISA. After several rounds of immunization, 293T cell display pools were constructed using rabbit spleens. Briefly, the 293T cell display library is obtained by taking the spleen of immunized rabbits, sorting B cells, extracting RNA, obtaining cDNA through reverse transcription, amplifying V H and V K fragments by using V H and V K specific primers, recovering and purifying by glue, connecting V H and V K into a lentivirus shuttle vector with a constant region, packaging recombinant lentivirus, subsequently infecting 293T cells with the recombinant lentivirus, and displaying antibodies on the cell surface.
Screening for anti-NKG 2A antibodies specifically recognizing huNKG A were isolated from the 293T cell display library described above. Briefly, positive single cells that bound huNKG a-musFc were sorted out using a flow cytometer and cultured in 96-well plates. After 2 weeks huNKG, C, huNKG a protein was coated on an elisa plate, and cell supernatants were added to screen positive clones that bound to human NKG2A and not NKG 2C. Genomic DNA (gDNA) of positive clones was extracted, and V H and V K fragments were PCR amplified using V H and V K specific primers, followed by sequencing to obtain candidate leader antibody sequences. The variable domain sequences of the heavy and light chains of the candidate lead antibodies are shown in tables 2 and 3.
EXAMPLE 2 preparation and characterization of full Length anti-NKG 2A antibody
Preparation of full-Length antibodies against NKG2A
The sequenced rabbit anti-NKG 2A antibody sequences, V L and V H, were constructed into eukaryotic expression vectors pTTa1-rab-CLB4 (comprising the rabbit-derived light chain constant region) and pTTa-rab IgG4-H (comprising the rabbit-derived IgG4 heavy chain constant region) for the construction of rabbit antibodies (rab-IgG 4 version), respectively, and V L and V H sequences were constructed into pTTa1-rab-CLB4 (comprising the light chain constant region) and pTTa1-rabCH1-hFc (comprising the heavy chain constant region), respectively, for the construction of chimeric antibodies (rab-IgG 4-hFc version). The plasmids expressing the corresponding light chain and heavy chain extracted respectively were co-transfected into 293F cells and cultured at 37℃with 8% CO 2 at 120rpm for 5 days to obtain rabbit total antibodies or chimeric antibodies, respectively.
The culture broth was purified using a protein a affinity column. Briefly, the protein A column was first equilibrated with 6 column volumes of 50mM PBS buffer (containing 0.15M NaCl, pH 7.2) at a flow rate of 150 cm/h. The culture supernatant (pH adjusted to 7.2) was passed through the column at a flow rate of 150 cm/h. After further equilibration of the column, elution was performed with 50mM sodium citrate buffer (pH 3.5), the eluate was collected and the pH was adjusted to neutral. The IgG solution was replaced with PBS buffer using a desalting column, and after ultrafiltration and concentration, the IgG concentration was measured to obtain a full-length anti-NKG 2A antibody.
ELISA method for detecting affinity of anti-NKG 2A antibody
ELISA binding assay the purified rabbit fully anti-or chimeric antibody was subjected to a binding assay with huNKG2A, huNKG C antigen for the identification of the binding activity of anti-NKG 2A antibodies. Briefly, huNKG2A, huNKG C antigen at a concentration of 2. Mu.g/ml was coated onto 3590 ELISA plates, 100. Mu.l/well, incubated overnight at 4℃with 0.5% PBST wash plate 3 times, then the anti-NKG 2A antibody to be detected was added in gradient dilution (initial concentration 200. Mu.g/ml, 6-fold gradient dilution, total of 8 concentrations), 100. Mu.l/well, and 100. Mu.l BSA blocking solution, incubated at 37℃for 1h after mixing, the liquid in the ELISA plates was discarded, the plates were washed 3 times with 0.5% PBST, then 100. Mu.l/well of goat anti-human kappa-AP secondary antibody (Cat#2060-04, southern Biotech) diluted 1:4000 (1% BSA), incubated at 37℃for 1h, the liquid in the ELISA plates was discarded, 3 washes with 0.5% PBST, the residual liquid was spun-dried, finally 100. Mu.l PNPP was added per well, 37℃color was measured for 15min, OD405 was determined, and binding affinity to huNKG EC 2 candidate curves were generated by PRISM software, and the affinity values were calculated for A, huNKG EC.
As shown in FIGS. 1 and 2, the anti-NKG 2A antibodies ST14-R57, ST14-R58, ST14-R59, ST14-R60 (FIG. 1A, rab-IgG4 format), ST14-R76, ST14-R77, ST14-R78 (FIG. 1B, rab-IgG4 format), ST14-R79, ST14-R90 (FIG. 1C, rab-IgG4-hFc format), ST14-R12 (FIG. 1D, rab-IgG4 format), ST14-R358 (FIG. 1E, rab-IgG4-hFc format) were able to bind effectively to huNKG A with binding activity superior to or comparable to that of the positive control antibody Mon (NOVO NORDISK), M15 (Shanghai-cross) or A9 (BRISTOL MYERS SQUIBB), and the antibodies did not bind substantially to huNKG C (FIGS. 2A-2E).
Anti-NKG 2A antibody blocks NK cell NKG2A binding assay (cell level) to HLA-E tetramer
The NKG2A-CD94 heterodimer is expressed on the surface of NK cells, and its ligand HLA-E tetramer can bind to NKG2A on NK cells. This experiment detects the activity of a rabbit full antibody or chimeric anti-NKG 2A antibody to block HLA-E binding to NKG2A by detecting the binding of HLA-E tetramers to the NKG2A on the surface of NK cells (e.g., NKL cells or NK92 cells).
Briefly, NKG2A antibody to be tested was diluted with 1% BSA (Cat# BSCELL-0491, shanghai ear Biotechnology Co.) or NK92 cells (Cat# BNCC339981, north Achilles) to a concentration of 1.0X10. 10 6/ml and inoculated into 96-well plates, 100. Mu.l/well, blocked at 4℃for 30min, followed by addition of a gradient dilution (initial concentration of 20. Mu.g/ml, 4-fold gradient dilution, total of 8 gradients), 50. Mu.l/well, and 50. Mu.l of streptavidin-phycoerythrin (SA-PE) conjugated HLA-E tetramer (Cat#TS-ME 01-1, MBL) dilution (containing 1.2. Mu.l stock solution and 98.8. Mu.l PBS), wherein Mon, M15 or A9 antibody was used as positive control, the blank was supplemented with 100. Mu.l of 1% BSA, each well was blotted, incubated at 4℃for 1h away from light, and the cells were washed by flow cytometry. Antibody binding data were analyzed using FlowJo software and the proportion of positive cells with HLA-E fluorescent markers was expressed as positive (%).
The results of experiments for blocking the binding of NKG2A to HLA-E tetramers by anti-NKG 2A antibodies are shown in FIGS. 3 and 5, and exemplary anti-NKG 2A antibodies ST14-R57, ST14-R58, ST14-R76, ST14-R77, ST14-R78 (FIG. 3A and Table 5, rab-IgG4 form), ST14-R79, ST14-R90 (FIG. 3B, rab-IgG4-hFc form), ST14-R358 (FIG. 3C, rab-IgG4-hFc form) were each able to effectively block the binding of NKG2A to HLA-E tetramers, which blocking activity was superior to or comparable to that of the positive control antibodies Mon, M15 or A9.
The results of experiments for blocking NK92 cell NKG2A binding to HLA-E tetramer by anti-NKG 2A antibodies are shown in FIG. 4 and Table 5, and exemplary anti-NKG 2A antibodies ST14-R57, ST14-R58, ST14-R76, ST14-R77, ST14-R78 (FIG. 4A and Table 5, rab-IgG4 form), ST14-R12 (FIG. 4B, rab-IgG4 form) were each able to effectively block NK92 cell NKG2A binding to HLA-E tetramer, with blocking activity superior to or comparable to that of positive control antibody Mon or A9.
TABLE 5 Activity of anti-human NKG2A antibodies to block NK cell NKG2A binding to HLA-E tetramers
Detection of Cross-binding Activity of anti-NKG 2A antibodies against different species of NKG2A
The cross-binding activity of rabbit total or chimeric anti-NKG 2A antibodies to rhesus NKG2A (rheNKG a) was examined using the ELISA method in example 2.
As shown in FIGS. 5A-5C, exemplary anti-NKG 2A antibodies ST14-R57, ST14-R58 (FIG. 5A, rab-IgG4 format), ST14-R76, ST14-R77, ST14-R78 (FIG. 5B, rab-IgG4 format), ST14-R79, ST14-R90 (FIG. 5C, rab-IgG4-hFc format) have strong cross-binding activity with rheNKG A.
DELFIA EuTDA cytotoxicity assay for NKG2A antibody to promote killing activity of NKG cells on K562-E4 cells
After co-culturing NKG2A expressing NKG cells on the cell surface with K562-E4 cell line over expressing ligand HLA-E, the NKG2A/HLA-E signal may be activated, leading to intracellular ITIM phosphorylation, thus inhibiting the killing activity of the NKG cells. In this experiment, anti-NKG 2A antibody promotes the killing activity of NKG cells against K562-E4 target cells by neutralizing NKG2A expressed in NKG cells, and utilizesEuTDA cytotoxicity.The EuTDA cytotoxicity method (Cat#AD 0116, perkin Elmer) is to label target cells specifically with the fluorescent amplification ligand BATDA. BATDA can rapidly enter cells, and forms hydrophilic TDA under hydrolysis, which is remained in the cells and released under target cell lysis, and DELIFA Eu reagent is combined to form strong fluorescence and stable chelate EuTDA for detecting target cell lysis.
The K562-E4 stable transgenic cell line is constructed first. Briefly, K562 cells were electrotransfected with plasmid pIRES2-SA-HLAE-EGFP (from Shutaishen) and selectively cultured in 1640 medium containing 400. Mu.g/ml of antibiotic G418 (containing 10% FBS+1% P.S. Double antibody) for several days, followed by sorting out the cells with fluorescent expression by flow cytometry, and the sorted monoclonal cells were plated in 24-well plates, cultured in 1640 medium containing G418 antibiotic for 7-10 days, followed by expansion culture in 75cm cell culture flasks (Cat #430720, corning) to give a K562-E4 stable cell line.
Short peptide stimulation treatment of K562-E4 stably transformed cells were resuspended in 3ml of Opti-MEM containing 500. Mu.g/ml short peptide VMAPRTVLL (synthesized by Nanjing gold Style) and incubated overnight (about 16 h) at 26℃in a CO 2 incubator, cells were washed with 1 XPBS buffer, 1.5. Mu.l of fluorescence enhancing ligand BATDA (Cat#AD 0116, perkinelmer) was added per 1ml of cell suspension under dark conditions, mixed and incubated in a CO 2 incubator for 30min at 37℃and then centrifuged at 1300rpm for 5min to supernatant, resuspended in 1ml of 1 XPBS and transferred to a new 15ml centrifuge tube, and repeated 3 times to achieve the purpose of sufficient washing of residual BATDA in the medium. K562-E4 cells while BATDA was incubated, NKL cells were prepared.
NKL cells were cultured in MyeloCult TM H5100 medium (Cat# 05150,STEMCELL Technologies) supplemented with 1% diabody and 100IU/ml IL-2 (Cat#589106, biolegend). 100 μl of NKL cells with a density of 2×10 5/ml were inoculated into 96-well V-bottom plates (Cat#701201, NEST), 50 μl of gradient-diluted whole or chimeric anti-NKG 2A antibody (8 μg/ml,1.6 μg/ml,0.32 μg/ml) was added, mon, A9 antibody was used as positive control, no antibody was added to the negative control wells, and the mixture was pipetted and mixed and incubated in a CO 2 incubator for 15min. Subsequently 50. Mu.l/well of the BATDA treated K562-E4 cells (1X 10 4 cells/well), after mixing, centrifugation at 1000rpm for 5min, incubation in a 37℃CCO 2 incubator for 1h, 500g centrifugation for 5min, 20. Mu.l of the supernatant from each well was transferred to a 96-well flat bottom transparent plate (supplied by DELFIA EuTDA cytotoxicity kit), 200. Mu. l Europium Solution (Cat#AD 0116, perkinelmer) was added to each well, incubation at room temperature with shaking for 15min, and the fluorescence values of each well were detected by an ELISA reader. The killing rate was calculated from the fluorescence values of each well to measure the functional activity of the anti-NKG 2 antibody, and the calculation formula was as follows:
The killing rate was plotted and EC 50 values calculated.
As shown in fig. 6 and table 6, the exemplary anti-NKG 2A antibodies ST14-R57, ST14-R76, ST14-R78 (rab-IgG 4 form), ST14-R358 (rab-IgG 4-hFc form) were able to effectively enhance the killing activity of NKL cells against K562-E4 cells, and the killing activity was significantly superior to positive control antibodies Mon and A9.
TABLE 6 anti-human NKG2A antibodies enhance the killing activity of NKL cells against K562-E4 cells
Detection of NKG2A antibodies based on FACS of CD107a marker facilitates NKL cytotoxicity assays
Activation of the NKG2A-HLAE signal can inhibit the killing activity of NKL cells. CD107a (also known as lysosomal associated membrane protein-1 or LAMP-1) is a highly glycosylated transmembrane protein present in lysosomes. In NK cells and cytotoxic T cells, CD107a is one of the most abundant proteins in lysosomal particles, located in the inner layer of the vesicle membrane, with its highly glycosylated portion hidden on the luminal side and the short tail exposed to the cytoplasm. At the end of degranulation, the outer membrane of the particle merges with the NK cell membrane, resulting in the exposure of the CD107a molecule to the surface, a mechanism that protects effector cells from degranulation-related suicide. The expression of CD107a on the membrane is considered a marker for activation of cytotoxic lymphocytes. In this experiment, the anti-NKG 2A antibody neutralizes NKG2A expressed in NKL cells, thereby releasing the inhibitory activity on NKL cells and promoting activation of NK cells. This experiment characterizes the promotion of NKL cytotoxicity by anti-NKG 2A antibodies by detecting increased expression of CD107 a.
Short peptide stimulation treatment of K562-E4 cells were subjected to short peptide stimulation treatment using the protocol described in the DELFIA EuTDA cytotoxicity protocol of example 2, followed by seeding of 50. Mu.l of treated cells at a density of 2X 10 6/ml into 96 well U bottom plates (Cat #3799, costar) at 1X 10 5 cells/well.
NKL cell treatment, namely culturing NKL cells according to the method in the DELFIA EuTDA cytotoxicity method scheme of the embodiment 2, adjusting the cell density to 2X 10 6 cells/ml, inoculating 100 mu l of NKL cells to the 96-well U bottom plate, 2X 10 5 cells/well, adding 50 mu l of whole-antibody or chimeric anti-NKG 2A antibody (initial concentration is 20 mu g/ml and 5 times serial gradient dilution is carried out, and total concentration is 6), taking Mon and A9 antibody as positive control, taking out blank control without antibody, sucking and beating uniformly, and placing the blank control into a 37-DEG CCO 2 incubator for incubation for 30-50 min. Subsequently, the cells were homogenized with K562-E4 cells stimulated with the above-mentioned short peptides, centrifuged at 250g for 5min, incubated in a 37℃CCO 2 incubator for 2h, washed with 1% BSA solution, 100. Mu.l of 1% BSA solution was added to each well, and 2. Mu.l of anti-hCD 56 flow antibody (Cat#318328, bioleged) and 4. Mu.l of anti-hCD 107a flow antibody (Cat#328606, bioleged) were added to each well except for the blank. After pipetting and mixing, incubation for 30min at 4℃in the absence of light, followed by washing and resuspension of the cells with 1 XPBS, detection of fluorescent signals by flow cytometry and analysis of flow data by CytExpert, generation of a curve by GRAPHPAD PRISM 8.0.0 for analysis of the biological activity of each candidate antibody.
As shown in FIG. 7 and Table 7, the exemplary anti-NKG 2A antibodies ST14-R57, ST14-R76, ST14-R77, ST14-R78 (FIG. 7A and Table 7, rab-IgG4 form), ST14-R79, ST14-R90 (FIG. 7B and Table 7, rab-IgG4-hFc form), ST14-R358 (FIG. 7C, rab-IgG4-hFc form) were effective in enhancing the expression of CD107A in NKL cells, indicating that the anti-NKG 2A antibodies of the invention were effective in promoting NKL cytotoxicity and that the activity was superior to or comparable to that of positive control antibodies Mon, A-9 and M15.
TABLE 7 Activity of anti-human NKG2A antibodies to enhance the expression of CD107a of NKL cells
Example 3 humanization of anti-NKG 2A antibody
Based on the CDR typical structure of V H/VL of the obtained rabbit leader antibody ST14-R76, the sequences of the heavy chain variable region and the light chain variable region are compared with the sequences in an antibody seed factor database to obtain the human seed template with high homology. The CDR regions of rabbit antibodies are grafted onto selected human germline templates to produce humanized variable regions, which are recombined with corresponding human IgG constant regions (preferably IgG4 heavy and kappa light chains). Subsequently, the embedded residues, residues having direct interactions with the CDR regions, and residues having important effects on the conformation of V H and V L were back mutated based on the three-dimensional structure of the rabbit antibody, and the chemically unstable amino acid residues of the CDR regions were optimized, thereby obtaining 4 humanized molecules hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12. The variable domain sequences of the heavy and light chains of the humanized antibodies are shown in tables 2 and 3.
According to the above-mentioned humanization method, the rabbit leader antibody ST14-R78 was humanized and CDR-mutated in the same manner, thereby obtaining 23 humanized molecules hum-ST14-R78-1 to hum-ST14-R78-23. The variable domain sequences of the heavy and light chains of the humanized antibodies are shown in tables 2 and 3.
Example 4 characterization of humanized antibodies
The affinity and biological activity of the humanized anti-NKG 2A antibodies, including affinity assay, neutralization activity assay and biological activity assay, were separately tested using the corresponding protocols in example 2.
ELISA method for detecting affinity of humanized anti-NKG 2A antibody
The affinity protocol for anti-NKG 2A antibodies was tested using the ELISA method described in example 2, and the ability of humanized antibodies (human IgG4 form) to bind to NKG2A and NKG2C proteins was tested.
The results of the binding activity of humanized molecules derived from the lead antibody ST14-R76 are shown in FIG. 8 and Table 8A, and the humanized anti-NKG 2A antibody (human IgG4 form) hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 showed more excellent huNKG A binding activity than the lead antibody ST14-R76 (rab-IgG 4-hFc form), and none of the above antibodies was bound to huNKG C (data not shown), and the humanized modification did not affect the binding ability of the antibodies.
The results of the binding activity of the humanized molecules derived from the lead antibody ST14-R78 are shown in table 8B, and the humanized anti-NKG 2A antibodies (human IgG4 form) all showed huNKG a binding activity comparable to that of the lead antibody ST14-R78 (rab-IgG 4-hFc form), and none bound huNKG C (data not shown), and the humanized modification did not affect the binding ability of the antibodies.
TABLE 8 binding Activity of humanized anti-NKG 2A antibodies to human NKG2A
TABLE 8 binding Activity of humanized anti-NKG 2A antibodies to human NKG2A
FACS method for detecting affinity (cell level) of humanized anti-NKG 2A antibody
The binding activity of the humanized anti-NKG 2A antibody to huNKG2, 2A, huNKG2C at the cellular level was examined using FACS method.
A CHO cell line overexpressing huNKG2A, huNKG C was first constructed. Briefly, huNKG A-CD94, huNKG C-CD94 expression vector plasmids were transfected into CHO cells, respectively, followed by flow cytometry to sort cells positive for cell surface staining using anti-NKG 2A flow antibody (Cat#375119, bioleged) and anti-CD 94 flow antibody (Cat#305506, bioleged), to give huNKG A-CHO cells, huNKG C-CHO cells, respectively.
HuNKG2A-CHO cells and huNKG C-CHO cells with a density of 2X 10 6/ml were inoculated into 96-well plates, 100. Mu.l/well, followed by a gradient dilution of 100. Mu.l/well (maximum concentration of 20. Mu.g/ml, 5-fold dilution, total of 8 concentrations) of the humanized anti-NKG 2A antibody to be tested, incubation at 4℃for 2h, washing with streaming buffer (containing 1% BSA), addition of 50. Mu.l/well of anti-human IgG secondary antibody (1:250 dilution, cat:9040-09,Southern Biotech), incubation at 4℃for 1h, washing with streaming buffer (containing 1% BSA), and detection of secondary anti-marker fluorescence with a flow cytometer.
As shown in FIG. 9 and Table 9, the humanized anti-NKG 2A antibodies hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 (human IgG4 form) all showed comparable CHO-huNKG A cell binding activity as compared to the lead antibody ST14-R76 (rab-IgG 4-hFc form), and none bound to CHO-huNKG2C cells (data not shown), indicating that the humanized modification did not affect the binding capacity of the antibodies.
TABLE 9 binding Activity of humanized anti-NKG 2A antibodies to CHO surface NKG2A
Anti-NKG 2A antibody blocks the binding assay (cell level) of NKG2A of NKG cells to HLA-E tetramer
The blocking protocol for anti-NKG 2A antibodies was tested using the FACS method described in example 2, and the humanized antibodies (human IgG4 format) were tested for their ability to block binding of NKL cells to HLA-E tetramers.
As shown in FIG. 10 and Table 10A, the results of blocking activity of the humanized molecules derived from ST14-R76 show that the humanized anti-NKG 2A antibodies hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 (human IgG4 form) exhibit superior activity of blocking binding of NKG2A to HLA-E tetramers, as compared to the lead antibodies ST14-R76 (rab-IgG 4-hFc form).
The results of the blocking activity of the humanized molecules derived from ST14-R78 are shown in Table 10B, and the exemplary humanized anti-NKG 2A antibody hum-ST14-R78-1 to hum-ST14-R78-22 (human IgG4 form) exhibited better or comparable activity of blocking the binding of NKG2A to HLA-E tetramers of NKG cells than the lead antibody ST14-R78 (rab-IgG 4-hFc form).
TABLE 10A Activity of humanized anti-NKG 2A antibodies to block the binding of NKG2A of NKG cells to HLA-E tetramers
TABLE 10B Activity of humanized anti-NKG 2A antibodies to block the binding of NKG2A of NKG cells to HLA-E tetramers
Cross-species activity detection
The cross-binding activity of the anti-NKG 2A antibody to rhesus NKG2A was examined using the ELISA method in example 2, and the FACS method (cell level) in example 3.
The results of the cross-reactivity of the humanized molecules derived from ST14-R76 are shown in FIGS. 11A-11B and Table 11A, and the humanized anti-NKG 2A antibodies hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 (human IgG4 form) have strong binding activity to rheNKG A (FIGS. 11A and 11A) and CHO-rheNKG A cells (FIG. 11B and 11A).
The results of the cross-reactivity of the species derived from the humanized molecules of ST14-R78 are shown in Table 11B, which shows that exemplary humanized anti-NKG 2A antibodies (human IgG4 form )hum-ST14-R78-1、hum-ST14-R78-2、hum-ST14-R78-5、hum-ST14-R78-6、hum-ST14-R78-7、hum-ST14-R78-11、hum-ST14-R78-12、hum-ST14-R78-13、hum-ST14-R78-14 has strong binding activity to rheNKG A.
TABLE 11 binding Activity of humanized anti-NKG 2A antibodies to rheNKG A
TABLE 11 binding Activity of humanized anti-NKG 2A antibodies to rheNKG A
BIAcore method for determining affinity of anti-NKG 2A antibody
Biacore 8K (GE) was used to characterize the affinity of anti-NKG 2A antibodies to human NKG2A, rhesus NKG2A, respectively. anti-NKG 2A antibodies were immobilized on sensor chip CM5, the affinities of antibodies at different concentrations with huNKG a-CD94 heterodimer protein, rheNKG a-CD94 heterodimer protein, respectively, were measured using SPR techniques to measure the binding and dissociation rates of the antibodies, and the binding affinities were determined.
The Kon, koff and Kd values of the anti-NKG 2A antibodies are shown in Table 12, from which it can be seen that the exemplary humanized anti-NKG 2A antibodies hum-ST14-R76-9, hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 (human IgG4 form) bind not only to human NKG2A, but also to rhesus NKG 2A.
TABLE 12 Biacore assay for the detection of the affinity of humanized antibodies
DELFIA EuTDA cytotoxicity assay to detect the killing Activity of humanized anti-NKG 2A antibodies against K562-E4 cells by NKL cells
Detection of humanized anti-NKG 2A antibodies by DELFIA EuTDA cytotoxicity as defined in example 2 promoted killing activity of NKL cells against K562-E4 cells.
The results of the humanized molecules derived from ST14-R76 are shown in FIG. 12 and Table 13A, and the humanized anti-NKG 2A antibodies hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 (human IgG4 form) all showed comparable killing activity against K562-E4 target cells by NKL cells, which was significantly superior to that of the control antibody Mon, compared to the ST14-R76 guide antibody (rab-IgG 4-hFc form).
The results of the killing activity of humanized molecules derived from ST14-R78 are shown in table 13B, exemplary humanized anti-NKG 2A antibody hum-ST14-R78-1、hum-ST14-R78-2、hum-ST14-R78-5、hum-ST14-R78-6、hum-ST14-R78-7、hum-ST14-R78-8、hum-ST14-R78-11、hum-ST14-R78-12、hum-ST14-R78-13、hum-ST14-R78-16、hum-ST14-R78-17、hum-ST14-R78-18( human IgG4 form) is capable of promoting killing of K562-E4 target cells by NKL cells, and the killing activity is superior to or comparable to positive control antibody M15.
TABLE 13A humanized anti-human NKG2A antibodies promote the killing activity of NKL cells against K562-E4 cells
TABLE 13B humanized anti-human NKG2A antibodies enhance the killing activity of NKL cells against K562-E4 cells
Detection of NKG2A antibodies based on FACS of CD107a marker facilitates NKL cytotoxicity assays
Anti-NKG 2A antibodies were tested for promotion of NKL cytotoxic activity using the FACS protocol based on CD107a markers described in example 2.
The results of humanized molecules derived from ST14-R76 are shown in FIG. 13 and Table 14A, and exemplary humanized anti-NKG 2A antibodies hum-ST14-R76-10, hum-ST14-R76-12 (human IgG4 form) exhibited comparable activity to that of the ST14-R76 lead antibody (rab-IgG 4-hFc form) for effectively enhancing CD107a expression in NKL cells.
The results of humanized molecules derived from ST14-R78 are shown in Table 14B, and the exemplary humanized anti-NKG 2A antibodies hum-ST14-R78-16, hum-ST14-R76-17 (human IgG4 form) exhibited comparable activity to that of the ST14-R78 lead antibody (rab-IgG 4-hFc form) for effectively enhancing CD107a expression in NKL cells, and were all superior to that of the positive control antibody M15.
TABLE 14A Activity of humanized anti-NKG 2A antibodies to enhance the expression of CD107a of NKL cells
TABLE 14B Activity of humanized anti-NKG 2A antibodies to enhance the expression of CD107a of NKL cells
Detection of humanized anti-NKG 2A antibody by DELFIA EuTDA cytotoxicity method for promoting NK cell killing activity on K562-E4 cells
Construction of K562-E4 cells and short peptide stimulation treatment protocol using the DELFIA EuTDA cytotoxicity protocol as described in example 2.
NK cell treatment NK cells (Cat#PB56-N-1C, TPCS) were cultured in NK medium (Cat#130-114-429, miltenyi) according to the culture method known to those skilled in the art, other treatment procedure was performed using the DELFIA EuTDA cytotoxicity protocol as described in example 2, wherein Mon, M15 antibodies were used as positive control, negative Control (NC) was not added with antibodies, and finally fluorescence values were measured with an ELISA.
As a result, as shown in FIG. 14, the exemplary humanized anti-NKG 2A antibodies hum-ST14-R76-10, hum-ST14-R76-11, hum-ST14-R76-12 (human IgG4 form) were effective in promoting the killing activity of NK cells against K562-E4 target cells, and the killing activity was superior to or comparable to that of the positive control antibodies Mon and M15.
EXAMPLE 5 pharmacokinetics of anti-NKG 2A-antibodies in rats
The 8 SD rats were randomly divided into 2 groups of 4, male and female halves. Each group of rats was intravenously injected with an anti-NKG 2A antibody to be tested, with M15 antibody as a positive control. 200-300 μl of serum is collected from the posterior venous plexus of the orbit after the animal orbit at 0h before administration, 15min after administration, 1h, 5h, 1d, 3d, 7d, 10d and 14d, and is placed at-20 ℃ for frozen storage and test after split charging. The serum drug concentration in each sample was determined by ELISA. GRAPHPAD PRISM 7 was used to plot the pharmaceutical time profile.
The results are shown in FIG. 15, where the plasma concentration of mice after administration of the exemplary anti-NKG 2A antibody hum-ST14-R76-10 (human IgG4 form) was substantially consistent with the trend of the positive control antibody M15.
Other exemplary anti-NKG 2A antibodies hum-ST14-R76-9, hum-ST14-R76-11, hum-ST14-R76-12 (human IgG4 form) also showed the same trend of blood concentration change (data not shown).

Claims (22)

  1. An isolated anti-NKG 2A antibody, wherein said anti-NKG 2A antibody comprises:
    a heavy chain variable domain (V H), the V H comprising:
    Heavy chain complementarity determining region (HC-CDR) 1 comprising SNTMS (SEQ ID NO: 1);
    HC-CDR2 comprising NINTGGNTYYANWAKG (SEQ ID NO: 9), and
    HC-CDR3 comprising GSTIDSSGLSL (SEQ ID NO: 24), and
    A light chain variable domain (V L), the V L comprising:
    A light chain complementarity determining region (LC-CDR) 1 comprising QASQNIGSDLA (SEQ ID NO: s);
    LC-CDR2 comprising LASTLAS (SEQ ID NO: 43), and
    LC-CDR3 comprising QQX 1 WSSSNVDNV (SEQ ID NO: 66) wherein X 1 is C, S or T.
  2. The isolated anti-NKG 2A antibody of claim 1, comprising:
    (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:33, LC-CDR2 comprising amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising amino acid sequence SEQ ID NO:51;
    (ii) V H, said V H comprising HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, and said V L comprising LC-CDR1 comprising the amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:52, or V L comprising LC-CDR2 comprising the amino acid sequence SEQ ID NO:43
    (Iii) V H, which V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:24, and V L, which V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:33, LC-CDR2 comprising the amino acid sequence SEQ ID NO:43, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:53.
  3. The isolated anti-NKG 2A antibody of any one of claims 1-2, comprising:
    (i) V H comprising the amino acid sequence SEQ ID NO. 68 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 68, and V L comprising the amino acid sequence SEQ ID NO. 92 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 92;
    (ii) V H comprising the amino acid sequence SEQ ID NO. 69 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 69, and V L comprising the amino acid sequence SEQ ID NO. 93 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 93;
    (iii) V H comprising the amino acid sequence SEQ ID NO. 70 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 70, and V L comprising the amino acid sequence SEQ ID NO. 93 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 93;
    (iv) V H comprising the amino acid sequence SEQ ID NO. 69 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 69, and V L comprising the amino acid sequence SEQ ID NO. 94 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 94;
    (v) V H comprising the amino acid sequence SEQ ID NO. 70 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 70, and V L comprising the amino acid sequence SEQ ID NO. 94 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 94, or
    (Vi) V H comprising the amino acid sequence SEQ ID NO. 71 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 71, and V L comprising the amino acid sequence SEQ ID NO. 95 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 95.
  4. An isolated anti-NKG 2A antibody, wherein said anti-NKG 2A antibody comprises:
    a heavy chain variable domain (V H), the V H comprising:
    Heavy chain complementarity determining region (HC-CDR) 1 comprising NYHMS (SEQ ID NO: 2);
    HC-CDR2 comprising YIGAAX 1X2X3 YYASWAKG (SEQ ID NO: 65) wherein X 1 is G, N or S, X 2 is N or S, X 3 is A, I or T, and
    HC-CDR3 comprising GVIYNNL (SEQ ID NO: 25), and
    A light chain variable domain (V L), the V L comprising:
    A light chain complementarity determining region (LC-CDR) 1 comprising QASESISNYLS (SEQ ID NO: 34);
    LC-CDR2 comprising DASDLAS (SEQ ID NO: 44), and
    LC-CDR3 comprising QX 1TYGSINX2 NYGVA (SEQ ID NO: 67), wherein X 1 is A or C and X 2 is A, Q or S.
  5. The isolated anti-NKG 2A antibody of claim 4, comprising:
    (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:54;
    (ii) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55;
    (iii) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56;
    (iv) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56;
    (v) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:56;
    (vi) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:13, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55;
    (vii) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:14, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55;
    (viii) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:15, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55;
    (ix) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:16, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55;
    (x) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:11, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55;
    (xi) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:12, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:55, or
    (Xii) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:2, HC-CDR2 comprising amino acid sequence SEQ ID NO:10, and HC-CDR3 comprising amino acid sequence SEQ ID NO:25, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:34, LC-CDR2 comprising amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising amino acid sequence SEQ ID NO:57.
  6. The isolated anti-NKG 2A antibody of any one of claims 4-5, comprising:
    (i) V H comprising the amino acid sequence SEQ ID NO. 72 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 72, and V L comprising the amino acid sequence SEQ ID NO. 96 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 96;
    (ii) V H comprising the amino acid sequence SEQ ID NO. 73 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 73, and V L comprising the amino acid sequence SEQ ID NO. 97 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 97;
    (iii) V H comprising the amino acid sequence SEQ ID NO. 74 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 74, and V L comprising the amino acid sequence SEQ ID NO. 97 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 97;
    (iv) V H comprising the amino acid sequence SEQ ID NO 75 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 75, and V L comprising the amino acid sequence SEQ ID NO 97 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 97;
    (v) V H comprising the amino acid sequence SEQ ID NO. 76 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 76, and V L comprising the amino acid sequence SEQ ID NO. 97 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 97;
    (vi) V H comprising the amino acid sequence SEQ ID NO. 77 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 77, and V L comprising the amino acid sequence SEQ ID NO. 97 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 97;
    (vii) V H comprising the amino acid sequence SEQ ID NO. 78 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 78, and V L comprising the amino acid sequence SEQ ID NO. 97 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 97;
    (viii) V H comprising the amino acid sequence SEQ ID NO. 73 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 73, and V L comprising the amino acid sequence SEQ ID NO. 98 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 98;
    (ix) V H comprising the amino acid sequence SEQ ID NO. 74 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 74, and V L comprising the amino acid sequence SEQ ID NO. 98 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 98;
    (x) V H comprising the amino acid sequence SEQ ID NO 75 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 75, and V L comprising the amino acid sequence SEQ ID NO 98 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO 98;
    (xi) V H comprising the amino acid sequence SEQ ID NO. 76 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 76, and V L comprising the amino acid sequence SEQ ID NO. 98 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 98;
    (xii) V H comprising the amino acid sequence SEQ ID NO. 77 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 77, and V L comprising the amino acid sequence SEQ ID NO. 98 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 98;
    (xiii) V H comprising the amino acid sequence SEQ ID NO. 78 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 78, and V L comprising the amino acid sequence SEQ ID NO. 98 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 98;
    (xiv) V H comprising the amino acid sequence SEQ ID NO. 78 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 78, and V L comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99;
    (xv) V H comprising the amino acid sequence SEQ ID NO. 78 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 78, and V L comprising the amino acid sequence SEQ ID NO. 100 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 100;
    (xvi) V H comprising the amino acid sequence SEQ ID NO. 79 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 79, and V L comprising the amino acid sequence SEQ ID NO. 100 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 100;
    (xvii) V H comprising the amino acid sequence SEQ ID NO. 80 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 80, and V L comprising the amino acid sequence SEQ ID NO. 100 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 100;
    (xviii) V H comprising the amino acid sequence SEQ ID NO. 81 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 81, and V L comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99;
    (xix) V H comprising the amino acid sequence SEQ ID NO. 82 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 82, and V L comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99;
    (xx) V H comprising the amino acid sequence SEQ ID NO. 83 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 83, and V L comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99;
    (xxi) V H comprising the amino acid sequence SEQ ID NO. 84 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 84, and V L comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99;
    (xxii) V H comprising the amino acid sequence SEQ ID NO. 79 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 79, and V L comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99;
    (xxiii) V H comprising the amino acid sequence SEQ ID NO. 80 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 80, and V L comprising the amino acid sequence SEQ ID NO. 99 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 99, or
    (Xxiv) V H comprising the amino acid sequence SEQ ID NO. 78 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 78, and V L comprising the amino acid sequence SEQ ID NO. 101 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO. 101.
  7. An isolated anti-NKG 2A antibody, comprising:
    (i) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:1, HC-CDR2 comprising amino acid sequence SEQ ID NO:9, and HC-CDR3 comprising amino acid sequence SEQ ID NO:24, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:35, LC-CDR2 comprising amino acid sequence SEQ ID NO:45, and LC-CDR3 comprising amino acid sequence SEQ ID NO:51;
    (ii) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:17, and HC-CDR3 comprising amino acid sequence SEQ ID NO:26, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:36, LC-CDR2 comprising amino acid sequence SEQ ID NO:46, and LC-CDR3 comprising amino acid sequence SEQ ID NO:58;
    (iii) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:3, HC-CDR2 comprising amino acid sequence SEQ ID NO:18, and HC-CDR3 comprising amino acid sequence SEQ ID NO:27, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:37, LC-CDR2 comprising amino acid sequence SEQ ID NO:47, and LC-CDR3 comprising amino acid sequence SEQ ID NO:59;
    (iv) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:4, HC-CDR2 comprising amino acid sequence SEQ ID NO:19, and HC-CDR3 comprising amino acid sequence SEQ ID NO:28, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:38, LC-CDR2 comprising amino acid sequence SEQ ID NO:48, and LC-CDR3 comprising amino acid sequence SEQ ID NO:60;
    (v) V H comprising HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, HC-CDR2 comprising the amino acid sequence SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:29, and V L comprising LC-CDR1 comprising the amino acid sequence SEQ ID NO:39, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:61;
    (vi) V H, said V H comprising HC-CDR1 comprising amino acid sequence SEQ ID NO:6, HC-CDR2 comprising amino acid sequence SEQ ID NO:21, and HC-CDR3 comprising amino acid sequence SEQ ID NO:30, and V L, said V L comprising LC-CDR1 comprising amino acid sequence SEQ ID NO:40, LC-CDR2 comprising amino acid sequence SEQ ID NO:49, and LC-CDR3 comprising amino acid sequence SEQ ID NO:62;
    (vii) V H, which V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence SEQ ID NO:22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:31, and V L, which V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:41, LC-CDR2 comprising the amino acid sequence SEQ ID NO:44, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:63, or
    (Viii) V H, which V H comprises HC-CDR1 comprising the amino acid sequence SEQ ID NO:8, HC-CDR2 comprising the amino acid sequence SEQ ID NO:23, and HC-CDR3 comprising the amino acid sequence SEQ ID NO:32, and V L, which V L comprises LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, LC-CDR2 comprising the amino acid sequence SEQ ID NO:50, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:64.
  8. The isolated anti-NKG 2A antibody of claim 7, comprising:
    (i) V H comprising the amino acid sequence shown as SEQ ID NO. 68 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 68, and V L comprising the amino acid sequence shown as SEQ ID NO. 102 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 102;
    (ii) V H comprising the amino acid sequence set forth in SEQ ID No. 85 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID No. 85, and V L comprising the amino acid sequence set forth in SEQ ID No. 103 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID No. 103;
    (iii) V H comprising the amino acid sequence set forth in SEQ ID NO. 86 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 86, and V L comprising the amino acid sequence set forth in SEQ ID NO. 104 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO. 104;
    (iv) V H comprising the amino acid sequence shown as SEQ ID NO. 87 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 87, and V L comprising the amino acid sequence shown as SEQ ID NO. 105 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 105;
    (v) V H comprising the amino acid sequence shown as SEQ ID NO. 88 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 88, and V L comprising the amino acid sequence shown as SEQ ID NO. 106 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 106;
    (vi) V H comprising the amino acid sequence shown as SEQ ID NO. 89 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 89, and V L comprising the amino acid sequence shown as SEQ ID NO. 107 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 107;
    (vii) V H comprising the amino acid sequence shown as SEQ ID NO. 90 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 90, and V L comprising the amino acid sequence shown as SEQ ID NO. 108 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 108, or
    (Viii) V H comprising the amino acid sequence shown as SEQ ID NO. 91 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 91, and V L comprising the amino acid sequence shown as SEQ ID NO. 109 or a variant thereof having at least about 80% sequence identity to the amino acid sequence shown as SEQ ID NO. 109.
  9. The isolated anti-NKG 2A antibody of any one of claims 1-8, wherein the anti-NKG 2A antibody binds to human NKG2A with a Kd value of about 0.1pM to about 10nM.
  10. The isolated anti-NKG 2A antibody according to any one of claims 1-9, wherein said anti-NKG 2A antibody comprises an Fc fragment.
  11. The isolated anti-NKG 2A antibody according to claim 10, wherein said anti-NKG 2A antibody is a full length IgA, igD, igE, igG or IgM antibody.
  12. The isolated anti-NKG 2A antibody of claim 11, wherein said anti-NKG 2A antibody is a full length IgG1, igG2, igG3 or IgG4 antibody.
  13. The isolated anti-NKG 2A antibody of any one of claims 1-12, wherein said anti-NKG 2A antibody is a chimeric, human or humanized antibody.
  14. The isolated anti-NKG 2A antibody of any one of claims 1-9, wherein the anti-NKG 2A antibody is an antigen-binding fragment selected from the group consisting of Fab, fab ', F (ab) ' 2, fab ' -SH, single chain Fv (scFv), fv fragment, dAb, fd, nanobody, diabody, and linear antibody.
  15. An isolated nucleic acid molecule encoding the anti-NKG 2A antibody of any one of claims 1-14.
  16. A vector comprising the nucleic acid molecule of claim 15.
  17. An isolated host cell comprising the anti-NKG 2A antibody of any one of claims 1-14, the nucleic acid molecule of claim 15, or the vector of claim 16.
  18. A method of making an anti-NKG 2A antibody, comprising:
    a) Culturing the host cell of claim 17 under conditions effective to express an anti-NKG 2A antibody, and
    B) The expressed anti-NKG 2A antibodies are obtained from the host cells.
  19. A pharmaceutical composition comprising the anti-NKG 2A antibody of any one of claims 1-14, the nucleic acid molecule of claim 15, the vector of claim 16, the isolated host cell of claim 17, or the antibody produced by the method of claim 18, and a pharmaceutically acceptable carrier.
  20. Use of the antibody of any one of claims 1-14, the nucleic acid molecule of claim 15, the vector of claim 16, the host cell of claim 17, the antibody produced by the method of claim 18, or the pharmaceutical composition of claim 19 in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.
  21. Use according to claim 20, wherein the disease or disorder is a disease and/or disorder caused by a deregulation of NKG2A signaling pathway, such as cancer, viral diseases, autoimmune diseases and/or inflammatory diseases.
  22. The use according to claim 21, wherein the disease or disorder is selected from cancers such as kidney, bladder, breast, colon, liver, lung, ovary, prostate, pancreas, stomach, uterus, thyroid, skin, melanoma, colored xeroderma, keratoacanthoma, seminoma, follicular thyroid, teratocarcinoma, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burketts lymphoma, multiple myeloma, acute and chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome; viral diseases such as hepatitis A, B, C, influenza, varicella, adenovirus, herpes simplex type I (HSV-1), herpes simplex type II (HSV-2), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type 1 or type 2 (HIV-1, HIV-2), autoimmune diseases such as hemolytic anemia, pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus, wegener's granulomatosis, autoimmune hepatitis, behcet's disease, crohn's disease, primary biliary cirrhosis, scleroderma, ulcerative colitis, sjogren's syndrome, type 1 diabetes mellitus, uveitis, ulcerative colitis, graves 'disease, alzheimer's disease, thyroiditis, inflammatory diseases such as conjunctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachian tube inflammation, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, liver splenitis, keratitis, inner ear inflammation, laryngitis, lymphangitis, mastitis, otitis media, meningitis, metritis, mucositis, myocarditis, myositis, tympanitis, nephritis, neuritis, orchitis, osteochondritis, otitis, pericarditis, tenosynovitis, peritonitis, pharyngitis, phlebitis, and the like.
CN202380065866.8A 2022-09-16 2023-09-14 Antibodies specifically recognizing NKG2A and uses thereof Pending CN119866349A (en)

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WO2025190332A1 (en) * 2024-03-14 2025-09-18 北京三诺佳邑生物技术有限责任公司 Multi-specific antibody specifically binding to nkg2a antigen and pd-l1 antigen, and use of multi-specific antibody
WO2026001907A1 (en) * 2024-06-24 2026-01-02 Elpiscience (Suzhou) Biopharma, Ltd. Anti-nkg2a antibodies, fusion proteins and uses thereof

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DK1831258T4 (en) * 2004-12-28 2023-08-28 Innate Pharma Sa Monoklonale antistoffer mod NKG2A
JP5774312B2 (en) * 2008-01-24 2015-09-09 ノボ・ノルデイスク・エー／エス Humanized anti-human NKG2A monoclonal antibody
US12534526B2 (en) * 2018-11-07 2026-01-27 Shanghai Hyamab Biotech Co., Ltd. NKG2A antibody, preparation method therefor and application thereof
JP7520003B2 (en) * 2018-11-16 2024-07-22 ブリストル－マイヤーズ スクイブ カンパニー Anti-NKG2A Antibodies and Uses Thereof
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