CN118324910A - Application of CCR8 antibody - Google Patents
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- CN118324910A CN118324910A CN202310037623.5A CN202310037623A CN118324910A CN 118324910 A CN118324910 A CN 118324910A CN 202310037623 A CN202310037623 A CN 202310037623A CN 118324910 A CN118324910 A CN 118324910A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- 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
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to the use of CCR8 antibodies. In particular, the disclosure relates to the use of a novel immunomodulator, in particular an antibody or antigen binding portion thereof that binds CCR 8. The application of the immunomodulator is mainly to treat non-Hodgkin's lymphoma, especially skin T cell lymphoma, peripheral T cell lymphoma and adult T cell lymphoma/leukemia.
Description
Technical Field
The present invention relates to the field of immunotherapy. More particularly to a method for treating cutaneous T cell lymphoma, peripheral T cell lymphoma and adult T cell lymphoma/leukemia by using a humanized monoclonal antibody targeting CCR8 and novel uses thereof.
Background
Cutaneous T Cell Lymphoma (CTCL) is one of Non-Hodgkin's lymphoma (NHL), a disease that is primarily in the skin caused by clonal proliferation of T lymphocytes. Mycosis fungoides (Mycosis fungoides, MF) and Sezary Syndrome (SS) are the two most common subtypes of cutaneous T cell lymphoma. Mycosis fungoides accounts for 50% -70% of cutaneous T cell lymphomas, which can lead to itchy rashes and skin wounds, and can spread to other parts of the body. Szechuri syndrome is a rare cutaneous lymphoma that affects blood and lymph nodes. The pathogenesis of cutaneous T cell lymphomas is currently unknown, and patients take an average of 2-7 years to be diagnosed. Prognosis for advanced patients is significantly worse, with survival of about half of patients (52%) being only 5 years.
Peripheral T cell lymphomas (ptcl) are a group of heterogeneous diseases that originate from postthymus T lymphocytes or mature NK cells. Peripheral T cell lymphoma is not a disease, but a group of diseases.
Adult T cell lymphoma/leukemia (ATLL) is a special type of malignant clonal proliferative disease of the lymphatic system that occurs in adults directly related to human T cell leukemia virus I (HTLV-I) infection, the pathology of which occurs mainly in peripheral blood lymphocytes, but also invades bone marrow. The disease was first proposed by Japanese scholars Gao Yueqing in 1976 and is characterized clinically by hepatopathy, splenomegaly, lymphadenopathy, skin infiltration, interstitial lung infiltration and hypercalcemia.
Chemokine receptor 8 (CCR 8) is a member of the C-C chemokine receptor superfamily and is upregulated in activated type II Th cell expression and its ligand CCL1/I-309 is effective in recruiting activated type II Th cells. The interaction of CCL1 with CCR8 (also known as CCL1/CCR8 axis) and the associated (D′Ambrosio,D.,et al.1998.Selective up-re gulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2Th cells.J Immunol 161(10)：5111-5;Zingoni,A.,et al.1998.The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells.J Immunol 161(2)：547-51.).CCL1 of type II Th cell mediated immune responses activate CCR8 mediated RAS/MAPK signaling pathways, promote intracellular calcium flux release, and inhibit apoptosis ( Denis,C.,et al.2012.C-terminal clipping of chemokine CCL1/I-309 enhances CCR8-mediated intracellular calcium release and anti-apoptotic activity.PLoS One 7(3)：e34199;Louahed,J.,et al.2003.CCR8-dependent activation of the RAS/MAPK pathway mediates anti-apoptotic activity of I-309/CCL1and vMIP-I.EurJ Immunol 33(2)：494-501).CCR8 to maintain regulatory T cell (Treg) survival, inhibit graft versus host response (GVHD) (Coghill,J.M.,et al.2013CC chemokine receptor 8potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease.Blood 122(5)：825-36.).CCR8+Treg is also believed to be a critical cell driving immunosuppressive effects, A potential therapeutic target (Barsheshet,Y.,et al.2017.CCR8(+)FOXp3(+)T(reg)cells as master drivers of immune regulation.Proc Natl Acad Sci USA 114(23)：6086-6091).CCR8 for autoimmune diseases is a class of mycosis in which chemokine receptors [McCully ML,Ladell K,Hakobyan S,Mansel RE,Price DA,Moser B.Epidermis instructs skin homing receptor expression in human T cells.Blood.2012;120(23)：4591-4598.], associated with lymphocyte skin homing are expressed in cutaneous memory T cells [McCully ML,Ladell K,Andrews R,et al.CCR8 expression defines tissue-resident memory T cells in human skin.J Immunol.2018;200(5)：1639-1650], cutaneous T cell lymphomas is thought to originate from this class of cells [Clark RA,Watanabe R,Teague JE,et al.Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab treated CTCL patients.Sci Transl Med.2012;4(117)：117ra7.]. and CCR8 is also expressed in tumor-infiltrating tregs, the [Van Damme H,Dombrecht B,Kiss M,et al.Therapeutic depletion of CCR8+tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1therapy.J Immunother Cancer.2021;9(2)：e001749;Plitas G,Konopacki C,Wu K,et al.Regulatory T cells exhibit distinct features in human breast cancer.Immunity.2016;45(5)：1122-1134.], is not or seldom expressed in the peripheral blood Treg, so that the tumor cells and the tumor invasive Treg are specifically killed by the anti-CCR 8 antibody or other CCR 8-targeted therapies, not only are the tumor cells directly killed, but also the anti-tumor immune response is enhanced, and simultaneously, the toxic response [Campbell JR,McDonald BR,Mesko PB,et al.Fc-optimized anti-CCR8 antibody depletes regulatory T cells in human tumor models.Cancer Res.2021;81(11)：2983-2994.]. caused by the deletion of the peripheral Treg is not brought about from the tumor microenvironment, Achieving specific clearance of suppressor Treg cells has been a significant challenge, for example, the use of non-fucosylated anti-CCR 4 antibody mogamulizumab while clearing Treg also significantly reduces the significant increase in expression of normal cd4+ T cells and cd8+ T cells (Kurose,K.,et al.2015 Phase Ia Study of FoxP3+CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody,KW-0761,in Cancer Patients.Clin Cancer Res 21(19)：4327-36).CCR8 on tumor-infiltrating Treg cells, facilitating differentiation of tumor-infiltrating Treg cells from normal T cells by CCR 8-targeting antibodies. therefore, developing therapies targeting CCR8 to effectively eliminate tumor-infiltrating Treg cells and cutaneous T cell lymphoma cells is currently an urgent clinical need for immunotherapy.
At present, no medicine for treating skin T cell lymphoma by taking CCR8 as a target spot, peripheral T cell lymphoma and adult T cell lymphoma/leukemia enter a clinical research stage. Preclinical studies have shown that the use of CCR 8-targeting CAR-T therapies can effectively inhibit the growth [Zheng DW,Wang XD,Cheng L,et al.The Chemokine Receptor CCR8 Is a Target of Chimeric Antigen T Cells for Treating T Cell Malignancies.Front Immunol.2022 May 26;13：808347], of CCR 8-positive T cell lymphomas both in vivo and in vitro, demonstrating that CCR8 can be a potential target for the treatment of CCR 8-positive tumors. However, the CAR-T therapy is complex in preparation process, high in price, high in toxic and side effects and difficult to benefit most patients. Monoclonal antibody therapy is more convenient and cheaper to administer than CAR-T therapy, and patient compliance is higher. Treatment of cutaneous T cell lymphoma using CCR8 monoclonal antibodies is therefore a potential therapeutic modality.
Disclosure of Invention
The present disclosure relates to the treatment of cutaneous T cell lymphoma, peripheral T cell lymphoma, and adult T cell lymphoma/leukemia with CCR8 humanized monoclonal antibodies.
In particular, the invention relates to the following aspects:
in one aspect, the invention relates to the use of a CCR8 antibody or antigen binding portion thereof, or a nucleic acid molecule encoding said antibody or antigen binding portion thereof, or a composition comprising said antibody or antigen binding portion thereof, in the manufacture of a medicament for the treatment or prevention of non-hodgkin's lymphoma in a subject.
In another aspect, the invention relates to a method for treating or preventing non-hodgkin's lymphoma in a subject comprising administering to the subject a therapeutically or prophylactically effective amount of a CCR8 antibody or antigen binding portion thereof, or a nucleic acid molecule encoding said antibody or antigen binding portion thereof, or a composition comprising said antibody or antigen binding portion thereof.
In another aspect, the invention relates to a CCR8 antibody or antigen binding portion thereof, or a nucleic acid molecule encoding said antibody or antigen binding portion thereof, or a composition comprising said antibody or antigen binding portion thereof, for use in the treatment or prevention of non-hodgkin's lymphoma in a subject.
In one embodiment, the non-hodgkin's lymphoma is selected from cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and adult T-cell lymphoma/leukemia.
In one embodiment, the CCR8 antibody or antigen binding portion thereof comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, and a light chain CDR1, a light chain CDR2, and a light chain CDR3, the heavy chain CDR1 comprising a sequence selected from the group consisting of SEQ ID NOs: 2 and 6, said heavy chain CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 3 and 8, and the heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:4, an amino acid sequence of seq id no; the light chain CDR1 comprises a sequence selected from SEQ ID NOs: 10 and 14, and the light chain CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 11 and 15, and the light chain CDR3 comprises the amino acid sequences of SEQ ID NOs: 12, and a sequence of amino acids.
In one embodiment, the CCR8 antibody or antigen binding portion thereof comprises a heavy chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs: 1.5 and 7, and the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 13.
In one embodiment, the CCR8 antibody or antigen binding portion thereof comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16. 18 and 20, and the light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 17. 19 and 21.
In one embodiment, the CCR8 antibody or antigen binding portion thereof comprises:
comprising SEQ ID NOs: 2. 3, 4, CDR1, CDR2 and CDR3; and comprising SEQ ID NOs: 10. 11 and 12, CDR1, CDR2, and CDR3;
Comprising SEQ ID NOs: 6. 3, 4, CDR1, CDR2 and CDR3; and comprising SEQ ID NOs: 10. 11 and 12, CDR1, CDR2, and CDR3; or (b)
Comprising SEQ ID NOs: 2.8, 4, CDR1, CDR2 and CDR3; and comprising SEQ ID NOs: 14. 15 and 12, CDR1, CDR2, and CDR3.
In one embodiment, the CCR8 antibody or antigen binding portion thereof comprises:
comprising SEQ ID NO:1 and a heavy chain comprising SEQ ID NO:9, a light chain variable region;
Comprising SEQ ID NO:5 and a heavy chain comprising SEQ ID NO:9, a light chain variable region; or (b)
Comprising SEQ ID NO:7 and a heavy chain comprising SEQ ID NO: 13.
In one embodiment, the CCR8 antibody or antigen binding portion thereof comprises:
Comprising SEQ ID NO:16 and a heavy chain comprising SEQ ID NO: 17;
Comprising SEQ ID NO:18 and a heavy chain comprising SEQ ID NO: 19; and
Comprising SEQ ID NO:20 and a heavy chain comprising SEQ ID NO: 21.
In one embodiment, the medicament is combined with an additional therapeutic agent, surgical treatment or radiation treatment.
In one embodiment, the additional therapeutic agent is selected from chemotherapeutic agents and other antibodies.
In one embodiment, the additional antibody is selected from an inhibitor of an immune checkpoint molecule, e.g., an anti-PD-1, anti-PD-L1, anti-TIM-3, anti-CEACAM, or anti-LAG-3 antibody, and an antibody that stimulates an immune cell, e.g., an agonistic GITR antibody or a CD137 antibody.
In one embodiment, the medicament is formulated for parenteral administration, e.g. intravenous, intramuscular, intraarterial, intraperitoneal or subcutaneous administration, or topical administration.
Definition of the definition
In this disclosure, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Also, protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, immunology-related terms and laboratory procedures as used herein are terms and conventional procedures that are widely used in the corresponding arts. Meanwhile, in order to better understand the present disclosure, definitions and explanations of related terms are provided below.
The term "CCR8" refers to any CCR8 receptor known to those skilled in the art. For example, the CCR8 may be from a mammal, such as a human or a cynomolgus monkey.
Antibodies (e.g., monoclonal antibodies) that specifically bind CCR8 and antigen binding fragments thereof are used herein. In a particular aspect, used herein is a monoclonal anti-CCR 8 antibody that specifically binds CCR8, wherein the anti-CCR 8 antibody comprises a variant of the parent antibody. In particular aspects, used herein are antibodies that specifically bind CCR8 (e.g., human CCR 8). In particular aspects, used herein are modified anti-CCR 8 antibodies comprising one or more amino acid residues (e.g., 1-3 amino acid substitutions in the framework regions of the heavy chain variable region) that retain affinity for an antigen as compared to the parent antibody without the modification.
The present invention uses an anti-CCR 8 antibody disclosed in the patent application number CN 202210272606.5. Specifically, the inventors synthesized humanized anti-CCR 8 antibodies in the above-mentioned patent applications. The sequence of the synthetic humanized CCR8 antibody is as follows:
the heavy chain variable region h87D8 VHv1 sequence is as follows:
(SEQ ID NO:1, bold CDR regions).
Wherein CDR1 is NTYAMN (SEQ ID NO: 2), CDR2 is RIRSKSNNYATYYADSVKG (SEQ ID NO: 3), and CDR3 is GKEAGAYYAMDY (SEQ ID NO: 4).
The heavy chain variable region h144D2 VHv1 sequence is as follows:
(SEQ ID NO:5, bold CDR regions).
Wherein CDR1 is NAFAMN (SEQ ID NO: 6), CDR2 is RIRSKSNNYATYYADSVKG (SEQ ID NO: 3), and CDR3 is GKEAGAYYAMDY (SEQ ID NO: 4).
The heavy chain variable region h87D8 VHv2 sequence is as follows:
(SEQ ID NO:7, bold CDR regions).
Wherein CDR1 is NTYAMN (SEQ ID NO: 2), CDR2 is RIRSKSNNYATYYAD SVID (SEQ ID NO: 8) and CDR3 is GKEAGAYYAMDY (SEQ ID NO: 4).
The light chain variable region h87D8 VKv1 sequence is as follows:
(SEQ ID NO:9, bold CDR regions).
Wherein CDR1 is RSSKSLLHSNGNTYLY (SEQ ID NO: 10), CDR2 is RMSNLAS (SEQ ID NO: 11), and CDR3 is MQHLEYPLT (SEQ ID NO: 12).
The light chain variable region h87D8 VKv4 sequence is as follows:
(SEQ ID NO:13, bold CDR regions).
Wherein CDR1 is RSSKSLLHSNYNTYLY (SEQ ID NO: 14), CDR2 is RTSNLAS (SEQ ID NO: 15), and CDR3 is MQHLEYPLT (SEQ ID NO: 12).
The heavy and light chain variable regions were variously combined to give humanized antibodies H87D8H1K1 (consisting of H87D8 vhv1+h8vkv1), H144D 2H 1K1 (consisting of H144D2vhv1+h87D8 vkv1) and H87D8H2K4 (consisting of H87D8 vhv2+h8vk4).
Fc functional optimization is carried out on the humanized antibodies H87D8H 1K1 and H87D8H2K4 to obtain humanized anti-CCR 8 antibodies H87D8H 1K1 hIgG1e5, H87D8H2K4 hIgG1e5 and H87D8H 1K1 hIgG1.
The heavy chain amino acid sequence of H87D 8H 1K1 hig 1e5 is as follows:
the light chain amino acid sequence of H87D 8H 1K1 hig 1e5 is as follows:
the heavy chain amino acid sequence of H87D 8H 2K4 hIgGle is as follows:
the light chain amino acid sequence of H87D 8H 2K4 hIgG1e5 is as follows:
The heavy chain amino acid sequence of H87D 8H 2K4 hIgG1 is as follows:
The light chain amino acid sequence of H87D 8H 2K4 hIgG1 is as follows:
as used herein and unless otherwise indicated, the term "about" or "approximately" means within plus or minus 10% of a given value or range. Where integers are required, the term refers to rounding up or down to the nearest integer within plus or minus 10% of a given value or range.
As used herein, "monoclonal antibody" refers to a population of identical antibodies, meaning that each individual antibody molecule in the monoclonal antibody population is identical to the other antibody molecules. This characteristic is in contrast to the characteristic of a polyclonal population of antibodies comprising antibodies having a plurality of different sequences. Monoclonal antibodies can be prepared by a number of well known methods (Smith et al (2004) J.Clin. Patho1.57, 912-917; and Nelson et al a1., J Clin Patho (2000), 53, 111-117). For example, monoclonal antibodies can be prepared by immortalizing B cells, e.g., by fusion with myeloma cells to produce hybridoma cell lines or by infecting B cells with a virus such as EBV. Recombinant techniques can also be used to produce antibodies from clonal populations of host cells in vitro by transforming the host cells with plasmids carrying artificial sequences of nucleotides encoding the antibodies.
By "humanized" antibody is meant a form of non-human (e.g., mouse) antibody that is a chimeric immunoglobulin, immunoglobulin chain or fragment thereof (e.g., fv, fab, fab ', F (ab') 2 or other antigen-binding subsequence of an antibody) that contains a minimal sequence derived from a non-human immunoglobulin. Preferably, the humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the Complementarity Determining Regions (CDRs) of the recipient antibody are replaced by CDR residues from a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. Furthermore, in humanization, it is also possible to mutate amino acid residues within the CDR1, CDR2 and/or CDR3 regions of VH and/or VL, thereby improving one or more binding properties (e.g., affinity) of the antibody. Mutations, such as PCR-mediated mutations, can be introduced, and their effect on antibody binding or other functional properties can be assessed using in vitro or in vivo assays described herein. Typically, conservative mutations are introduced. Such mutations may be amino acid substitutions, additions or deletions. In addition, mutations within the CDRs typically do not exceed one or two. Thus, humanized antibodies described in the present disclosure also encompass antibodies comprising 1 or 2 amino acid mutations within the CDRs.
As used herein, the term "CDR" refers to the complementarity determining region (complementarity-DETERMINING REGION), known as an antibody molecule, having 3 CDRs per heavy and light chain. CDRs are also known as hypervariable regions and are found in the variable regions of each of the heavy and light chains of antibodies with very high variability sites in the primary structure of the CDRs. In the present specification, CDRs of the heavy chain are represented by CDR1, CDR2, and CDR3 from the amino terminus of the amino terminal sequence of the heavy chain, and CDRs of the light chain are represented by CDR1, CDR2, and CDR3 from the amino terminus of the amino terminal sequence of the light chain. These sites are adjacent to each other in tertiary structure and determine the specificity of the antigen to which the antibody binds.
As used herein, the term "epitope" refers to any antigenic determinant on an antigen to which the paratope of an antibody binds. Epitope determinants generally comprise chemically active surface groupings of molecules such as amino acids or sugar side chains, and generally have specific three dimensional structural characteristics as well as specific charge characteristics.
As used herein, "treating" an individual with a disease or condition means that the symptoms of the individual are partially or fully alleviated, or remain unchanged after treatment. Thus, treatment includes prophylaxis, treatment and/or cure. Prevention refers to preventing an underlying disease and/or preventing worsening of symptoms or disease progression. Treatment also includes any antibody or antigen-binding fragment thereof provided, and any pharmaceutical use of the compositions provided herein.
As used herein, "therapeutic effect" refers to the effect resulting from treatment of an individual that alters, generally improves or ameliorates symptoms of, or cures a disease or condition.
As used herein, a "therapeutically effective amount" or "therapeutically effective dose" refers to an amount of a substance, compound, material, or composition comprising a compound that is at least sufficient to produce a therapeutic effect after administration to a subject. Thus, it is the amount necessary to prevent, cure, ameliorate, block or partially block the symptoms of a disease or disorder.
As used herein, a "prophylactically effective amount" or "prophylactically effective dose" refers to an amount of a substance, compound, material, or composition comprising a compound that, when administered to a subject, will have the desired prophylactic effect, e.g., prevent or delay the onset or recurrence of a disease or symptom, reducing the likelihood of the onset or recurrence of a disease or symptom. The fully prophylactically effective dose need not occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations.
As used herein, the term "patient" or "subject" refers to a mammal, such as a human.
As used herein and unless otherwise indicated, the terms "comprising," "including," "having," "containing," and their grammatical equivalents are generally understood to be open-ended and not to be limiting, e.g., not to exclude other, unrecited elements or steps.
Use of CCR8 antibodies of the invention
The present invention relates to the use of a CCR8 antibody or antigen binding portion thereof, or a nucleic acid molecule encoding said antibody or antigen binding portion thereof, or a composition comprising said antibody or antigen binding portion thereof, for the manufacture of a medicament for the treatment or prevention of non-hodgkin's lymphoma in a subject.
In one embodiment, wherein the non-hodgkin's lymphoma is selected from the group consisting of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and adult T-cell lymphoma/leukemia.
The subject may be a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient suffering from or at risk of suffering from a disease described herein). In one embodiment, the subject has or is at risk of having a disease described herein (e.g., a tumor as described herein). In certain embodiments, the subject receives or has received other treatments, such as chemotherapy and/or radiation therapy.
In some embodiments, the treatment described herein further comprises co-administering to the subject or individual a CCR8 antibody or antigen binding portion thereof or a pharmaceutical composition disclosed herein, and one or more other therapies, such as therapeutic modalities and/or other therapeutic agents.
In some embodiments, the treatment modality includes surgery (e.g., tumor resection); radiation therapy (e.g., external particle beam therapy, which involves three-dimensional conformal radiation therapy in which the irradiation region is designed), localized irradiation (e.g., irradiation directed at a preselected target or organ), or focused irradiation, among others. The focused radiation may be selected from stereotactic radiosurgery, split stereotactic radiosurgery, and intensity modulated radiation therapy. The focused irradiation may have a radiation source selected from the group consisting of a particle beam (proton), cobalt-60 (photon) and a linear accelerator (X-ray), for example as described in WO2012177624 A2.
Radiation therapy may be administered by one or a combination of several methods including, but not limited to, external particle beam therapy, internal radiation therapy, implant irradiation, stereotactic radiation surgery, whole body radiation therapy, and permanent or brief interstitial brachytherapy.
In some embodiments, the therapeutic agent is selected from chemotherapeutic agents and other antibodies.
Exemplary other antibodies include, but are not limited to, inhibitors of immune checkpoint molecules (e.g., anti-PD-1, anti-PD-L1, anti-TIM-3, anti-CEACAM, or anti-LAG-3); antibodies that stimulate immune cells (e.g., agonistic GITR antibodies or CD1 37 antibodies), and the like. Preferably, the other antibodies are selected from anti-PD-1 antibodies and/or anti-PD-L1 antibodies. More preferably, the anti-PD-1 antibody is Nivolumab (Nivolumab) from the company Bevacizumab (BMS), pemetrexed (Pembrolizumab) from the company Merck; the anti-PD-L1 antibody was atezolizumab developed by Roche (Roche), avelumab developed by the cooperation of Merck (MERCK KGAA) and Fabry-Perot (Pfizer) in Germany, durvalumab developed by Aspirin.
Combination therapies of the invention encompass both combined administration (wherein two or more therapeutic agents are contained in the same formulation or separate formulations) and separate administration. In the case of separate administration, the administration of the invention, etc., may be performed prior to, concurrently with, and/or after the administration of the other therapies.
In one embodiment, administration of the CCR8 antibody or antigen binding portion thereof and administration of the other therapy (e.g., therapeutic regimen or agent) occurs within about one month, or within about one, two, or three weeks, or within about 1,2,3,4,5, or 6 days of each other.
The CCR8 antibodies, or antigen binding portions thereof (and pharmaceutical compositions comprising the same) of the invention may be administered by any suitable method, including parenteral, intrapulmonary and intranasal, and, if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. Depending in part on whether the administration is short-term or long-term, the administration may be by any suitable route, such as by injection, e.g., intravenous or subcutaneous injection. Various dosing schedules are contemplated herein, including but not limited to single administration or multiple administrations at multiple points in time, bolus administration, and pulse infusion.
For the prevention or treatment of a disease, the appropriate dosage of the CCR8 antibody or antigen binding portion thereof of the present invention (when used alone or in combination with one or more other therapeutic agents) will depend on the type of disease to be treated, the type of CCR8 antibody or antigen binding portion binding molecule thereof, the severity and course of the disease, whether the CCR8 antibody or antigen binding portion thereof is administered for prophylactic or therapeutic purposes, previous treatments, the clinical history of the patient and the response to the CCR8 antibody or antigen binding portion thereof, and the discretion of the attending physician. The CCR8 antibody or antigen binding portion thereof is suitably administered to a patient in one treatment or over a series of treatments. The dosage and treatment regimen of the CCR8 antibody or antigen binding portion thereof can be determined by the skilled artisan.
It will be appreciated that any of the above-described prophylaxis or treatment can be carried out using the compositions or combinations of the invention in place of the CCR8 antibody or antigen binding portion thereof.
Drawings
FIG. 1 shows the ADCC killing activity of the H87D 8H 2K4 hIgG1 e5 antibody against human skin T cell lymphoma cell line HuT78 expressing CCR 8.
Detailed Description
The invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are for illustration of the invention only and are not intended to limit the scope of the invention in any way. The experimental methods in the following examples are conventional methods unless otherwise specified. The reagents, raw materials, etc. used in the examples described below were commercially available products unless otherwise specified.
Example 1 ADCC Activity of H87D 8H 2K4 hIgG1e5 against human skin T cell lymphoma HuT78 cells
Construction of a lentiviral vector plasmid of the full-length sequence of human CD16A, NK92 cells (purchased from ATCC, cat. No. CRL-2408) were packaged and transfected according to Lenti-Pac HIV Expression PACKAGING KIT (Gene Copoeia, HPK-LvTR-20), and NK92-CD16A stably transfected cells were obtained by screening. 5X 10 4 HuT78 cells were added to each well of a 96-well U-shaped plate, 50. Mu.L of a gradient diluted H87D 8H 2K4 hIgG1e5 antibody or isotype control was added, and incubated in an incubator for 30 minutes; mu.L of 2X 10 6/mL NK92-CD16A cells were added to each well and the culture was continued for 4 hours. 30 minutes before detection, 2 mu L of cell lysate (100×) is added to the largest pore of target cells, centrifugation is carried out for 3 minutes at 300×g, 50 mu L of supernatant is taken to a black ELISA plate, 50 mu L of Lactate Dehydrogenase (LDH) detection substrate is added, shaking and mixing are carried out, 25 mu L of stop solution is added after 10 minutes, shaking is carried out for 10 seconds, and fluorescence (excitation wavelength 560nm and emission wavelength 590 nm) is selected for plate reading. Target cell killing rate is calculated according to LDH release level, an antibody concentration-killing rate (%) curve is obtained through fitting of a four-parameter model, and half-effective concentration (EC 50) of a test sample is calculated by adopting the regression curve. The results showed that H87D 8H 2K4 hIgG1e5 had ADCC activity against HuT78 cells and half-effect killing concentration EC 50 was 0.53nM (FIG. 1)
Example 2 ADCC Activity of H87D 8H 2K4 hIgG1e5 against human T lymphocyte leukemia cell Jurkat
Construction of a lentiviral vector plasmid of the full-length sequence of human CD16A, NK92 cells (purchased from ATCC, cat. No. CRL-2408) were packaged and transfected according to Lenti-Pac HIV Expression PACKAGING KIT (Gene Copoeia, HPK-LvTR-20), and NK92-CD16A stably transfected cells were obtained by screening. 5X 10 4 Jurkat cells were added to each well of a 96 well U-plate, 50. Mu.L of a gradient diluted H87D 8H 2K4 hIgG1e5 antibody or isotype control, respectively, and incubated in an incubator for 30 minutes; mu.L of 2X 10 6/mL NK92-CD16A cells were added to each well and the culture was continued for 4 hours. 30 minutes before detection, 2 mu L of cell lysate (100×) is added to the largest pore of target cells, centrifugation is carried out for 3 minutes at 300×g, 50 mu L of supernatant is taken to a black ELISA plate, 50 mu L of Lactate Dehydrogenase (LDH) detection substrate is added, shaking and mixing are carried out, 25 mu L of stop solution is added after 10 minutes, shaking is carried out for 10 seconds, and fluorescence (excitation wavelength 560nm and emission wavelength 590 nm) is selected for plate reading. Target cell killing rate is calculated according to LDH release level, an antibody concentration-killing rate (%) curve is obtained through fitting of a four-parameter model, and half-effective concentration (EC 50) of a test sample is calculated by adopting the regression curve.
EXAMPLE 3 Effect of H87D 8H 2K4 hIgG1e5 on human T-lymphocyte leukemia cell Jurkat mouse engraftment tumor growth
Jurkat subcutaneous transplantation tumor model was established on CB17-SCID female mice. The test was carried out in the H87D 8H 2K4 hIgG1e5, 0.3mg/kg, 1mg/kg and 3mg/kg dosing groups, the IgG1 isotype control 3mg/kg group. By intravenous administration to Jurkat tumor-bearing mice, a total of 5 doses were administered 1 time every 3 days. The tumor growth inhibitory effect of H87D 8H 2K4 hIgG1e5 on Jurkat model was evaluated by monitoring tumor growth inhibition rate TGI. (tumor inhibition ratio (TGI) (%) =100-T/C (%), tumor relative growth ratio T/C (%) = (T-T0)/(C-C0) ×100, where T and T0 are the tumor volumes of the administration group at the end of the experiment and at the beginning of the experiment, respectively, and C0 are the tumor volumes of the control group at the end of the experiment and at the beginning of the experiment, respectively.
Claims (12)
- Use of a ccr8 antibody or antigen binding portion thereof, or a nucleic acid molecule encoding said antibody or antigen binding portion thereof, or a composition comprising said antibody or antigen binding portion thereof, in the manufacture of a medicament for the treatment or prevention of non-hodgkin's lymphoma in a subject.
- 2. The use of claim 1, wherein the non-hodgkin's lymphoma is selected from the group consisting of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and adult T-cell lymphoma/leukemia.
- 3. The use of claim 1 or 2, wherein the CCR8 antibody or antigen binding portion thereof comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, and a light chain CDR1, a light chain CDR2, and a light chain CDR3, said heavy chain CDR1 comprising a sequence selected from the group consisting of SEQ ID NOs: 2 and 6, said heavy chain CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 3 and 8, and the heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:4, an amino acid sequence of seq id no; the light chain CDR1 comprises a sequence selected from SEQ ID NOs: 10 and 14, and the light chain CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 11 and 15, and the light chain CDR3 comprises the amino acid sequences of SEQ ID NOs: 12, and a sequence of amino acids.
- 4. The use of claim 3, wherein the CCR8 antibody or antigen binding portion thereof comprises a heavy chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs: 1.5 and 7, and the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 13.
- 5. The use of claim 4, wherein the CCR8 antibody or antigen binding portion thereof comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16. 18 and 20, and the light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 17. 19 and 21.
- 6. The use of claim 3, wherein the CCR8 antibody or antigen binding portion thereof comprises:comprising SEQ ID NOs: 2. 3, 4, CDR1, CDR2 and CDR3; and comprising SEQ ID NOs: 10. 11 and 12, CDR1, CDR2, and CDR3;Comprising SEQ ID NOs: 6. 3, 4, CDR1, CDR2 and CDR3; and comprising SEQ ID NOs: 10. 11 and 12, CDR1, CDR2, and CDR3; or (b)Comprising SEQ ID NOs: 2.8, 4, CDR1, CDR2 and CDR3; and comprising SEQ ID NOs: 14. 15 and 12, CDR1, CDR2, and CDR3.
- 7. The use of claim 4, wherein the CCR8 antibody or antigen binding portion thereof comprises:comprising SEQ ID NO:1 and a heavy chain comprising SEQ ID NO:9, a light chain variable region;Comprising SEQ ID NO:5 and a heavy chain comprising SEQ ID NO:9, a light chain variable region; or (b)Comprising SEQ ID NO:7 and a heavy chain comprising SEQ ID NO: 13.
- 8. The use of claim 5, wherein the CCR8 antibody or antigen binding portion thereof comprises:Comprising SEQ ID NO:16 and a heavy chain comprising SEQ ID NO: 17;Comprising SEQ ID NO:18 and a heavy chain comprising SEQ ID NO: 19; andComprising SEQ ID NO:20 and a heavy chain comprising SEQ ID NO: 21.
- 9. The use of any one of claims 1-8, wherein the medicament is combined with an additional therapeutic agent, surgical treatment or radiation treatment.
- 10. The use of claim 9, wherein the additional therapeutic agent is selected from the group consisting of chemotherapeutic agents and other antibodies.
- 11. The use of claim 10, wherein the additional antibody is selected from the group consisting of an inhibitor of an immune checkpoint molecule, e.g., an anti-PD-1, anti-PD-L1, anti-TIM-3, anti-CEACAM, or anti-LAG-3 antibody, and an antibody that stimulates immune cells, e.g., an agonistic GITR antibody or a CD137 antibody.
- 12. The use of any one of claims 1-11, wherein the medicament is formulated for parenteral administration, such as intravenous, intramuscular, intraarterial, intraperitoneal or subcutaneous administration, or topical administration.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310037623.5A CN118324910A (en) | 2023-01-10 | 2023-01-10 | Application of CCR8 antibody |
| PCT/CN2024/071275 WO2024149224A1 (en) | 2023-01-10 | 2024-01-09 | Use of ccr8 antibody |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310037623.5A CN118324910A (en) | 2023-01-10 | 2023-01-10 | Application of CCR8 antibody |
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| CN202310037623.5A Pending CN118324910A (en) | 2023-01-10 | 2023-01-10 | Application of CCR8 antibody |
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| IL295023A (en) * | 2020-02-14 | 2022-09-01 | Jounce Therapeutics Inc | Antibodies and fusion proteins that bind to ccr8 and their uses |
| MX2022011701A (en) * | 2020-03-23 | 2022-10-07 | Bristol Myers Squibb Co | Anti-ccr8 antibodies for treating cancer. |
| WO2022003156A1 (en) * | 2020-07-02 | 2022-01-06 | Oncurious Nv | Ccr8 non-blocking binders |
| AU2021330067A1 (en) * | 2020-08-28 | 2023-03-30 | Harbour Biomed (Shanghai) Co., Ltd. | CCR8 antibody and application thereof |
| EP4010378A4 (en) * | 2020-10-16 | 2023-07-26 | LaNova Medicines Limited | Anti-ccr8 monoclonal antibodies and uses thereof |
| EP4313317A1 (en) * | 2021-03-23 | 2024-02-07 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the diagnosis and treatment of t cell-lymphomas |
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