Antibody molecule to PD-1 and use of the same

Abstract

To provide an anti PD-1 antibody molecule to be used for treating cancer in a subject.SOLUTION: An anti PD-1 antibody molecule to be used for treating cancer in a subject once a 3 weeks or once a 4 weeks at the dosage of approximately 300 mg to 400 mg, which may be used in combination with a medicine enhancing tumor antigen presentation selected from one or more of STING agonist, TLR agonist, A2AR antagonist, oncolytic virus, TIM-3 modulator, vascular endothelial cell growth factor receptor (VEGFR) inhibitor, c-Met inhibitor, TGF-β inhibitor, IDO / TDO inhibitor, vaccine or two or three specific cell engagers.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Application No. 62 / 269,044, filed December 17, 2015. U.S. Provisional Application No. 62 / 331,371, filed May 3, 2016, U.S. Provisional Application No. 62 / 331,371, filed June 2, 2016 Provisional Application No. 62 / 344,784, filed June 8, 2016, and U.S. Provisional Application No. 62 / 347,33 No. 1, U.S. Provisional Application No. 62 / 359,781, filed July 8, 2016, and U.S. Provisional Application No. 62 / 359,781, filed August 3, 2016 U.S. Provisional Application No. 62 / 381,384 filed on September 28, 2016 No. 62 / 400,787, and U.S. Provisional Application No. 62 / 414,128, filed October 28, 2016. No. 62 / 431,846, filed December 9, 2016. The contents of said application are incorporated herein by reference in their entirety.

[0002] Sequence Listing This application contains a Sequence Listing which has been provided electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy was created on December 14, 2016 and is incorporated herein by reference. It is named O_SL.txt and is 280,741 bytes in size. [Background technology]

[0003] background The ability of T cells to mediate immune responses to antigens depends on two distinct signaling interactions (Viglietta, V. et al. (2007) Neurotherapeutics 4:666-675; Korman, A. J. et al. (2007) Adv. Immunol. 90:297-339). First, the surface of antigen-presenting cells (APCs) The antigens located on the surface are antigen-specific naive CD4 + It is presented to T cells. The presentation delivers a signal through the T cell receptor (TCR), which directs the T cell to recognize the antigen specific for the presented antigen. Second, interactions between APCs and distinct T cell surface molecules. Various costimulatory and inhibitory signals mediated by interactions contribute to T cell activation and proliferation. This triggers proliferation and ultimately its inhibition.

[0004] The immune system is tightly controlled by a network of costimulatory and co-inhibitory ligands and receptors. These molecules provide a second signal for T cell activation and promote self-immunity. Netting positive and negative signals to maximize immune responses to infection while limiting disease Provides work balance (Wang, L. et al. (Epub Mar. 7, 2011) J. Exp. Med. 208(3):5 77-92; Lepenies, B. et al. (2008) Endocrine, Metabolic & Immune Disorders--Drug Targets 8:279-288). Examples of costimulatory signals are B7.1 (CD80) and B7 on APCs. 2 (CD86) ligand and CD4 + CD28 and CTLA-4 receptors on T lymphocytes binding (Sharpe, AH et al. (2002) Nature Rev. Immunol. 2:116-126; Lindley, PS et al. (2009) Immunol. Rev. 229:307-321). B7.1 or B7.2 to CD28 Binding of B7.1 or B7.2 to CTLA-4 stimulates T cell activation, whereas binding of B7.1 or B7.2 to CTLA-4 stimulates T cell activation. inhibits such activation (Dong, C. et al. (2003) Immunolog. Res. 28(1):39-48; G (Reenwald, RJ et al. (2005) Ann. Rev. Immunol. 23:515-548). CD28 is a T cell It is constitutively expressed on the surface (Gross, J., et al. (1992) J. Immunol. 149:380-388), while C TLA-4 expression is rapidly upregulated after T cell activation (Linsley, P. et al. (1996) Imm unity 4:535-543).

[0005] Other ligands for the CD28 receptor are related members of the B7 superfamily, also known as the "B7 superfamily." including the B7 molecule group (Coyle, AJ et al. (2001) Nature Immunol. 2(3):203-209; Sharpe , AH et al. (2002) Nature Rev. Immunol. 2:116-126; Collins, M. et al. (2005) Genome Biol. 6:223.1-223.7; Korman, AJ et al. (2007) Adv. Immunol. 90:297-339 ). Several members of the B7 superfamily are known, including B7.1 (CD80), B7.2 (CD8 6), inducible costimulatory ligand (ICOS-L), programmed death 1 ligand (PD-L1; B7 -H1), programmed death 2 ligand (PD-L2; B7-DC), B7-H3, B7-H4 and B7-H6 (Collins, M. et al. (2005) Genome Biol. 6:223.1-223.7).

[0006] Programmed death 1 (PD-1) protein is a T cell regulator that extends CD28 / CT It is an inhibitory member of the LA-4 family (Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8). CD28 family Other members of the PD-1 family include CD28, CTLA-4, ICOS, and BTLA. As a monomer, it lacks the unpaired cysteine ​​residue characteristic of other CD28 family members. PD-1 is expressed on activated B cells, T cells, and monocytes. .

[0007] The PD-1 gene encodes a 55 kDa type I transmembrane protein (Agata et al. (1996) Int Immunol. 8:765-72). Although structurally similar to CTLA-4, PD-1 is a cytotoxic antagonist of B7-1 and It lacks the MYPPY motif (SEQ ID NO: 236) that is important for B7-2 binding. The ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) have been identified, and P It has been shown to downregulate T cell activation by binding to D-1 (Freeman et al. (2000) J. Exp. Med. 192:1027-34; Carter et al. (2002) Eur. J. Immunol. 32:634-43 Both PD-L1 and PD-L2 bind to PD-1, but not to other members of the CD28 family. PD-L1 is a B7 homolog that does not bind to other members of the PD-L1 family. PD-L1 is abundant in various human cancers. (Dong et al. (2002) Nat. Med. 8:787-9).

[0008] PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signaling (Ish ida, Y. et al. (1992) EMBO J. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745). The interaction between PD-1 and PD-L1 is an immune checkpoint. can act as a checkpoint, e.g., for reducing tumor-infiltrating lymphocytes, T-cell receptor-mediated This may result in reduced proliferation and / or immune evasion by cancer cells (Dong et al. (2003) J. M ol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; K Onishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immunosuppression is mediated by PD-1 and PD This effect can be reversed by inhibition of the local interaction of PD-1 with PD-L1 or PD-L2. When PD-L2 interaction is similarly inhibited, it is additive (Iwai et al. (2002) Proc Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66) . Summary of the Invention [Problem to be solved by the invention]

[0009] Considering the importance of immune checkpoint pathways in regulating immune responses, Novel combinations that modulate the activity of immunoinhibitory proteins, thereby resulting in activation of the immune system There is a need to develop combined therapies. Such agents are useful in, for example, cancer immunotherapy and chronic It can be used to treat other conditions such as ulcers and ulcerative colitis. [Means for solving the problem]

[0010] summary Disclosed herein, at least in part, is a method for inhibiting programmed death 1 (P D-1). Nucleic acid molecules, expression vectors, host cells and methods for producing the antibody molecules are also provided. Pharmaceutical compositions and dosage formulations containing the molecules are also provided. The anti-PD-1 antibody molecules disclosed herein are , cancer disorders (e.g., solid and soft tissue tumors) and infectious diseases (e.g., chronic infectious disorders) for the treatment, prevention and / or diagnosis (alone or in combination with other agents) of disorders such as cerebrospinal fluid poisoning or sepsis Therefore, anti-PD-1 antibody molecules can be used to and methods for detecting PD-1 using the method, including cancer and / or infectious diseases. Disclosed herein are methods for treating a variety of disorders, including: The molecule is administered or used in a uniform or fixed dose.

[0011] Thus, in one aspect, the present invention provides a method for treating a disorder, e.g., a hyperproliferative condition or The present invention relates to methods of treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder (e.g., cancer). The method includes administering an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule described herein, to about 300 The method involves administering to a subject a dose of 100 mg to 400 mg once every three weeks or once every four weeks. In an embodiment, the anti-PD-1 antibody molecule is administered in a dose of about 300 mg once every three weeks. In other embodiments, the anti-PD-1 antibody molecule is administered in a dose of about 400 mg once every four weeks. In some embodiments, the disorder is cancer, e.g., a cancer described herein. In some embodiments, the cancer is a skin cancer, e.g., Merkel cell carcinoma or melanoma. In another embodiment, the cancer is Merkel cell carcinoma. In another embodiment, the cancer is melanoma. In embodiments, the cancer is breast cancer, e.g., triple-negative breast cancer (TNBC) or HER2 In other embodiments, the cancer is a renal cancer, e.g., a renal cell carcinoma (e.g., clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC). In some embodiments, the cancer is thyroid cancer, e.g., anaplastic thyroid carcinoma (ATC). In the present study, the cancer is a neuroendocrine tumor (NET), e.g., an atypical lung carcinoid tumor or a pancreatic In some embodiments, the cancer is lung cancer, NET in the gastrointestinal (GI) tract, or lung. For example, non-small cell lung cancer (NSCLC) (e.g., squamous cell NSCLC or non-squamous cell NSCLC) In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is colorectal cancer (CRC) (e.g., microsatellite MSI-high colorectal cancer (MSI-high CRC) or microsatellite-stable colorectal cancer In some embodiments, the cancer is leukemia (e.g., acute myeloid leukemia (MSS CRC)). Leukemia (AML), e.g., relapsed or refractory AML or de novo AML. In embodiments, the cancer is myelodysplastic syndrome (MDS) (eg, high-risk MDS).

[0012] In one embodiment, the anti-PD-1 antibody molecule is administered in a dose of about 400 mg once every four weeks or about 30 mg once every six weeks. 0 mg once every 3 weeks to treat lung cancer, e.g., non-small cell lung cancer (NSCLC) (e.g. In one embodiment, the method treats NSCLC (squamous NSCLC or non-squamous NSCLC). The anti-PD-1 antibody molecule is administered at a dose of about 300 mg once every three weeks to treat lung cancer, e.g., non-small cell lung cancer. Treating small cell lung cancer (NSCLC) (e.g., squamous NSCLC or non-squamous NSCLC) In one embodiment, the anti-PD-1 antibody molecule is administered at a dose of about 400 mg once every four weeks. to treat skin cancer, e.g., Merkel cell carcinoma or melanoma. In this study, anti-PD-1 antibody molecules were administered at a dose of approximately 400 mg once every four weeks to treat Merkel cells. In another embodiment, the anti-PD-1 antibody molecule is administered in a dose of about 400 mg once every four weeks to treat ovarian cancer. In one embodiment, the anti-PD-1 antibody molecule is administered in a single dose to treat melanoma. , about 400 mg once every four weeks to treat breast cancer, e.g., triple-negative breast cancer ( In one embodiment, the anti-PD- One antibody molecule is administered at a dose of about 400 mg once every four weeks to treat thyroid cancer, e.g., undifferentiated thyroid cancer. In one embodiment, the anti-PD-1 antibody molecule is administered in a dose of about 400 mg to treat adenocarcinoma of the thyroid gland (ATC). is administered in a dose once every four weeks to treat neuroendocrine tumors (NETs), such as atypical pulmonary carcinoma In one embodiment, the present invention treats tumors or NETs in the pancreas, gastrointestinal (GI) tract, or lungs. In this study, the anti-PD-1 antibody molecule was administered at a dose of approximately 400 mg once every four weeks to treat kidney cancer, For example, renal cell carcinoma (e.g., clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (NCC) In one embodiment, the anti-PD-1 antibody molecule is administered in a dose of about 400 mg every 4 weeks to treat RCC. In one embodiment, the anti-PD-1 antibody compound is administered in a single dose to treat ovarian cancer. The drug is administered in a dose of about 400 mg once every four weeks to treat fallopian tube cancer. The anti-PD-1 antibody molecule is administered at a dose of approximately 400 mg once every four weeks to treat colorectal cancer ( For example, microsatellite instability-high colorectal cancer (MSI-high CRC) or microsatellite In one embodiment, anti-PD-L1 inhibitors are used to treat multiple sclerosis (MSS) colorectal cancer (MSS CRC). The α-1 antibody molecule is administered at a dose of approximately 400 mg once every four weeks to treat leukemia (e.g., AML, For example, to treat relapsed or refractory AML or de novo AML. The anti-PD-1 antibody molecule is administered at a dose of approximately 400 mg once every four weeks to treat myelodysplastic syndromes. Group (MDS) (e.g., high-risk MDS) is treated.

[0013] In one embodiment, the anti-PD-1 antibody molecule is administered in a dose of about 100 mg to 600 mg, e.g., about 2 00mg to 500mg, for example, about 100mg to 300mg, about 250mg to 450mg, about 300mg ~400mg, about 250mg~350mg, about 350mg~450mg, or about 100mg, about 20 Injection (e.g., subcutaneous or intravenous) at doses (e.g., flat doses) of 0 mg, about 300 mg, or about 400 mg The administration schedule (e.g., a flat-dose schedule) is For example, it can vary from once a week to once every 2, 3, 4, 5, or 6 weeks. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to 400 mg every three weeks or every four weeks. In one embodiment, the anti-PD-1 antibody molecule is administered in a single dose of about 300 mg. In one embodiment, the anti-PD-1 antibody molecule is administered at a dose of from once every three weeks. In one embodiment, the anti-PD-1 antibody is administered at a dose of about 400 mg or more once every four weeks. The antibody molecule is administered at a dose of about 300 mg every four weeks. The PD-1 antibody molecule is administered at doses starting from approximately 400 mg once every three weeks.

[0014] In other aspects, the present invention provides a method for inhibiting the activity (e.g., proliferation, survival) of hyperproliferative (e.g., cancer) cells. The method further relates to a method for reducing the cell viability or viability (or all of the cell viability or ... The method comprises contacting the cells with a biological molecule, such as an anti-PD-1 antibody molecule described herein. For example, as part of a treatment protocol, for example, about 300 mg to 400 mg of an anti-PD-1 antibody The molecule may be administered to a subject in a dose once every three weeks or once every four weeks. In another embodiment, the dose is about 300 mg of the anti-PD-1 antibody molecule once every three weeks. The dose is approximately 400 mg of anti-PD-1 antibody molecules once every four weeks. Cancer (squamous epithelium), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous epithelium), stomach cancer, thyroid cancer, skin cancer, melanoma, nasopharyngeal carcinoma (e.g., differentiated or undifferentiated metastatic or locally recurrent nasopharyngeal carcinoma), renal carcinoma, Neuroendocrine tumors (NETs), ovarian cancer, fallopian tube cancer, colorectal cancer, or breast cancer, as described herein The cells may be from a cancer. In some embodiments, the cancer is a skin cancer, e.g., a Merkel cell carcinoma. Or melanoma. In some embodiments, the cancer is Merkel cell carcinoma. In another embodiment, the cancer is breast cancer, e.g., triple negative breast cancer. In another embodiment, the cancer is refractory breast cancer (TNBC) or HER2-negative breast cancer. kidney cancer, e.g., renal cell carcinoma (e.g., clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (CCRCC) In other embodiments, the cancer is thyroid cancer, e.g., anaplastic thyroid carcinoma (nccRCC). In other embodiments, the cancer is a neuroendocrine tumor (NET), e.g., atypical endocrine tumor (ATC). Pulmonary carcinoid tumors or NETs in the pancreas, gastrointestinal (GI) tract, or lungs. In embodiments, the cancer is lung cancer, e.g., non-small cell lung cancer (NSCLC) (e.g., squamous NSCLC). In one embodiment, the cancer is ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is colorectal cancer. (CRC) (e.g., microsatellite instability-high colorectal cancer (MSI-high CRC) or In one embodiment, the cancer is a microsatellite-stable colorectal cancer (MSS CRC). The cancer may be a leukemia (e.g., acute myeloid leukemia (AML), e.g., relapsed or refractory AML or is de novo AML). In some embodiments, the cancer is myelodysplastic syndrome (MDS) (e.g., , high-risk MDS).

[0015] In other embodiments, the present invention provides an anti-PD-1 antibody molecule (e.g., an anti-PD-1 antibody molecule described herein). The present invention relates to compositions (e.g., one or more compositions or dosage forms) comprising an anti-PD antibody (e.g., one or more antibody molecules). formulations, e.g., administration products, comprising an anti-PD-1 antibody molecule (e.g., an anti-PD-1 antibody molecule described herein). Agents and kits, e.g., therapeutic kits, are also described herein. In some embodiments, The composition or formulation may contain 300 mg or 400 mg of an anti-PD-1 antibody molecule (e.g., a PD-1 antibody molecule described herein). In one embodiment, the composition or formulation comprises an anti-PD-1 antibody molecule (anti-PD-1 antibody molecule that inhibits PD-1 production). Administer or use once or once every four weeks.

[0016] Also disclosed herein are antibodies in the following categories: (i) antibodies that enhance antigen presentation (e.g., tumor antigen presentation); (ii) agents that enhance effector cell responses (e.g., B cell and / or T cell activation and (i) to (iii) of agents that enhance tumor immunosuppression or (iii) of agents that reduce tumor immunosuppression. ) In one embodiment, the combination comprises an inhibitor of PD-1 ( In one embodiment, the anti-PD-1 antibody molecule comprises an anti-PD-1 antibody molecule described herein. A flat or fixed dose of one antibody molecule is administered or used.

[0017] Without intending to be bound by theory, therapeutic approaches to enhance anti-tumor immunity may be used to treat tumors in which the immune response is Targeting multiple components at one or more stages of an immune response, e.g., an anti-tumor immune response, It is thought that it will work more efficiently when optimized by combining these two. Blockade of cell proliferation (e.g., increased macrophage polarization, T reg Increased depletion and / or bone marrow For example, by reducing myocardial infarction (MDSCs), the cellular and humoral immune responses are suppressed. means to enhance (e.g., enhance the activity of phagocytes and / or tumor-infiltrating lymphocytes (e.g., NK cells and and T cells), e.g., by disinhibition) in combination with activation of dendritic cells and Means of enhancing antigen presentation, by immunization and / or maturation, may result in more effective and / or prolonged antigen presentation. Thus, disclosed herein are methods for (i) antigen presentation, e.g., Antigen presentation (e.g., one of the events in dendritic cell activity or maturation, antigen uptake, or antigen processing) (ii) an increase in effector cell responses (e.g., by enhancing For example, B cell and / or T cell activation and / or activity in lymph nodes. or (iii) tumor immunosuppression, e.g., tumor immunosuppression (e.g., T cell infiltration and The combination therapy optimizes one, two, or all of the following: The combinations described may provide, for example, improved efficacy and safety in treating disorders compared to administration of the therapeutic agents in the combination alone. and the like, which have excellent beneficial effects such as enhanced anti-cancer effect, reduced toxicity and / or reduced side effects in the treatment of For example, one or more of the therapeutic agents in the combination may be administered in a manner that achieves the same therapeutic effect. It can be administered at lower doses or for shorter periods of time compared to the single drug administration required to achieve the desired effect. Thus, compositions and methods for the treatment of cancer and other immune disorders using said combination therapy are provided. A method is disclosed.

[0018] Thus, in one aspect, the present invention provides a method for treating a disorder, e.g., a hyperproliferative condition or The present invention relates to methods of treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder (e.g., cancer). The method includes administering to a subject an agent that is one of the following categories: (i) an agent that enhances antigen (e.g., tumor antigen) presentation; effector cell responses (e.g., B cell and / or T cell activation and / or recruitment) or (iii) one, two, or all of (i) to (iii) a drug that enhances tumor immunosuppression. administering a combination of two, three or more therapeutic agents selected from the group consisting of In some embodiments, the present invention includes treating a hyperproliferative condition or disorder (e.g., cancer). wherein the combination comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) Cancers to be treated include, for example, lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (metastatic), and squamous epithelium), gastric cancer, thyroid cancer, skin cancer, melanoma, nasopharyngeal cancer (e.g. differentiated or undifferentiated metastasis) or locally recurrent nasopharyngeal carcinoma), renal cancer, neuroendocrine tumors (NETs), or breast cancer, as described herein In some embodiments, the cancer is a skin cancer, e.g., a Merkel cell carcinoma or In one embodiment, the cancer is melanoma. In another embodiment, the cancer is Merkel cell carcinoma. In other embodiments, the cancer is breast cancer, e.g., triple negative breast cancer. In other embodiments, the cancer is renal cell carcinoma (TNBC) or HER2-negative breast cancer. renal cell carcinoma (e.g., clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma ( In other embodiments, the cancer is thyroid cancer, e.g., anaplastic thyroid cancer. In other embodiments, the cancer is a neuroendocrine tumor (NET), e.g., an atypical Pulmonary carcinoid tumors or NETs in the pancreas, gastrointestinal (GI) tract, or lungs. In embodiments, the cancer is lung cancer, e.g., non-small cell lung cancer (NSCLC) (e.g., squamous NSCLC). In one embodiment, the cancer is ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is colorectal cancer. (CRC) (e.g., microsatellite instability-high colorectal cancer (MSI-high CRC) or In one embodiment, the cancer is a microsatellite-stable colorectal cancer (MSS CRC). The cancer may be a leukemia (e.g., acute myeloid leukemia (AML), e.g., relapsed or refractory AML or is de novo AML). In some embodiments, the cancer is myelodysplastic syndrome (MDS) (e.g., , high-risk MDS).

[0019] In other aspects, the present invention provides a method for inhibiting the activity (e.g., proliferation, survival) of hyperproliferative (e.g., cancer) cells. The present invention relates to a method for reducing the viability or viability of cells in the following categories: - (i) agents that enhance antigen (e.g., tumor antigen) presentation, (ii) agents that enhance effector cell responses (e.g., (iii) an agent that enhances tumor suppression, B cell and / or T cell activation and / or recruitment; or (iv) a tumor suppressor. Two, three or more drugs selected from one, two or all of (i) to (iii) of the drugs that reduce tumor immunosuppression contacting the combination of further therapeutic agents, thereby reducing the activity of the hyperproliferative cells. In certain embodiments, the combination includes a PD-1 inhibitor (e.g., a PD-1 inhibitor described herein). The method can be used, for example, as part of a treatment protocol. The cancer cells may be, for example, lung cancer (squamous cell carcinoma), lung cancer (adenocarcinoma), head and neck cancer, , cervical cancer (squamous), gastric cancer, thyroid cancer, skin cancer, melanoma, nasopharyngeal cancer (e.g. differentiated or or undifferentiated metastasis or local recurrence of nasopharyngeal carcinoma), renal cancer, neuroendocrine tumor (NET), ovarian cancer, The cells may be from a cancer described herein, such as fallopian tube cancer, colorectal cancer, or breast cancer. In embodiments, the cancer is a skin cancer, e.g., Merkel cell carcinoma or melanoma. In another embodiment, the cancer is Merkel cell carcinoma. In another embodiment, the cancer is melanoma. In embodiments, the cancer is breast cancer, e.g., triple-negative breast cancer (TNBC) or HER2. In other embodiments, the cancer is a renal cancer, e.g., a renal cell carcinoma (e.g., a 2-negative breast cancer). For example, clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC). In an embodiment, the cancer is thyroid cancer, e.g., anaplastic thyroid carcinoma (ATC). In such cases, the cancer is a neuroendocrine tumor (NET), e.g., atypical lung carcinoid tumor or pancreatic In one embodiment, the cancer is lung cancer. , e.g., non-small cell lung cancer (NSCLC) (e.g., squamous cell NSCLC or non-squamous cell NSCLC) In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is colorectal cancer (CRC) (e.g., microscopic Satellite instability-high colorectal cancer (MSI-high CRC) or microsatellite stable colon In some embodiments, the cancer is leukemia (e.g., acute myeloid leukemia (MSS CRC)). The present invention relates to acute myeloid leukemia (AML), such as relapsed or refractory AML or de novo AML. In embodiments, the cancer is myelodysplastic syndrome (MDS) (eg, high-risk MDS).

[0020] In certain embodiments of the methods disclosed herein, the method further comprises: (e.g., T cell) infiltration levels (e.g., tumor infiltrating lymphocyte (TIL) levels) In certain embodiments, the level of immune cell infiltration is measured in vivo, e.g., non-invasively. (e.g., using a suitable imaging technique, e.g., positron emission tomography (PET) scanning) and detecting antibodies against a detectably labeled T cell marker). In other embodiments, the level of immune cell infiltration is measured by measuring the level of immune cell infiltration in a sample (e.g., tumor) obtained from the subject. The tumor invasion in the subject is determined (e.g., using immunohistochemical techniques) in a biopsy. In some embodiments, the response of the category - one or more of (i) or (ii) or both (i) and (ii) are administered to the subject. In other embodiments where the response of tumor infiltration is detectable or high, The detection step may also be performed by administering one or more agents of interest (iii), e.g., a therapeutic agent described herein. For example, the detection step may be performed using a method for detecting a compound in categories (i), (ii), or (iii). and / or (iii) may be used to monitor the effectiveness of a therapeutic agent.

[0021] In another aspect, the present invention provides a method for enhancing antigen (e.g., tumor antigen) presentation in the following categories: (i) (ii) agents that induce effector cell responses (e.g., B cell and / or T cell activation and (i) to (iii) of agents that enhance tumor immunosuppression or (iii) of agents that reduce tumor immunosuppression. ) In some embodiments, the composition relates to a composition (e.g., one or more compositions or dosage forms). The combination includes a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein).

[0022] In yet another aspect, the present invention provides a composition for use in treating a disorder, e.g., cancer. In some embodiments, the present invention relates to a pharmaceutical composition (e.g., one or more compositions or dosage forms described herein). In this regard, compositions for use fall into the following categories: (i) antigen (e.g., tumor antigen) presentation enhancement; (ii) agents that induce effector cell responses (e.g., B cell and / or T cell activation and (i) to (iii) of agents that enhance tumor immunosuppression (i.e., tumor immunosuppression and / or tumor immunorepression) or (iii) of agents that reduce tumor immunosuppression The present invention includes a combination of two, three or more therapeutic agents selected from one, two or all of the following: In certain embodiments, the combination used includes a PD-1 inhibitor (e.g., a PD-1 inhibitor described herein). The cancer includes, for example, lung cancer (squamous cell carcinoma), lung cancer (adenocarcinoma), and head and neck cancer. , cervical cancer (squamous), gastric cancer, thyroid cancer, skin cancer, melanoma, nasopharyngeal cancer (e.g. differentiated or or undifferentiated metastasis or local recurrence of nasopharyngeal carcinoma), renal cancer, neuroendocrine tumor (NET), ovarian cancer, The cancer may be a cancer described herein, such as fallopian tube cancer, colorectal cancer, or breast cancer. In one embodiment, the cancer is a skin cancer, e.g., Merkel cell carcinoma or melanoma. In another embodiment, the cancer is melanoma. In this study, the cancer is breast cancer, e.g., triple-negative breast cancer (TNBC) or HER2-negative In other embodiments, the cancer is a renal cancer, e.g., a renal cell carcinoma (e.g., a clear cell carcinoma). In other embodiments, the tumor is a clear cell renal cell carcinoma (CCRCC) or a non-clear cell renal cell carcinoma (nccRCC). In another embodiment, the cancer is thyroid cancer, e.g., anaplastic thyroid carcinoma (ATC). The cancer may be a neuroendocrine tumor (NET), e.g., atypical lung carcinoid tumor or a pancreatic or gastrointestinal tumor. In some embodiments, the cancer is lung cancer, e.g., NETs in the (GI) tract or lung. Non-small cell lung cancer (NSCLC) (e.g., squamous or non-squamous NSCLC) In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is colorectal cancer (CRC) (e.g., microsatellite-positive Stable-high colorectal cancer (MSI-high CRC) or microsatellite-stable colorectal cancer (MS In some embodiments, the cancer is leukemia (e.g., acute myeloid leukemia (A CRC)). AML), e.g., relapsed or refractory AML or de novo AML). In one embodiment, the cancer is a myelodysplastic syndrome (MDS) (e.g., high-risk MDS).

[0023] These agents are classified into the following categories: (i) agents that enhance antigen (e.g., tumor antigen) presentation; (ii) agents that enhance effector cell presentation; Agents that enhance cell responses (e.g., activation and / or recruitment of B cells and / or T cells) or (iii) an agent that reduces tumor immunosuppression. Therapeutic agents include combinations of two, three or more therapeutic agents that reduce the activity of cells. and (optionally) instructions for use, e.g., dosage formulations and kits, e.g., therapeutic Therapeutic kits are also disclosed. In some embodiments, the combination includes a PD-1 inhibitor (e.g., For example, an anti-PD-1 antibody molecule described herein.

[0024] A combination of therapeutic agents disclosed herein includes two or more of the therapeutic agents described herein. Therapeutic agents in the combination may belong to the same category, as described below, but may be classified as category (i), In the case of two or more therapeutic agents, at least one agent from two or more categories (e.g., category (i) A therapeutic agent may include a combination of a therapeutic agent in category (1) and a therapeutic agent in category (ii). For example, a therapeutic agent (e.g., a number of GITR agonists, IDO antagonists, and TGF-β inhibitors are classified into multiple categories. It may act as a therapeutic agent for Lee.

[0025] Further features or embodiments of the methods, compositions, dosage formulations and kits described herein include: , including one or more of the following:

[0026] combination In certain embodiments, the combination comprises one or more of the following: , 3, 4 or more therapeutic agents (referred to herein as an "antigen-presenting combination"). In certain embodiments, the antigen-presenting combination may also include an agent that enhances antigen presentation (e.g., a vaccine). vaccines, e.g., cell- or antigen-based vaccines), agents that enhance tumor cell lysis (e.g., , oncolytic viruses), agents that stimulate (e.g., deinhibit) phagocytes, e.g., type I insulin Interferon (IFN) activators (e.g., TLR agonists, RIG-I-like receptor agonists) agonists (RLRs)) and / or dendritic cells or macrophages (e.g., macrophages Agents that activate and / or recruit phage I, e.g., bi- or trispecific cell antigens Contains one or more of the word "engager."

[0027] In one embodiment, the antigen-presenting combination comprises: (i) an interferon gene stimulator; agonists (STING agonists), (ii) Toll-like receptor (TLR) agonists (e.g., TLR-3, -4, -5, -7, -8, or -9 agonists), (iii) TIM-3 modules (iv) vascular endothelial growth factor receptor (VEGFR) inhibitors, (v) c-Met inhibitors, (vi) TGF-β inhibitors (e.g., anti-TGF-β antibodies), (v ii) IDO / TDO inhibitors, (viii) A2AR antagonists, (ix) oncolytic viruses, ( x) vaccines (e.g., scaffold vaccines) or (xi) bi- or tri-specific cell antigens The drug (i) comprises one, two, three, four, five or more therapeutic agents selected from the group consisting of: Any combination of (xi) to (xi) can be used in the antigen-presenting combination. In embodiments, the antigen-presenting combination includes a STING agonist. In the present invention, the antigen-presenting combination includes a TLR agonist (e.g., a TLR7 agonist). In other exemplary embodiments, the antigen-presenting combination comprises a STING agonist and In one embodiment, the antigen presentation comprises a TLR agonist (e.g., a TLR7 agonist). The combinations shown are STING agonist, TLR agonist, A2AR antagonist, or an oncolytic virus or a combination thereof and optionally, (iii) to (vii) or In one embodiment, the antigen-presenting combination is selected from one or more of (x) to (xi). ING agonist or TLR agonist or a combination of both and optionally, (i In another embodiment, the antigen-presenting combination is selected from one or more of: TING agonists, TLR agonists (e.g., TLR7 agonists), and TIM-3 In another embodiment, the antigen presentation modulator comprises a TIM-3 inhibitor. The combination may include a STING agonist, a TLR agonist (e.g., a TLR7 agonist), and a VEGFR inhibitor. ING agonists, TLR agonists (e.g., TLR7 agonists) and c-MET inhibitors In yet another embodiment, the antigen-presenting combination comprises an oncolytic virus. In another embodiment, the antigen-presenting combination comprises an oncolytic virus and a cytolytic virus. one or more of a cytokine, e.g., GM-CSF or a CSF (e.g., CSF1 or CSF2) In one embodiment, the antigen-presenting combination comprises an oncolytic virus expressing , bi- or trispecific cell angina with or without an Fc domain, e.g., CD4 In one embodiment, the antibody molecule comprises a bispecific antibody molecule directed against CD7 and CD19. The proposed combination includes a TGF-β inhibitor (e.g., an anti-TGF-β antibody). In some embodiments, the antigen-presenting combination includes an IDO / TDO inhibitor. In yet another embodiment, the antigen-presenting combination comprises an A2AR antagonist. In the present invention, the antigen-presenting combination is a vaccine (e.g., MUC1 or dendritic cell-based Further examples include vaccines (e.g., IL-2 in combination with Provenge®). In embodiments, the antigen-presenting combination comprises a vaccine and a TLR agonist (e.g., In one embodiment, the antigen-presenting combination comprises a TLR agonist (e.g., a TLR agonist as described herein). In one embodiment, the antigen-presenting combination comprises a vaccine and a STING agonist. Combinations include vaccines, STING agonists, and TLR agonists.

[0028] In one embodiment, the combination comprises one, two, three, or more of the following: four, five, or more therapeutic agents (referred to herein as an "effector cell combination"); In one embodiment, the effector cell combination comprises a lymphocyte activator -, for example, NK cell activators and / or T cell activators. In one embodiment, the effector cell combination comprises tumor infiltrating lymphocytes (TILs), e.g. For example, NK cells or T cells are activated (e.g., disinhibited). The effector cell combination may comprise a modulator of the NK receptor (e.g., an antibody molecule) (e.g., , NKG2A, KIR3DL, NKp46, MICA, or CEACAM1 indulator), interleukin or interleukin variant (e.g., IL-2 , IL-15, IL-21, IL-13R or IL-12 cytokines or their variants ants or combinations thereof), bi- or tri-specific cell angina (e.g., NKG2 A and CD138 bispecific antibody molecule or CD3 and TCR bispecific antibody molecule) , NK cell therapy, or a vaccine comprising NK cells and an antigen / immunostimulator. In one embodiment, the effector cell combination comprises an NK cell modulator. , immunomodulatory agents (e.g., activators of costimulatory molecules or immune activators described herein), In one embodiment, the effector cells comprise one or more inhibitors of a checkpoint molecule. The combination may include inhibitors of checkpoint inhibitors (e.g., PD-1, PD-L1, T IM-3, LAG-3, VISTA, DKG-α, B7-H3, B7-H4, TIGIT , CTLA-4, BTLA, CD160, TIM1, IDO, LAIR1, IL-12 or or a combination of one or more inhibitors thereof, e.g., an inhibitor of PD-1 and TIM-3 or The present invention includes a T cell modulator selected from the group consisting of inhibitors of PD-1 and LAG-3. In embodiments, the inhibitor of a checkpoint inhibitor is an antibody molecule (e.g., a (mono- or bispecific antibodies or fragments thereof) that target checkpoint Inhibitors of inhibitors include PD-1, PD-L1, TIM-3, LAG-3, VISTA, and B 7-H4, CTLA-4, or TIGIT, or any combination thereof (e.g., as described herein). In one embodiment, the effector The cell combination may comprise a T cell selected from agonists or activators of costimulatory molecules. In one embodiment, the agonist of a costimulatory molecule is a GI agonist. TR, OX40, ICOS, SLAM (e.g., SLAMF7), HVEM, LIGHT, CD2, CD27, CD28, CDS, ICAM-1, LFA-1(CD11a / CD1 8), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFF R, CD7, NKG2C, NKp80, CD160, B7-H3 or CD83 ligand agonists (e.g., agonist antibodies or antigen-binding fragments thereof or soluble fusion proteins) of In another embodiment, the effector cell combination is selected from a bispecific combination. Targeted T cell antigens (e.g., CD3) and tumor antigens (e.g., EGFR, PS, among others) It contains a bispecific antibody molecule that binds to (PSMA, EpCAM, HER2).

[0029] In one embodiment, the effector cell combination comprises: (i) a GITR modulator; (e.g., a GITR agonist), (ii) a PD-1 inhibitor (e.g., an anti-PD-1 inhibitor described herein), 1 antibody molecule), (iii) PD-L1 inhibitor, (iv) IAP inhibitor ( I inhibitor of A Poptosis P rot ein), (v) EGFR inhibitor ( E pidermal G rowth F actor R receptor), (vi) inhibitor of the target (mTOR), (vii) IL-15 or a variant thereof, (viii) a CTLA-4 inhibitor, (ix) Bispecific T cell antigens (e.g., CD3 and tumor antigens (e.g., EGFR, among others) , PSCA, PSMA, EpCAM, HER2), (x)CD (xi) OX40 agonists (e.g., anti-O X40 antibody molecule) or (xii) a CD27 agonist (e.g., an anti-CD27 antibody molecule). Any combination of the above therapeutic agents. may be used in effector cell combinations. In another embodiment, the effector cell combination includes a GITR agonist. The vector cell combination may include a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein). In other embodiments, the effector cell combination comprises a PD-L1 inhibitor. In other embodiments, the effector cell combination comprises a GITR agonist and and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein). In this study, the effector cell combination was a GITR agonist and a PD-L1 inhibitor. In other embodiments, the effector cell combination comprises a GITR agonist, a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) and a PD-L1 inhibitor In other embodiments, the effector cell combination includes a PD-1 inhibitor (e.g., , an anti-PD-1 antibody molecule described herein) and a PD-L1 inhibitor. wherein the effector cell combination comprises a GITR agonist and an IAP inhibitor. In other embodiments, the effector cell combination comprises a GITR agonist and an E In yet another embodiment, the effector cell combination comprises an inhibitor of a GFR inhibitor. The combination includes a GITR agonist and an inhibitor of an mTOR inhibitor. In some embodiments, the effector cell combination includes IL-15 or a variant thereof. In some embodiments, the effector cell combination includes a CTLA-4 inhibitor. In such cases, the effector cell combination may be a bispecific T cell angina (e.g., CD4+). 3 and tumor antigens (e.g., EGFR, PSCA, PSMA, EpCAM, H, among others). In one embodiment, the effector cell comprises a bispecific antibody molecule that binds to the ER2. The combination includes a CD40 agonist (e.g., an anti-CD40 antibody molecule). In the present invention, the effector cell combination may comprise an OX40 agonist (e.g., an anti-OX40 antibody In one embodiment, the effector cell combination comprises a CD27 receptor molecule. The antibody may comprise a chemist (e.g., an anti-CD27 antibody molecule).

[0030] In one embodiment, the combination reduces tumor immunosuppression. five or more therapeutic agents (referred to herein as an "anti-tumor immunosuppressive combination"). In one embodiment, the combination is reg , macrophages 2 or MDSC 1 or more In one embodiment, the combination modulates the activity or level of M2 polarization, T reg In one embodiment, the anti-tumor immune system enhances one or more of T cell depletion or T cell recruitment. The immunosuppressive combination may comprise: (i) an immunomodulatory agent (e.g., an agent that inhibits the activity of a costimulatory molecule as described herein); beta-activators (e.g., GITR agonists) or inhibitors of immune checkpoint molecules (e.g., For example, one or more of PD-1, PD-L1, LAG-3, TIM-3, or CTLA-4 or more), (ii) CSF-1 / 1R inhibitors (e.g., macrophage colony-stimulating factor (MC SF) inhibitor), (iii) IL-17 inhibitor, (iv) IL-1β inhibitor, (v) CXCR2 inhibitor (vi) phosphoinositide 3-kinase (PI3K, e.g., PI3Kγ or PI3Kδ) inhibitors, (vii) BAFF-R inhibitors, (viii) MALT-1 / BTK inhibitors, (ix) JAK inhibitors (x) a CRTH2 inhibitor, (xi) a VEGFR inhibitor, (xiii) an IL-15 or its derivatives (xiv) CTLA-4 inhibitors, (xv) IDO / TDO inhibitors, (xvi) A2AR antagonists (xvii) a TGF-β inhibitor, or (xviii) a PFKFB3 inhibitor; In certain embodiments, the immunomodulatory agent comprises one, two, three, four, five, or more therapeutic agents. The inhibitors of immune checkpoint molecules (e.g., inhibitors of PD-1, PD-L1, LA G-3, TIM-3, CEACAM (e.g., CEACAM-1, -3 and / or - 5) or CTLA-4 or any combination thereof). In one exemplary embodiment, the combination of: The anti-tumor immunosuppressive combination may include a PD-1 inhibitor (e.g., an anti-PD-1 antibody described herein). molecules), PD-L1 inhibitors, LAG-3 inhibitors, TIM-3 modulators (e.g., anti-T IM-3 inhibitors), GITR agonists, CSF-1 / 1R inhibitors (e.g., M-CSF inhibitors), an IL-17 inhibitor, an IL-1β inhibitor, or a CXCR2 inhibitor In some embodiments, the anti-tumor immunosuppressant comprises one or more of the following therapeutic agents: The combination is a CSF-1 / 1R inhibitor (e.g., M-CSF inhibitor), an IL-17 inhibitor, In certain embodiments, the anti-tumor immunosuppressant comprises one, two, or all of: an anti-tumor agent; an IL-1β inhibitor; and an IL-1β inhibitor. The combination is an IL-17 inhibitor, a CXCR2 inhibitor, a CRTH2 inhibitor, and an A2AR inhibitor. The present invention includes a PFKFB3 inhibitor or a PFKFB3 antagonist or a combination thereof.

[0031] In certain embodiments, the combination comprises one or more therapeutic agents of an antigen-presenting combination. In other embodiments, the combination comprises one or more therapeutic agents of the effector cell combination. In yet another embodiment, the combination comprises one or more of an anti-tumor immunosuppressive combination. In other embodiments, the combination comprises one or more of the following therapeutic agents: Therapeutic Agent and Effector Cell Combination includes one or more therapeutic agents. Thus, the combination may comprise one or more therapeutic agents of the antigen-presenting combination and one or more therapeutic agents of the anti-tumor immunosuppressive combination. In other embodiments, the combination comprises one or more therapeutic agents selected from the group consisting of an antigen-presenting combination. one or more therapeutic agents of the effector cell combination and anti-tumor immunosuppression In other embodiments, the combination comprises one or more therapeutic agents. Combination of one or more therapeutic agents, effector cells, combination of one or more therapeutic agents and anti-tumor It includes one or more therapeutic agents of the immunosuppressive combination.

[0032] In one embodiment, the combination is: (i) a STING agonist, a TLR agonist (e.g., a TLR7 agonist), or a TI an anti-TIM-3 modulator (e.g., a TIM-3 inhibitor) selected from one, two, or all of the following: one or more of the therapeutic agents of the original proposed combination; (ii) GITR modulators (e.g., GITR agonists), PD-1 inhibitors (e.g., and one, two, or all of the anti-PD-1 antibody molecules described herein or PD-L1 inhibitors. one or more therapeutic agents of the effector cell combination selected; (iii) a CSF-1 / 1R inhibitor (e.g., an M-CSF inhibitor), an IL-17 inhibitor, or an I one or more of an antitumor immunosuppressive combination selected from one, two or all of an L-1β inhibitor therapeutic agents; (iv) a combination of (i) and (ii); (v) a combination of (i) and (iii); (vi) a combination of (ii) and (iii); or (vii) A combination of (i), (ii), and (iii) Includes:

[0033] This combination is effective against lung cancer (squamous cell carcinoma), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell carcinoma), and gastric cancer. , thyroid cancer, skin cancer, melanoma (e.g., advanced melanoma), nasopharyngeal cancer, kidney cancer, neuroendocrine tumors The present invention is directed to the treatment of cancers described herein, such as ovarian cancer, fallopian tube cancer, colorectal cancer, or breast cancer. In some embodiments, the cancer is a skin cancer, e.g., Merkel cell carcinoma or melanoma. In some embodiments, the cancer is Merkel cell carcinoma. In other embodiments, the cancer is In other embodiments, the cancer is breast cancer, e.g., triple-negative breast cancer (TBC). In other embodiments, the cancer is renal cancer, e.g., HER2-negative breast cancer. For example, renal cell carcinoma (e.g., clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC) In other embodiments, the cancer is thyroid cancer, e.g., anaplastic thyroid carcinoma (ATC). In other embodiments, the cancer is a neuroendocrine tumor (NET), e.g., atypical lung cancer. In some embodiments, the tumor is a thyroid tumor or a NET in the pancreas, gastrointestinal (GI) tract, or lung. In the present invention, the cancer is lung cancer, e.g., non-small cell lung cancer (NSCLC) (e.g., squamous cell NSCLC or non-squamous NSCLC). In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is colorectal cancer (CRC). (e.g., microsatellite instability-high colorectal cancer (MSI-high CRC) or microsatellite instability-high CRC) In one embodiment, the cancer is leukemia-associated cancer (MSS CRC). Diseases (e.g., acute myeloid leukemia (AML), e.g., relapsed or refractory AML or de novo In some embodiments, the cancer is myelodysplastic syndrome (MDS) (e.g., high-risk MDS).

[0034] In other embodiments, the combination comprises a therapeutic agent (e.g., S) from the antigen-presenting combination. TING agonist, TLR agonist, vaccine, or oncolytic virus) and effector cells and / or therapeutic agents from the antitumor immunosuppressive combination (e.g., Inhibitors of checkpoint inhibitors, such as inhibitors of PD-1, PD-L1, LAG- 3, TIM-3, CEACAM (e.g., CEACAM-1, -3, and / or -5) or or CTLA-4, or any combination thereof. In this regard, STING agonists, TLR agonists, vaccines, or oncolytic viruses are administered in combination with an anti-PD-1 antibody molecule described herein. In one embodiment, the STING agonist and / or vaccine is administered in combination with an anti-PD-1 In one embodiment, the oncolytic virus is administered in combination with an antibody molecule. The combination is administered in combination with an anti-PD-1 antibody molecule described in 2. , lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell carcinoma), stomach cancer, thyroid cancer, skin cancer, melanoma (e.g. advanced melanoma), nasopharyngeal carcinoma, renal cancer, neuroendocrine tumors (NETs), ovarian cancer, fallopian tube cancer, It can be used to treat cancers described herein, such as colorectal cancer or breast cancer. In some embodiments, the cancer is a skin cancer, e.g., Merkel cell carcinoma or melanoma. In another embodiment, the cancer is a melanoma. The cancer is breast cancer, e.g., triple-negative breast cancer (TNBC) or HER2-negative In other embodiments, the cancer is a renal cancer, e.g., a renal cell carcinoma (e.g., a clear cell renal cell carcinoma). In another embodiment, the tumor is a clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC). In other embodiments, the cancer is thyroid cancer, e.g., anaplastic thyroid carcinoma (ATC). The cancer may be a neuroendocrine tumor (NET), e.g., atypical lung carcinoid tumor or a tumor of the pancreas, gastrointestinal ( In some embodiments, the cancer is lung cancer, e.g., NETs in the GI tract or lung. Non-small cell lung cancer (NSCLC) (e.g., squamous or non-squamous NSCLC) In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is colorectal cancer (CRC) (e.g., microsatellite-positive Stable-high colorectal cancer (MSI-high CRC) or microsatellite-stable colorectal cancer (MS In some embodiments, the cancer is leukemia (e.g., acute myeloid leukemia (A CRC)). AML), e.g., relapsed or refractory AML or de novo AML). In one embodiment, the cancer is a myelodysplastic syndrome (MDS) (e.g., high-risk MDS).

[0035] In some embodiments, the combination is referred to as an "antigen-presenting combination," as provided in the detailed description. "Examples of effector cell combinations and antitumor immunosuppressive combinations" This includes the therapeutic agent combinations provided in the section.

[0036] In one embodiment, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and IAP inhibitors, S)-N-((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl) Thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino ) propanamide (compound A21) or compounds disclosed in U.S. Pat. No. 8,552,003. In one embodiment, an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1, is used. The inhibitor (e.g., anti-PD-1 antibody molecule) is administered at a dose of 200 mg to 600 mg (e.g., 400 mg In one embodiment, the compound is administered intravenously, e.g., once every four weeks at a dose of 100 mg / kg / day. AP inhibitor, (S)-N-((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluoyl) (benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2- (Methylamino)propanamide (compound A21) or as disclosed in U.S. Pat. No. 8,552,003 The compound is administered at a dose of 200 mg to 400 mg (e.g., a dose of 300 mg), for example, once a week. In some embodiments, the combination is administered to treat cancers described herein, e.g., orally. For example, colorectal cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), or breast cancer (e.g., For use in the treatment of ripple-negative breast cancer (e.g., NTBC).

[0037] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1 (e.g., an anti-PD-1 antibody molecule described herein) and an mTOR inhibitor; Everolimus (compound A36) or any of the compounds disclosed in PCT Publication WO2014 / 085318 In one embodiment, an inhibitor of an immune checkpoint molecule, e.g., PD Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules) are administered at doses of 200 mg to 600 mg (e.g., 4 In one embodiment, the drug is administered intravenously, for example, at a dose of 000 mg, for example, once every four weeks. and the mTOR inhibitor, everolimus (compound A36) or PCT Publication WO2014 / 0 The compounds disclosed in No. 85318 are administered at a dose of 2 mg to 8 mg (e.g., a dose of 5 mg), for example, once a week. In some embodiments, the combination is administered once a day, e.g., orally. cancers, such as colorectal cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), or breast cancer (e.g., For example, it is used to treat triple-negative breast cancer (e.g., NTBC).

[0038] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and DAC inhibitors, Novinostat (compound A19) or compounds disclosed in PCT Publication WO2014 / 072493 In some embodiments, the compounds include inhibitors of immune checkpoint molecules, e.g., P Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules) are administered at doses of 200 mg to 600 mg (e.g., In one embodiment, the drug is administered intravenously, e.g., once every four weeks, at a dose of 400 mg. In the present invention, the DAC inhibitor, panobinostat (compound A19) or PCT publication WO2014 The compounds disclosed in / 072493 are administered in doses of 5 mg to 15 mg (e.g., 10 mg), e.g. For example, three times a week (e.g., on a one week on / one week off schedule), e.g., orally In some embodiments, the combination is administered to treat a cancer described herein, e.g., colorectal cancer. , lung cancer (e.g., non-small cell lung cancer (NSCLC)) or breast cancer (e.g., triple-negative breast cancer) For use in the treatment of cancer (e.g., NTBC).

[0039] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and IL-1β inhibitors , canakinumab, or compounds disclosed in PCT Publication WO 2002 / 16436. In some embodiments, inhibitors of immune checkpoint molecules, such as inhibitors of PD-1 ( For example, an anti-PD-1 antibody molecule) is administered at a dose of 200 mg to 600 mg (for example, a 400 mg dose). In one embodiment, IL-1 is administered intravenously, e.g., once every four weeks. β-blocking agents, canakinumab or compounds disclosed in PCT Publication WO2002 / 16436 , at a dose of 50 mg to 150 mg (for example, a dose of 100 mg), for example, once every 8 weeks, for example, In one embodiment, the combination is administered subcutaneously to treat any of the cancers described herein, e.g., colorectal cancer (e.g., microsatellite stable colorectal cancer (MSS CRC)), lung cancer (e.g., non-small cell lung cancer (NSCLC)) or breast cancer (e.g., triple-negative breast cancer (e.g., Used to treat NTBC).

[0040] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and IL-17 inhibitors , CJM112 or compounds disclosed in PCT Publication WO2014 / 122613. In one embodiment, an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1 (e.g., anti-PD-1 antibody molecule) in a dose of 200 mg to 600 mg (e.g., a 400 mg dose) In one embodiment, IL-1 is administered intravenously, e.g., once every four weeks. 7 inhibitor, CJM112 or compounds disclosed in PCT Publication WO2014 / 122613 is administered intravenously, for example, once every four weeks, at a dose of 10 mg to 50 mg (for example, a dose of 25 mg). In one embodiment, the combination is administered intravenously to treat any of the cancers described herein, e.g., colorectal cancer (e.g., MSS CRC), lung cancer (e.g., non-small cell lung cancer (NSCLC)), or breast cancer For use in treating cancer (eg, triple-negative breast cancer (eg, NTBC)).

[0041] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and MEK inhibitors or In some embodiments, inhibitors of immune checkpoint molecules, e.g., trametinib, For example, PD-1 inhibitors (e.g., anti-PD-1 antibody molecules) are administered at doses of 200 mg to 600 mg ( For example, at a dose of 400 mg, the drug is administered intravenously, for example, once every four weeks. In embodiments, the MEK inhibitor or trametinib is administered at a dose of 0.2 mg to 1 mg (e.g., In one embodiment, the compound is administered orally, e.g., once a day, e.g., at a dose of 0.5 mg. The combinations are also used in the treatment of cancers described herein, such as colorectal cancer, lung cancer (e.g., non-small cell lung cancer ( for the treatment of NSCLC) or breast cancer (e.g., triple-negative breast cancer (e.g., NTBC)) Use.

[0042] In one embodiment, the combination includes an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1 (e.g., an anti-PD-1 antibody molecule described herein), a BRAF inhibitor, or In one embodiment, therapies include dabrafenib and a MEK inhibitor or trametinib. Inhibitors of immune checkpoint molecules, for example, inhibitors of PD-1 (e.g., anti-PD-1 antibodies) The total molecule is administered at a dose of 200 mg to 600 mg (for example, at a dose of 400 mg), for example, once every 4 weeks. In one embodiment, the antibody is administered intravenously, for example, once daily to inhibit the inhibition of immune checkpoint molecules. The inhibitor, for example, a PD-1 inhibitor (for example, an anti-PD-1 antibody molecule), is administered at a dose of 200 mg to 600 mg. (for example, a 400 mg dose), for example, once every 8 weeks, e.g., intravenously. In one embodiment, the BRAF inhibitor or dabrafenib is administered at a dose of 50 mg to 250 mg. In one embodiment, the compound is administered orally, for example, at a dose of 150 mg twice daily. MEK inhibitors or trametinib are administered at doses of 1 mg to 3 mg (e.g., 2 mg), e.g., For example, it is administered once a day, e.g., orally. Inhibitors of PD-1 molecules, such as PD-1 inhibitors (e.g., anti-PD-1 antibody molecules), inhibit BRAF inhibitors or dabrafenib, MEK inhibitors or trametinib or both, e.g. For a period of 2 to 8 weeks, e.g., 4 weeks, after administration, e.g., at a dose of 200 mg to 600 mg (e.g., In one embodiment, the combination is administered at a dose of, for example, 400 mg, for example, once every four weeks. The combination is used to treat cancers described herein, e.g., skin cancers (e.g., melanoma, e.g., unresectable or In one embodiment, the combination is used to treat melanoma (melanoma or metastatic melanoma). For example, for the treatment of cancers with a BRAF V600 mutation. The combination was compared to control serum lactate dehydrogenase (LDH) levels. In one embodiment, the combination is used to treat cancer in subjects with increased BR. Patients with AF mutations (e.g., BRAF V600 mutations) and elevated serum LDH levels compared with control patients It is used to treat subjects with unresectable or metastatic melanoma who have elevated LDH levels in their serum. Use.

[0043] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and EGFR inhibitors , (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl))a (1H-benzo[d]imidazol-2-yl)-2-methylisonicotin amide (compound A40) or compounds disclosed in PCT Publication WO2013 / 184757 In one embodiment, an inhibitor of an immune checkpoint molecule, e.g., PD-1 The inhibitors (e.g., anti-PD-1 antibody molecules) are administered at doses of 200 mg to 600 mg (e.g., 400 mg g), e.g., once every four weeks, e.g., intravenously. EGFR inhibitor, (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but- 2-Enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2- Methylisonicotinamide (Compound A40) or PCT Publication WO2013 / 184757 The compounds disclosed in are administered at a dose of 10 mg to 50 mg (e.g., a dose of 25 mg), for example, once a day. (e.g., days 1 to 10 of the first administration cycle), for example, orally. In embodiments, the combination is administered to treat a cancer described herein, e.g., colorectal cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)) or breast cancer (e.g., triple-negative breast cancer (NT Used to treat BC).

[0044] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and CSF-1 / 1R Binding agents (e.g., CSF-1R tyrosine kinase inhibitors), 4-((2-(((1R,2R)-2 -hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methyl Chilpicolinamide (compound A15) or as disclosed in PCT Publication WO2005 / 073224 In some embodiments, inhibitors of immune checkpoint molecules, e.g., PD-1 inhibitors (e.g., anti-PD-1 antibody molecules) are administered at doses of 200 mg to 600 mg (e.g., , 400 mg) administered, e.g., intravenously, e.g., once every four weeks. CSF-1 / 1R binding agents (e.g., CSF-1R tyrosine kinase inhibitors), -((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazole (6-yl)oxy)-N-methylpicolinamide (Compound A15) or PCT Publication WO2 The compounds disclosed in 005 / 073224 are available in doses of 50 mg to 1000 mg (e.g., 100 mg , 150mg, 300mg, 600mg, 900mg doses), for example, 7 days on / 7 days off. The dosage is administered daily or weekly, e.g., orally. The combinations are used in the treatment of cancers described herein, such as brain tumors (e.g., glioblastoma multiforme (GBM)), For use in treating breast cancer (e.g., triple-negative breast cancer (e.g., NTBC)) or pancreatic cancer. do.

[0045] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1 (e.g., an anti-PD-1 antibody molecule described herein) and 6-phosphofructose Inhibitors of PFK-2-kinase / fructose-2,6-biphosphatase 3 (PFKFB3) , PFK-158 or compounds disclosed in PCT Publication WO2013 / 148228. In one embodiment, an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1 (e.g., anti-PD-1 antibody molecule) in a dose of 200 mg to 600 mg (e.g., a 400 mg dose) In one embodiment, the combination is administered intravenously, for example, once every four weeks. The method may be used to treat a cancer described herein, such as ovarian cancer, fallopian tube cancer, or colorectal cancer (CRC). Use.

[0046] In one embodiment, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and chemotherapeutic agents, e.g., Examples include paclitaxel (e.g., nab-paclitaxel). Inhibitors of immune checkpoint molecules, for example, inhibitors of PD-1 (e.g., anti-PD-1 antibodies) The total molecule is administered at a dose of 200 mg to 600 mg (for example, at a dose of 400 mg), for example, once every 4 weeks. In some embodiments, the chemotherapeutic agent, e.g., paclitaxel, is administered intravenously. Paclitaxel (e.g., nab-paclitaxel) is administered at a dose of 50 mg / m 2 ~200mg / m2 Dosage (e.g. For example, 100 mg / m 2 dose), for example, on days 1, 8, and 15 every 4 weeks (qw 3 / 4), e.g., intravenously. In some embodiments, the combination is administered intravenously. The present invention is used to treat cancers such as breast cancer (e.g., HER2-negative breast cancer).

[0047] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and TGF-β inhibitors , XOMA 089 or compounds disclosed in PCT Publication WO2012 / 167143. In one embodiment, an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1, is used. The inhibitor (e.g., anti-PD-1 antibody molecule) is administered in a dose of 100 mg to 600 mg (e.g., 100 mg to In one embodiment, the compound is administered intravenously, e.g., once every three weeks (e.g., at a dose of 300 mg or 300 mg). In such cases, TGF-β inhibitors, XOMA 089 or PCT Publication WO2012 / 16 The compounds disclosed in No. 7143 are administered in a dose range of 0.1 mg / kg to 15 mg / kg, for example, 0.1 mg / kg to 6 mg / kg. kg or a dose of 0.3 mg / kg to 3 mg / kg (e.g., 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3mg / kg, 6mg / kg, 10mg / kg or 15mg / kg) once every 3 weeks, e.g. In some embodiments, the combination is administered intravenously to treat any of the cancers described herein, e.g., For example, pancreatic cancer, colorectal cancer (e.g., microsatellite stable colorectal cancer (MSS-CR) C)), lung cancer (e.g., non-small cell lung cancer), breast cancer (e.g., triple-negative breast cancer), liver cancer ( for use in the treatment of hepatocellular carcinoma, prostate cancer, or kidney cancer (e.g., clear cell renal cell carcinoma) .

[0048] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and PD-L1 inhibition or the anti-PD-L1 antibody molecules disclosed in U.S. Patent Application Publication No. 2016 / 0108123. In one embodiment, an inhibitor of an immune checkpoint molecule, e.g., PD-1, The inhibitor (e.g., anti-PD-1 antibody molecule) is administered at a dose of 100 mg to 600 mg (e.g., 100 mg or 300 mg), for example, once every three weeks, e.g., intravenously. In embodiments, an inhibitor of PD-L1 or U.S. Patent Application Publication No. 2016 / 0108123 The anti-PD-L1 antibody molecules disclosed herein are administered in doses of 10 mg to 2000 mg (e.g., 20 mg to 160 mg). 0 mg or 80 mg to 1200 mg (e.g., 20 mg, 80 mg, 240 mg, 800 mg or 1 200 mg)) administered intravenously, for example, once every 3 weeks or once every 6 weeks In some embodiments, the combination is administered to a cancer described herein, e.g., a solid tumor, e.g., , lung cancer (e.g., non-small cell lung cancer), breast cancer (e.g., triple-negative breast cancer), uterine cancer (e.g., For example, endometrial cancer) or thyroid cancer (e.g., anaplastic thyroid cancer).

[0049] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of PD-1 (e.g., anti-PD-1 antibody molecules described herein) and chemotherapeutic agents (e.g., Examples include hypomethylating agents, such as decitabine. In such cases, inhibitors of immune checkpoint molecules, such as inhibitors of PD-1 (e.g., The anti-PD-1 antibody molecule) is administered at a dose of 200 mg to 600 mg (e.g., 300 mg to 500 mg, e.g., For example, at a dose of 400 mg, the drug is administered, for example, intravenously, for example, once every four weeks. In such cases, the chemotherapeutic agent (e.g., a methylation inhibitor, e.g., decitabine) is administered at a dose of 5 mg / m 2 ~50mg / m 2 dose (e.g., 10 mg / m 2 ~30mg / m 2 , e.g., 20 mg / m 2 of dose), for example, every day, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, or more, e.g., intravenously. Inhibitors of PD-1 molecules, such as PD-1 inhibitors (e.g., anti-PD-1 antibody molecules), were administered for 28 days. chemotherapeutic agents (e.g., methylation inhibitors, e.g., decitabine) are administered on day 8 of the course. Dosing is on days 1, 2, 3, 4, and 5 of an 8-day cycle. In the present invention, the combination is administered to a cancer described herein, e.g., a blood cancer, e.g., leukemia (e.g., acute myeloid leukemia (AML), e.g., relapsed or refractory AML or de novo AML) or or for use in the treatment of myelodysplastic syndromes (MDS) (e.g., high-risk MDS).

[0050] In other embodiments, the combination includes an inhibitor of an immune checkpoint molecule, e.g., Inhibitors of TIM-3 or anti-TI agents disclosed in U.S. Patent Application Publication No. 2015 / 0218274 M-3 antibody molecule and a chemotherapeutic agent (e.g., a methylation inhibitor, e.g., decitabine) In one embodiment, an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of TIM-3, is used. or the anti-TIM-3 antibody molecule disclosed in U.S. Patent Application Publication No. 2015 / 0218274. is given in doses of 50 mg to 500 mg (e.g., 100 mg to 400 mg, e.g., 240 mg). In one embodiment, the chemotherapeutic agent is administered intravenously, e.g., once every two weeks. (e.g., methylation inhibitors, e.g., decitabine) at 5 mg / m 2 ~50mg / m 2 Dosage ( For example, 10 mg / m 2 ~30mg / m 2 , e.g., 20 mg / m 2 (dose), for example, every day , for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days or more, e.g., In some embodiments, inhibitors of immune checkpoint molecules, e.g., , an inhibitor of TIM-3 or an anti-T The IM-3 antibody molecule is administered on days 8 and 22 of a 28-day cycle, and chemotherapy (e.g., For example, a methylation inhibitor (e.g., decitabine) is administered on days 1, 2, and 3 of a 28-day cycle. In certain embodiments, the combination is administered on days 1, 2, 3, 4, and 5. Cancers that cause cancer, such as blood cancers, for example, leukemia (e.g., acute myeloid leukemia (AML)), for example, relapsed or refractory AML or de novo AML) or myelodysplastic syndromes (MDS) (e.g., It is used to treat high-risk MDS.

[0051] In other embodiments, the combination includes an inhibitor of PD-1 (e.g., an inhibitor described herein). PD-1 antibody molecules), inhibitors of TIM-3 (e.g., U.S. Patent Application Publication No. 2015 / 0218 274) and chemotherapeutic agents (e.g., methylation inhibitors, e.g., In certain embodiments, inhibitors of PD-1 (e.g., anti-PD- 1 antibody molecule) is administered in a dose of 200 mg to 600 mg (e.g., 300 mg to 500 mg, e.g., 40 In one embodiment, the compound is administered intravenously, e.g., at a dose of 0 mg, e.g., once every four weeks. and TIM-3 inhibitors (e.g., those disclosed in U.S. Patent Application Publication No. 2015 / 0218274). The anti-TIM-3 antibody molecule) is administered in a dose of 20 mg to 400 mg (e.g., 40 mg to 200 mg or 50 mg to 100 mg, e.g., 80 mg), for example, once every two weeks, e.g., intravenously. In some embodiments, a chemotherapeutic agent (e.g., a methylation inhibitor, e.g., a dextran) is administered. Tabine) is 5 mg / m 2 ~50mg / m 2 dose (e.g., 10 mg / m 2 ~30mg / m 2 ,example For example, 20 mg / m 2 (dose), for example, every day, for example, 1 day, 2 days, 3 days, 4 days, 5 days In some embodiments, the compound is administered intravenously for 6, 7, 8, or more days, e.g., intravenously. administering an inhibitor of PD-1 (e.g., an anti-PD-1 antibody molecule) on day 8 of a 28-day cycle; Inhibitors of TIM-3 (e.g., the inhibitors disclosed in U.S. Patent Application Publication No. 2015 / 0218274) TIM-3 antibody molecule) is administered on days 8 and 22 of a 28-day cycle, and chemotherapy (e.g., For example, decitabine) on days 1, 2, 3, 4, and 5 of a 28-day cycle. In one embodiment, the combination is administered to a cancer described herein, e.g., a hematological cancer, For example, leukemia (e.g., acute myeloid leukemia (AML), e.g., relapsed or refractory AML) or de novo AML) or myelodysplastic syndrome (MDS) (e.g., high-risk MDS) Used for.

[0052] The combinations disclosed herein may be administered together in a single composition or in two or more different compositions. Therapeutic Agents may be administered separately, e.g., in compositions or dosage forms described herein. The first agent and the additional agent (e.g., the second and third agents) may be administered via the same route. The first therapeutic agent may be administered by one route or by a different route of administration. For example, the first therapeutic agent may be administered by the same route as the additional agent. In some embodiments, the first agent is administered topically, e.g., simultaneously with, before, or after the first agent is administered topically. For example, a therapeutic agent in any of categories (i) to (iii) can be administered as a tumor targeting agent, e.g., tumor-targeting antibodies (e.g., to form antibody-drug conjugates) or any and other delivery agents (e.g., formulations such as targeted formulations) and administration of the first agent to a desired site, e.g. The antibody may be bound to the tumor so that it is localized at the tumor site (e.g., a dendritic cell-enriched site). In embodiments, the therapeutic agent is an antigen (e.g., a vaccine, e.g., an in situ cancer vaccine); This targets the tumor environment, thus resulting in activation of dendritic cells. Therapeutic agents may also be administered locally, e.g., by injection (e.g., intratumoral or peritumoral administration). Delivery or administration to a site may otherwise be associated with one or more side effects or side effects associated with systemic administration of the therapeutic agent. In certain exemplary embodiments, a therapeutic agent (e.g., a STING or TLR) is conjugated to a tumor-binding antibody (e.g., an antibody that binds to HER2), This allows for the delivery of therapeutic agents to HER-2 expressing cells.

[0053] When administered in combination, the first agent, the additional agent (e.g., the second or third agent), or the total The amount or dose of each drug may be higher or lower than that used individually, e.g., as monotherapy. In some embodiments, the first agent, the additional agent (e.g., The amount or dose of each drug individually, e.g., a second or third drug) or all administered may vary. For example, an amount or dose lower (e.g., at least 20% lower) than that used as monotherapy at least 30%, at least 40%, or at least 50%). A first agent that produces a desired effect (e.g., treatment of cancer), an additional agent (e.g., a second or third agent), agent) or all amounts or doses are low (e.g., at least 20%, at least 30%, at least 40% or at least 50% lower).

[0054] In one embodiment, the combination is an antigen-presenting combination, an effector cell combination, or or an antitumor immunosuppressant combination, or any combination thereof. Antibody molecules, e.g., bispecific or trispecific molecules, directed against the above therapeutic agents may be used. For example, bispecific molecules against two or more checkpoint inhibitors (e.g., anti-PD-1 1 and an anti-LAG-3 antibody molecule). In other embodiments, the combination is an antigen-presenting combination. combination of effector cells and / or antitumor immunosuppressive combinations antibody molecules, e.g., bispecific or trispecific, directed against one or more therapeutic agents selected from all of the above. In some embodiments, the antibody molecule may be in the form of a complete antibody or a fragment thereof. ment (e.g., Fab, F(ab')2, Fv, or single-chain Fv fragment (scFv)) In yet other embodiments, the antibody molecule is, for example, an IgG1, IgG2, or Ig From the heavy chain constant regions of G3, IgG4, IgM, IgA1, IgA2, IgD, and IgE The heavy chain constant regions of IgG1, IgG2, IgG3 and IgG4 are selected, in particular More particularly, IgG1 or IgG4 (e.g., human IgG1 or In one embodiment, the antibody comprises a heavy chain constant region (Fc) selected from the heavy chain constant regions of IgG1 and IgG2. In one embodiment, the heavy chain constant region is human IgG1 or human IgG4. The constant region is used to modify the properties of the antibody molecule (e.g., Fc receptor binding, antibody glycosylation, etc.). Increased or decreased one or more of: cosylation, number of cysteine ​​residues, effector cell function, or complement function In some embodiments, the antibody molecule is a bispecific In the form of a specific or multispecific antibody molecule, e.g., a bispecific or trispecific antibody molecule as described herein. be.

[0055] Examples of certain therapeutic agents and combinations thereof are provided below. Further details are provided in the detailed description.

[0056] immunomodulators In some embodiments, the combinations disclosed herein (e.g., antigen-presenting combinations) The immunomodulatory agent used in combination with a therapeutic agent selected from the group consisting of immune checkpoint modulators In certain embodiments, the immunomodulatory agent is an inhibitor of PD-1, PD-L 1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g. CE ACAM-1, -3 and / or -5), VISTA, BTLA, TIGIT, LAI R1, CD160, 2B4 and / or TGF beta. Inhibitors of immune checkpoint molecules include PD-1, PD-L1, LAG-3, and TIM-3. , CEACAM (e.g., CEACAM-1, -3, and / or -5), CTLA-4, or or any combination thereof.

[0057] Inhibition of inhibitory molecules can be carried out at the DNA, RNA or protein level. In embodiments, an inhibitory nucleic acid (e.g., dsRNA, siRNA, or shRNA) is administered to In another embodiment, the inhibitory signal can be inhibited. The agent may be a polypeptide that binds to an inhibitory molecule, e.g., a soluble ligand (e.g., PD-1- Ig or CTLA-4 Ig) or an antibody or antigen-binding fragment thereof, e.g. PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3, and and / or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGF-beta or An antibody or fragment thereof (also referred to herein as an "antibody molecule") that binds to a combination of is.

[0058] In some embodiments, the antibody molecule is in the form of a bispecific or multispecific antibody molecule. In some embodiments, the bispecific antibody molecule has a first binding domain to PD-1 or PD-L1. specificity and second binding specificity, e.g., TIM-3, CEACAM (e.g., CEACA M-1, -3 and / or -5), a second binding specificity for LAG-3 or PD-L2 In one embodiment, the bispecific antibody molecule binds PD-1 or PD-L1 and and TIM-3. In other embodiments, the bispecific antibody molecule binds to PD-1 or binds to PD-L1 and LAG-3. In another embodiment, the bispecific antibody molecule , PD-1 or PD-L1 and CEACAM (e.g., CEACAM-1, -3 and In other embodiments, the bispecific antibody molecule binds to PD-1 or PD-5. In yet another embodiment, the antibody binds to both PD-L1 and CEACAM-1. The specific antibody molecule binds to PD-1 or PD-L1 and CEACAM-3. In other embodiments, the bispecific antibody molecule binds PD-1 or PD-L1 and CEAC In another embodiment, the bispecific antibody molecule binds to PD-1 or PD-AM-5. In yet another embodiment, the bispecific antibody molecule binds to PD-1 and In another embodiment, the bispecific antibody molecule binds to TIM-3 and PD-L2. In another embodiment, the bispecific antibody molecule binds to CEACAM (e.g., LAG-3). For example, it binds to CEACAM-1, -3 and / or -5) and LAG-3. In an embodiment, the bispecific antibody molecule is a CEACAM (e.g., CEACAM-1, - 3 and / or -5) and TIM-3. Multispecific antibody molecules, e.g., a first binding specificity to PD-1 or PD-1 and a T.I. M-3, CEACAM (e.g., CEACAM-1, -3, and / or -5), LAG- 3 or a trispecific antibody containing a second and a third binding specificity for two or more of PD-L2. That's fine.

[0059] In certain embodiments, the immunomodulatory agent is an inhibitor of PD-1, e.g., human PD-1 (e.g., In other embodiments, the immunomodulatory agent is a PD- In one embodiment, the inhibitor of PD-1 is an inhibitor of PD-L1, e.g., human PD-L1. PD-1 or PD-L1 is an antibody molecule directed against PD-1 or PD-L1. or PD-L1 inhibitors may be administered alone or in combination with other immunomodulatory agents, e.g. AG-3, TIM-3, CEACAM (e.g., CEACAM-1, -3 and / or In an exemplary embodiment, the compound may be administered in combination with an inhibitor of CTLA-4. In this case, inhibitors of PD-1 or PD-L1, e.g., anti-PD-1 or PD-L1 antibodies The compound is administered in combination with a LAG-3 inhibitor, such as an anti-LAG-3 antibody molecule. In embodiments, an inhibitor of PD-1 or PD-L1, e.g., anti-PD-1 or PD -L1 antibody molecule is administered in combination with a TIM-3 inhibitor, e.g., an anti-TIM-3 antibody molecule. In other embodiments, an inhibitor of PD-1 or PD-L1, e.g., an anti-PD- 1 or PD-L1 antibody molecule, in combination with a CEACAM inhibitor (e.g., CEACAM-1, -3 and / or -5 inhibitors), e.g., in combination with an anti-CEACAM antibody molecule In other embodiments, inhibitors of PD-1 or PD-L1, e.g., anti-PD-1 or The PD-L1 antibody molecule may be combined with a CEACAM-1 inhibitor, e.g., an anti-CEACAM-1 antibody molecule. In another embodiment, an inhibitor of PD-1 or PD-L1 , for example, an anti-PD-1 or PD-L1 antibody molecule, a CEACAM-5 inhibitor, e.g., In yet another embodiment, P an inhibitor of PD-L1 or PD-L1, e.g., an anti-PD-1 antibody molecule, For example, anti-LAG-3 antibody molecules and TIM-3 inhibitors, e.g., anti-TIM-3 antibody molecules Administered in combination with immunomodulatory agents and PD-1 inhibitors (e.g., PD-L2, CTLA -4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, -3, and / or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGF-beta) are also within the scope of the present invention. Any of the antibody molecules known in the art or disclosed herein may be used in combination with inhibitors of checkpoint molecules. The following combinations can be used:

[0060] In other embodiments, the immunomodulatory agent is a CEACAM (e.g., CEACAM-1, 3 and / or -5), e.g., human CEACAM (e.g., CEACAM-1, -3 and and / or -5). In certain embodiments, the immunomodulatory agent is an inhibitor of CEACA. In another embodiment, the immunomodulator is an inhibitor of M-1, e.g., human CEACAM-1. The modulator is an inhibitor of EACAM-3, e.g., human CEACAM-3. In the present invention, the immunomodulator is an inhibitor of CEACAM-5, e.g., human CEACAM-5. In some embodiments, CEACAM (e.g., CEACAM-1, -3 and / or -4) is or -5) inhibitors of CEACAM (e.g., CEACAM-1, -3 and / or -5). CEACAM (e.g., CEACAM-1, -3 and / or -5). or -5) the inhibitor is administered alone or in combination with other immunomodulators, e.g., L In combination with inhibitors of AG-3, TIM-3, PD-1, PD-L1, or CTLA-4 It may also be administered.

[0061] In other embodiments, the immunomodulatory agent is an inhibitor of LAG-3, e.g., human LAG-3. In one embodiment, the inhibitor of LAG-3 is an antibody molecule against LAG-3. LAG-3 inhibitors can be administered alone or in combination with other immunomodulatory agents, e.g. , CEACAM (e.g., CEACAM-1, -3 and / or -5), TIM-3, P It may also be administered in combination with an inhibitor of D-1, PD-L1 or CTLA-4.

[0062] In other embodiments, the immunomodulatory agent is an inhibitor of TIM-3, e.g., human TIM-3. In one embodiment, the inhibitor of TIM-3 is an antibody molecule against TIM-3. TIM-3 inhibitors can be administered alone or in combination with other immunomodulatory agents, e.g. , CEACAM (e.g., CEACAM-1, -3 and / or -5), LAG-3, P It may also be administered in combination with an inhibitor of D-1, PD-L1 or CTLA-4.

[0063] In some embodiments, the combinations disclosed herein (e.g., antigen-presenting combinations) The immunomodulatory agent used (in combination with a therapeutic agent selected from the group consisting of: In one embodiment, the agonist of a costimulatory molecule is , OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1(CD1 1a / CD18), ICOS(CD278), 4-1BB(CD137), GITR, CD3 0, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7 , agonists of NKp80, CD160, B7-H3 or CD83 ligands (e.g., agonist antibody or antigen-binding fragment thereof or soluble fusion thereof).

[0064] In other embodiments, the immunomodulatory agent is a GITR agonist. In this case, the GITR agonist is an antibody molecule against GITR. , either administered alone or in combination with other immunomodulatory agents, e.g., PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3, and / or -5), T It may be administered in combination with an inhibitor of IM-3 or LAG-3. The anti-GITR antibody molecule binds to GITR and PD-1, PD-L1, CTLA-4, and CE. ACAM (e.g., CEACAM-1, -3 and / or -5), TIM-3 or LA In one exemplary embodiment, the anti-GITR antibody fragment is a bispecific antibody that binds to GITR-3. and administering the antibody in combination with an anti-PD-1 antibody molecule (e.g., an anti-PD-1 molecule described herein). The GITR antibody molecule and the anti-PD-1 antibody molecule may be used in the form of separate antibody compositions or as a dual-specific antibody. In other embodiments, the GITR agonist may be administered as a co-immunoglobulin molecule. Inhibitory molecules, such as OX40, CD2, CD27, CD28, CDS, ICAM-1, L FA-1(CD11a / CD18), ICOS(CD278), 4-1BB(CD137), C D30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAM In combination with agonists of F7, NKp80, CD160, B7-H3 or CD83 ligands Can be administered together.

[0065] In other embodiments, the immunomodulatory agent is an activator of costimulatory molecules (e.g., O In one embodiment, the OX40 agonist is an OX40 agonist. OX40 agonists can be administered alone or in combination with other immunomodulators. In combination, for example, PD-1, PD-L1, CTLA-4, CEACAM (e.g., C In combination with inhibitors of EACAM-1, -3 and / or -5), TIM-3 or LAG-3 In certain embodiments, the anti-OX40 antibody molecule is an OX40 antibody or an OX40 antibody. and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5), which are bispecific antibodies that bind to TIM-3 or LAG-3 In an exemplary embodiment, the OX40 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (e.g., OX40 antibody molecule and anti-PD-1 molecule described herein. The -1 antibody molecules may be in the form of separate antibody compositions or as bispecific antibody molecules. In embodiments, the OX40 agonist is administered in combination with other costimulatory molecules, such as GITR, CD2 , CD27, CD28, CDS, ICAM-1, LFA-1(CD11a / CD18), I COS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, HV EM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7 It can be administered in combination with an agonist of -H3 or CD83 ligand.

[0066] Examples of checkpoint inhibitor or costimulatory molecule agonist combinations Further combinations of these agents are within the scope of the present invention. do.

[0067] Antibody molecules against PD-1 In one embodiment, a PD-1 inhibitor is an "antibody molecule against PD-1 and its use." No. 2015 / 0210769 (USSN 14 / 604), entitled "Use of a Fluorescent Lamp for a Microscope-Based Microscope," 415), which are incorporated herein by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP049-hum01, BAP049-hum02, BAP049-hum03, B AP049-hum04, BAP049-hum05, BAP049-hum06, BA P049-hum07, BAP049-hum08, BAP049-hum09, BAP 049-hum10, BAP049-hum11, BAP049-hum12, BAP0 49-hum13, BAP049-hum14, BAP049-hum15, BAP04 9-hum16, BAP049-Clone-A, BAP049-Clone-B, BA P049-Clone-C, BAP049-Clone-D or BAP049-Clo At least one antigen-binding region, e.g., a variable region, from an antibody selected from any of or an antigen-binding fragment thereof; or a nucleotide sequence as set forth in Table 1 or in Table 1 or substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more (i) includes sequences in which

[0068] In yet other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP049-hum01, BAP049-hum02, BAP049-hum03, B AP049-hum04, BAP049-hum05, BAP049-hum06, BA P049-hum07, BAP049-hum08, BAP049-hum09, BAP 049-hum10, BAP049-hum11, BAP049-hum12, BAP0 49-hum13, BAP049-hum14, BAP049-hum15, BAP04 9-hum16, BAP049-Clone-A, BAP049-Clone-B, BA P049-Clone-C, BAP049-Clone-D or BAP049-Clo at least one, two, three, or four variable regions from an antibody selected from any of ne-E; or or as set forth in or encoded by the nucleotide sequence in Table 1; or Substantially identical (e.g., at least 80%, 85%, 90%, 92%, 94%, 96%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110, 111, 112, 113, 114, 115, 1 5%, 97%, 98%, 99% or more identical).

[0069] In yet other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP049-hum01, BAP049-hum02, BAP049-hum03, B AP049-hum04, BAP049-hum05, BAP049-hum06, BA P049-hum07, BAP049-hum08, BAP049-hum09, BAP 049-hum10, BAP049-hum11, BAP049-hum12, BAP0 49-hum13, BAP049-hum14, BAP049-hum15, BAP04 9-hum16, BAP049-Clone-A, BAP049-Clone-B, BA P049-Clone-C, BAP049-Clone-D or BAP049-Clo at least one or two heavy chain variable regions from an antibody selected from any of ne-E; or or encoded by the nucleotide sequence in Table 1; or Substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95% , 97%, 98%, 99% or more identical).

[0070] In yet other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP049-hum01, BAP049-hum02, BAP049-hum03, B AP049-hum04, BAP049-hum05, BAP049-hum06, BA P049-hum07, BAP049-hum08, BAP049-hum09, BAP 049-hum10, BAP049-hum11, BAP049-hum12, BAP0 49-hum13, BAP049-hum14, BAP049-hum15, BAP04 9-hum16, BAP049-Clone-A, BAP049-Clone-B, BA P049-Clone-C, BAP049-Clone-D or BAP049-Clo at least one or two light chain variable regions from an antibody chosen from any of ne-E; or or encoded by the nucleotide sequence in Table 1; or Substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95% , 97%, 98%, 99% or more identical).

[0071] In yet other embodiments, the anti-PD-1 antibody molecule is an IgG4, e.g., human IgG In one embodiment, the human IgG4 comprises a heavy chain constant region of In yet another embodiment, the amino acid sequence includes a substitution at position 228 (e.g., a Ser to Pro substitution) by Thus, the anti-PD-1 antibody molecule comprises the heavy chain constant region of IgG1, e.g., human IgG1. In some embodiments, the human IgG1 has a substitution at position 297 according to EU numbering (e.g., In one embodiment, the human IgG1 comprises the EU numbering Replaced by position 265 in the EU numbering system, replaced by position 329 in the EU numbering system, or both. (e.g., Asp to Ala substitution at position 265 and / or Pro to Ala at position 329) In one embodiment, human IgG1 has a substitution at position 234 according to EU numbering. substitution at position 235 according to EU numbering, or both (e.g., Le at position 234 In one embodiment, a Leu to Ala substitution at position 235 and / or a Leu to Ala substitution at position 236. In this case, the heavy chain constant region has an amino acid sequence set forth in Table 3 or substantially identical thereto (e.g., at least At least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more This includes sequences that are identical to or greater than 1.

[0072] In yet other embodiments, the anti-PD-1 antibody molecule comprises a kappa light chain constant region, e.g., In one embodiment, the light chain constant region comprises a human kappa light chain constant region. amino acid sequence or substantially identical thereto (e.g., at least 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 2%, 95%, 97%, 98%, 99% or more identical).

[0073] In other embodiments, the anti-PD-1 antibody molecule is an IgG4, e.g., human IgG4, heavy chain. and kappa light chain constant regions, e.g., human kappa light chain constant regions, e.g., those listed in Table 3 or substantially identical thereto (e.g., at least 80%, 85%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 3 92%, 95%, 97%, 98%, 99% or more identical In one embodiment, human IgG4 comprises heavy and light chain constant regions. A substitution at position 228 (e.g., a Ser to Pro substitution) by amino acid substitution. In the present invention, the anti-PD-1 antibody molecule comprises a heavy chain constant region of IgG1, e.g., human IgG1, and and a kappa light chain constant region, e.g., a human kappa light chain constant region, e.g., the amino acid sequence shown in Table 3. sequence or substantially identical thereto (e.g., at least 80%, 85%, 90%, 92%, heavy and light chains containing sequences that are 95%, 97%, 98%, 99% or more identical In one embodiment, human IgG1 comprises a 29 constant region according to EU numbering. In one embodiment, the human IgG 1 is replaced by 265th in the EU numbering system, and 329th in the EU numbering system or both (e.g., an Asp to Ala substitution at position 265 and / or an Asp to Ala substitution at position 329) In one embodiment, the human IgG1 has a Pro to Ala substitution according to EU numbering. substitution at position 234 according to the EU numbering system, substitution at position 235 according to the EU numbering system, or both (e.g. , a Leu to Ala substitution at position 234 and / or a Leu to Ala substitution at position 235).

[0074] In other embodiments, the anti-PD-1 antibody molecule is BAP049-Clone-A, BA P049-Clone-B, BAP049-Clone-C, BAP049-Clone the amino acid sequence of BAP049-Clone-D or BAP049-Clone-E; or encoded by the nucleotide sequence in (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%) heavy chain variable domain and constant region, light chain variable domain and constant region, containing sequences that are identical (9% or more) The anti-PD-1 antibody molecule, optionally, comprises a variable domain and a constant region, or both. 4 or a sequence substantially identical thereto; Contains columns.

[0075] In yet other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP049-hum01, BAP049-hum02, BAP049-hum03, B AP049-hum04, BAP049-hum05, BAP049-hum06, BA P049-hum07, BAP049-hum08, BAP049-hum09, BAP 049-hum10, BAP049-hum11, BAP049-hum12, BAP0 49-hum13, BAP049-hum14, BAP049-hum15, BAP04 9-hum16, BAP049-Clone-A, BAP049-Clone-B, BA P049-Clone-C, BAP049-Clone-D or BAP049-Clo ne-E; or an antibody selected from any of the nucleoside analogs of Table 1 or or substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher and at least one, two, or three complementarity determining regions (CDs) from the heavy chain variable region of the sequence (which is identical to the sequence of the heavy chain variable region of the sequence). R).

[0076] In yet other embodiments, the anti-PD-1 antibody molecule is a nucleotide sequence shown in Table 1 or a nucleotide sequence shown in Table 1. At least one amino acid sequence from a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence In some embodiments, the CDRs include 1, 2, or 3 CDRs (or collectively all of the CDRs). (or collectively all of the CDRs) are selected from the group consisting of the nucleotide sequences shown in Table 1 or the nucleotide sequences shown in Table 1 1, 2, 3, 4, 5, 6 or more amino acids compared to the amino acid sequence encoded by It has alterations, such as amino acid substitutions or deletions.

[0077] In yet other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP049-hum01, BAP049-hum02, BAP049-hum03, B AP049-hum04, BAP049-hum05, BAP049-hum06, BA P049-hum07, BAP049-hum08, BAP049-hum09, BAP 049-hum10, BAP049-hum11, BAP049-hum12, BAP0 49-hum13, BAP049-hum14, BAP049-hum15, BAP04 9-hum16, BAP049-Clone-A, BAP049-Clone-B, BA P049-Clone-C, BAP049-Clone-D or BAP049-Clo ne-E; or an antibody selected from any of the nucleoside analogs of Table 1 or or substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher The CDRs comprise at least one, two, or three CDRs from the light chain variable region of a sequence that is identical to the sequence of the light chain variable region of the target gene.

[0078] In yet other embodiments, the anti-PD-1 antibody molecule is a nucleotide sequence shown in Table 1 or a nucleotide sequence shown in Table 1. At least one amino acid sequence from a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence In some embodiments, the CDRs include 1, 2, or 3 CDRs (or collectively all of the CDRs). (or collectively all of the CDRs) are selected from the group consisting of the nucleotide sequences shown in Table 1 or the nucleotide sequences shown in Table 1 1, 2, 3, 4, 5, 6 or more amino acids compared to the amino acid sequence encoded by In one embodiment, the anti-PD-1 antibody has an alteration, e.g., an amino acid substitution or deletion. The antibody molecule may be substituted into the light chain CDRs, e.g., CDR1, CDR2 and / or CDR3 in the light chain. In one embodiment, the anti-PD-1 antibody molecule comprises one or more substitutions in the light chain CDR3. a substitution in the light chain CDR3 at position 102 of the variable region, e.g., a substitution in the light chain CDR3 at position 103 of the light chain variable region according to Table 1 Substitution of a cysteine ​​residue at position 2 with a tyrosine residue or a serine residue (e.g., SEQ ID NO: 16 or 24 for murine or chimeric, unmodified; or For modified sequences, see SEQ ID NOs: 34, 42, 46, 54, 58, 62, 66, 70, 74 or is one of 78).

[0079] In other embodiments, the anti-PD-1 antibody molecule is a nucleotide sequence shown in Table 1 or a nucleotide sequence shown in Table 1. At least one amino acid sequence from the heavy and light chain variable regions containing the amino acid sequence encoded by the peptide sequence Also contains 1, 2, 3, 4, 5, or 6 CDRs (or collectively all of the CDRs). wherein one or more of the CDRs (or collectively all of the CDRs) are as set forth in Table 1 or as set forth in Table 1 1, 2, 3, 4, 5, 6 compared to the amino acid sequence encoded by the nucleotide sequence or more alterations, such as amino acid substitutions or deletions.

[0080] In one embodiment, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP 049-hum01, BAP049-hum02, BAP049-hum03, BAP0 49-hum04, BAP049-hum05, BAP049-hum06, BAP04 9-hum07, BAP049-hum08, BAP049-hum09, BAP049 -hum10, BAP049-hum11, BAP049-hum12, BAP049- hum13, BAP049-hum14, BAP049-hum15, BAP049-h um16, BAP049-Clone-A, BAP049-Clone-B, BAP04 9-Clone-C, BAP049-Clone-D or BAP049-Clone- all six CDRs from an antibody selected from any of Table 1 or Table 1B; CDRs encoded by the same or closely related nucleotide sequences, e.g., identical or at least one amino acid modification, but the modification (e.g., substitution, deletion or In some embodiments, the CDRs contain no more than two, three, or four insertions (e.g., conservative substitutions). In some embodiments, the anti-PD-1 antibody molecule can comprise any of the CDRs described herein. In the anti-PD-1 antibody molecule, the light chain CDRs are substituted, e.g., CDR1 in the light chain, In one embodiment, the anti-PD-L1 antibody comprises one or more substitutions in CDR2 and / or CDR3. The -1 antibody molecule has a substitution in the light chain CDR3 at position 102 of the light chain variable region, e.g., as shown in Table 1 A cysteine ​​residue at position 102 of the light chain variable region is replaced by a tyrosine residue or a cysteine ​​residue. to serine residue (e.g., murine or chimeric, unmodified SEQ ID NO: 16 or 24; or SEQ ID NOs: 34, 42, 46, 54, 58, 62 for modified sequences , 66, 70, 74 or 78).

[0081] In other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP 049-hum01, BAP049-hum02, BAP049-hum03, BAP0 49-hum04, BAP049-hum05, BAP049-hum06, BAP04 9-hum07, BAP049-hum08, BAP049-hum09, BAP049 -hum10, BAP049-hum11, BAP049-hum12, BAP049- hum13, BAP049-hum14, BAP049-hum15, BAP049-h um16, BAP049-Clone-A, BAP049-Clone-B, BAP04 9-Clone-C, BAP049-Clone-D or BAP049-Clone- E. at least one of the heavy chain variable regions of an antibody according to Kabat et al. Two or three CDRs (e.g., at least one, two, or three CDRs according to the Kabat definition shown in Table 1) or as set forth in or encoded by the nucleotide sequence in Table 1; and is substantially identical (e.g., at least 80%, 85%, 90%, 92%) to any of the above sequences. 95%, 97%, 98%, 99% or more identical); or a sequence shown in Table 1 At least one amino acid alteration compared to one, two or three CDRs according to Kabat et al. but with 2, 3, or 4 alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). Including those not exceeding

[0082] In other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP 049-hum01, BAP049-hum02, BAP049-hum03, BAP0 49-hum04, BAP049-hum05, BAP049-hum06, BAP04 9-hum07, BAP049-hum08, BAP049-hum09, BAP049 -hum10, BAP049-hum11, BAP049-hum12, BAP049- hum13, BAP049-hum14, BAP049-hum15, BAP049-h um16, BAP049-Clone-A, BAP049-Clone-B, BAP04 9-Clone-C, BAP049-Clone-D or BAP049-Clone- E. At least one or two of the antibody light chain variable regions according to Kabat et al. or 3 CDRs (e.g., at least 1, 2, or 3 CDRs according to the Kabat definition shown in Table 1) or as set forth in or encoded by the nucleotide sequence in Table 1; or Substantially identical (e.g., at least 80%, 85%, 90%, 92% , 95%, 97%, 98%, 99% or more identical); or a sequence shown in Table 1 having at least one amino acid alteration compared to one, two or three CDRs according to abat et al. but alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) may be present in 2, 3, or 4 Including those not exceeding.

[0083] In yet other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP049-hum01, BAP049-hum02, BAP049-hum03, B AP049-hum04, BAP049-hum05, BAP049-hum06, BA P049-hum07, BAP049-hum08, BAP049-hum09, BAP 049-hum10, BAP049-hum11, BAP049-hum12, BAP0 49-hum13, BAP049-hum14, BAP049-hum15, BAP04 9-hum16, BAP049-Clone-A, BAP049-Clone-B, BA P049-Clone-C, BAP049-Clone-D or BAP049-Clo The heavy and light chain variable regions of an antibody selected from either ne-E are prepared by the method of Kabat et al. at least 1, 2, 3, 4, 5, or 6 CDRs (e.g., at least one CDR according to the Kabat definition shown in Table 1) at least 1, 2, 3, 4, 5, or 6 CDRs); or encoded by a nucleotide sequence; or substantially identical to any of the foregoing sequences (e.g. , at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or or sequences that are 1, 2, 3, 4, 5, or more identical according to Kabat et al. as shown in Table 1; or 6 CDRs, but have at least one amino acid modification (e.g., substitution , deletions or insertions (e.g., conservative substitutions) not exceeding two, three or four.

[0084] In yet other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP049-hum01, BAP049-hum02, BAP049-hum03, B AP049-hum04, BAP049-hum05, BAP049-hum06, BA P049-hum07, BAP049-hum08, BAP049-hum09, BAP 049-hum10, BAP049-hum11, BAP049-hum12, BAP0 49-hum13, BAP049-hum14, BAP049-hum15, BAP04 9-hum16, BAP049-Clone-A, BAP049-Clone-B, BA P049-Clone-C, BAP049-Clone-D or BAP049-Clo The heavy and light chain variable regions of an antibody selected from either ne-E are prepared by the method of Kabat et al. all 6 CDRs (e.g., all 6 CDRs according to the Kabat definition as set forth in Table 1); or or encoded by the nucleotide sequence in Table 1; or substantially identical to any of the foregoing sequences. substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%) %, 99% or more identical); or all six sequences by Kabat et al. shown in Table 1 At least one amino acid alteration compared to the CDRs, but no alteration (e.g., substitution, deletion) or containing no more than 2, 3, or 4 insertions (e.g., conservative substitutions). In such a manner, the anti-PD-1 antibody molecule can comprise any of the CDRs described herein.

[0085] In other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP 049-hum01, BAP049-hum02, BAP049-hum03, BAP0 49-hum04, BAP049-hum05, BAP049-hum06, BAP04 9-hum07, BAP049-hum08, BAP049-hum09, BAP049 -hum10, BAP049-hum11, BAP049-hum12, BAP049- hum13, BAP049-hum14, BAP049-hum15, BAP049-h um16, BAP049-Clone-A, BAP049-Clone-B, BAP04 9-Clone-C, BAP049-Clone-D or BAP049-Clone- at least one, two, or three Chothia sequences from the heavy chain variable region of an antibody selected from any of Hypervariable loops (e.g., at least 1, 2, or 3 hypervariable loops according to the Chothia definition shown in Table 1) or as set forth in or encoded by the nucleotide sequence in Table 1; or at least the amino acids from the hypervariable loops that contact PD-1; or Ch as shown in Table 1 At least one amino acid modification compared to one, two, or three hypervariable loops according to Othia et al. mutations, but with two, three or more alterations (e.g., substitutions, deletions or insertions, e.g., conservative substitutions). includes not more than 4.

[0086] In other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP 049-hum01, BAP049-hum02, BAP049-hum03, BAP0 49-hum04, BAP049-hum05, BAP049-hum06, BAP04 9-hum07, BAP049-hum08, BAP049-hum09, BAP049 -hum10, BAP049-hum11, BAP049-hum12, BAP049- hum13, BAP049-hum14, BAP049-hum15, BAP049-h um16, BAP049-Clone-A, BAP049-Clone-B, BAP04 9-Clone-C, BAP049-Clone-D or BAP049-Clone- E. A method for the preparation of a light chain variable region of an antibody comprising: Hypervariable loops (e.g., at least 1, 2, or 3 hypervariable loops according to the Chothia definition shown in Table 1) or as set forth in or encoded by the nucleotide sequence in Table 1; and indicates at least the amino acids from the hypervariable loop that contacts PD-1; or the Chothi At least one amino acid alteration compared to one, two, or three hypervariable loops according to a et al. but with 2, 3, or 4 alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). Including those not exceeding

[0087] In yet other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP049-hum01, BAP049-hum02, BAP049-hum03, B AP049-hum04, BAP049-hum05, BAP049-hum06, BA P049-hum07, BAP049-hum08, BAP049-hum09, BAP 049-hum10, BAP049-hum11, BAP049-hum12, BAP0 49-hum13, BAP049-hum14, BAP049-hum15, BAP04 9-hum16, BAP049-Clone-A, BAP049-Clone-B, BA P049-Clone-C, BAP049-Clone-D or BAP049-Clo At least one or two heavy and light chain variable regions of an antibody selected from either ne-E , 3, 4, 5, or 6 hypervariable loops (e.g., at least 1 according to the Chothia definition shown in Table 1) 1, 2, 3, 4, 5 or 6 hypervariable loops); or a nucleic acid sequence as described in Table 1 or a nucleic acid sequence as described in Table 1 or at least the hypervariable loop that contacts PD-1. or 1, 2, 3, 4, 5 or more amino acids according to Chothia et al. as shown in Table 1 at least one amino acid modification compared to the mutant loop, but the modification (e.g., substitution, deletion) It includes no more than two, three, or four deletions or insertions (e.g., conservative substitutions).

[0088] In one embodiment, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP 049-hum01, BAP049-hum02, BAP049-hum03, BAP0 49-hum04, BAP049-hum05, BAP049-hum06, BAP04 9-hum07, BAP049-hum08, BAP049-hum09, BAP049 -hum10, BAP049-hum11, BAP049-hum12, BAP049- hum13, BAP049-hum14, BAP049-hum15, BAP049-h um16, BAP049-Clone-A, BAP049-Clone-B, BAP04 9-Clone-C, BAP049-Clone-D or BAP049-Clone- All six hypervariable loops of an antibody selected from any of the following (e.g., according to the Chothia definition shown in Table 1): all six hypervariable loops) or closely related hypervariable loops, e.g., identical or At least one amino acid alteration, but no alteration (e.g., substitution, deletion, or insertion, e.g., hypervariable loops with no more than two, three, or four conservative substitutions; or at least one amino acid alteration compared to all six hypervariable loops by No more than two, three, or four mutations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) In some embodiments, the anti-PD-1 antibody molecule comprises any of the hypervariable groups described herein. It may also include a loop.

[0089] In yet other embodiments, the anti-PD-1 antibody molecule is an antibody described herein, e.g., BAP049-hum01, BAP049-hum02, BAP049-hum03, B AP049-hum04, BAP049-hum05, BAP049-hum06, BA P049-hum07, BAP049-hum08, BAP049-hum09, BAP 049-hum10, BAP049-hum11, BAP049-hum12, BAP0 49-hum13, BAP049-hum14, BAP049-hum15, BAP04 9-hum16, BAP049-Clone-A, BAP049-Clone-B, BA P049-Clone-C, BAP049-Clone-D or BAP049-Clo ne-E, the same canonical structure as the corresponding hypervariable loop of an antibody selected from having the same canonical structure as at least loop 1 and / or loop 2 of the antibodies described herein. The canonical structure of the hypervariable loops is described in detail below. , for example, Chothia et al., (1992) J. Mol. Biol. 227:799-817; Tomlinson et al., (1 992) J. Mol. Biol. 227:776-798. These structures are based on the This can be determined by inspection of the table.

[0090] In certain embodiments, the anti-PD-1 antibody molecule is selected from the group consisting of those described in Kabat et al. and Chothia et al. It includes a combination of more defined CDRs or hypervariable loops.

[0091] In certain embodiments, the anti-PD-1 antibody molecule is defined as defined herein by the Kabat and Chothia definition. The antibodies described herein, e.g., BAP049-hum01, BAP049-hum02, BAP 049-hum03, BAP049-hum04, BAP049-hum05, BAP0 49-hum06, BAP049-hum07, BAP049-hum08, BAP04 9-hum09, BAP049-hum10, BAP049-hum11, BAP049 -hum12, BAP049-hum13, BAP049-hum14, BAP049- hum15, BAP049-hum16, BAP049-Clone-A, BAP049 -Clone-B, BAP049-Clone-C, BAP049-Clone-D or or BAP049-Clone-E. At least one, two, or three CDRs or hypervariable loops (e.g., Kabat and Chothi sequences shown in Table 1) a at least 1, 2, or 3 CDRs or hypervariable loops as defined); or in Table 1 encoded by a nucleotide sequence; or substantially identical to any of the foregoing sequences (e.g. , at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or or sequences according to Kabat and / or Chothia as shown in Table 1; or has at least one amino acid modification compared to the three CDRs or hypervariable loops , no more than two, three, or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) This includes:

[0092] For example, the anti-PD-1 antibody molecule may be, for example, a VH CD3 sequence according to Kabat et al., as shown in Table 1. R1 or VH hypervariable loop 1 according to Chothia et al., or a combination thereof. In one embodiment, a combination of Kabat and Chothia CDRs in VH CDR1 is the amino acid sequence GYTFTTYWMH (SEQ ID NO: 224) or an amino acid sequence substantially identical thereto A sequence (e.g., a sequence having at least one amino acid alteration, but not including alterations (e.g., substitutions, deletions, or contains no more than 2, 3, or 4 insertions, e.g., conservative substitutions). Further, for example, VH CDR2-3 and VH CDR3 of Kabat et al., as shown in Table 1, and VL CDRs 1-3 according to Kabat et al. Thus, in one embodiment, The framework regions are the CDRs defined by Kabat et al. and the CDRs defined by Chothia et al. The antibody is defined based on the combination of hypervariable loops defined by the The molecules may be based on VH hypervariable loop 1 according to Chothia et al., e.g., as shown in Table 1. VH FR1 defined by Kabat et al. and VH CDR1-2 defined by Kabat et al. The anti-PD-1 antibody molecule may further comprise a VH FR2 comprising the VH FR2 sequence described in, for example, Kabat et al. VH FR3-4 defined based on VH CDR2-3 and VH FR4 defined by Kabat et al. It may comprise VL FR1 to FR4 defined based on L CDR1 to 3.

[0093] Anti-PD-1 antibody molecules consist of CDRs or hypervariable loops according to the Kabat and Chothia definition. In certain embodiments, the anti-PD-1 antibody molecule comprises a Kabat antibody or a combination thereof. and antibodies described herein, e.g., BAP049-hum01, B AP049-hum02, BAP049-hum03, BAP049-hum04, BA P049-hum05, BAP049-hum06, BAP049-hum07, BAP 049-hum08, BAP049-hum09, BAP049-hum10, BAP0 49-hum11, BAP049-hum12, BAP049-hum13, BAP04 9-hum14, BAP049-hum15, BAP049-hum16, BAP049 -Clone-A, BAP049-Clone-B, BAP049-Clone-C, B Select from either AP049-Clone-D or BAP049-Clone-E At least one, two, or three CDRs from the light chain variable region of an antibody (e.g., the Kabat and at least 1, 2, or 3 CDRs according to the Chothia definition).

[0094] In one embodiment, the anti-PD-1 antibody molecule comprises: (a) the VHCDR1 amino acid sequence of SEQ ID NO: 4, the VHCDR2 amino acid sequence of SEQ ID NO: 5, and and a heavy chain variable region (VH) comprising the VHCDR3 amino acid sequence of SEQ ID NO: 3; and SEQ ID NO: The VLCDR1 amino acid sequence of SEQ ID NO: 13, the VLCDR2 amino acid sequence of SEQ ID NO: 14 and the sequence a light chain variable region (VL) comprising the VLCDR3 amino acid sequence of number 33; (b) a VHCDR1 amino acid sequence selected from SEQ ID NO: 1; a VHCDR2 amino acid sequence selected from SEQ ID NO: 2 VH comprising the amino acid sequence of SEQ ID NO: 3 and the VHCDR3 amino acid sequence of SEQ ID NO: 1; The VLCDR1 amino acid sequence of SEQ ID NO: 0, the VLCDR2 amino acid sequence of SEQ ID NO: 11, and VL containing the VLCDR3 amino acid sequence of No. 32; (c) the VHCDR1 amino acid sequence of SEQ ID NO: 224 and the VHCDR2 amino acid sequence of SEQ ID NO: 5 VH comprising the VHCDR3 amino acid sequence of SEQ ID NO: 3; and VL comprising the VHCDR3 amino acid sequence of SEQ ID NO: 13 CDR1 amino acid sequence of SEQ ID NO: 14, VLCDR2 amino acid sequence of SEQ ID NO: 33 a VL comprising a VLCDR3 amino acid sequence; or (d) the VHCDR1 amino acid sequence of SEQ ID NO: 224; the VHCDR2 amino acid sequence of SEQ ID NO: 2 VH comprising the VHCDR3 amino acid sequence of SEQ ID NO: 3; and VL comprising the VHCDR3 amino acid sequence of SEQ ID NO: 10. CDR1 amino acid sequence of SEQ ID NO: 11, VLCDR2 amino acid sequence of SEQ ID NO: 32 VL containing the VLCDR3 amino acid sequence Includes:

[0095] In other embodiments of the combinations herein, the anti-PD-1 antibody molecule comprises: (i) a sequence a VHCDR1 amino acid sequence selected from sequence number 1, SEQ ID NO: 4, or SEQ ID NO: 224; VHCDR2 amino acid sequence of SEQ ID NO:2 or SEQ ID NO:5; and VHCD of SEQ ID NO:3 a heavy chain variable region (VH) comprising the R3 amino acid sequence; and (ii) SEQ ID NO: 10 or SEQ ID NO: 1 VLCDR1 amino acid sequence of SEQ ID NO:3, VLCDR2 amino acid sequence of SEQ ID NO:11 or SEQ ID NO:14 and a light chain variant comprising the VLCDR3 amino acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33. Contains variable region (VL).

[0096] In some embodiments, e.g., variable regions, CDRs (e.g., Chothia CDRs or Kabat CDRs) DR) or other sequences described herein, e.g., in Table 1. The antibody may be a monospecific antibody molecule, a bispecific antibody molecule, or an antigen-binding fragment of an antibody, e.g., An antibody molecule comprising a half antibody or an antigen-binding fragment of a half antibody. The antibody molecule has a first binding specificity for PD-1 and a second binding specificity for TIM-3, LAG-3, and CE ACAMs (e.g., CEACAM-1, CEACAM-3 and / or CEACAM- 5) A bispecific antibody molecule with a second binding specificity for PD-L1 or PD-L2. In one embodiment, the bispecific antibody molecule binds to PD-1 and TIM-3. In other embodiments, the bispecific antibody molecule binds to PD-1 and LAG-3. In other embodiments, the bispecific antibody molecule binds PD-1 and CEACAM (e.g., Binds to CEACAM-1, CEACAM-3 and / or CEACAM-5) and others In one embodiment, the bispecific antibody molecule binds to PD-1 and CEACAM-1. In yet another embodiment, the bispecific antibody molecule binds PD-1 and CEACAM-5 In another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L1. In yet another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L. Any combination of the above molecules may be used to form a multispecific antibody molecule, e.g., a PD-1 specific antibody molecule. and primary binding specificity for TIM-3, LAG-3, CEACAM (e.g., CEAC AM-1, CEACAM-3 or CEACAM-5), PD-L1 or PD-L2 Trispecific antibodies can be made which contain a second and a third binding specificity for one or more of the antibodies.

[0097] In other embodiments, the anti-PD-1 antibody molecule is selected from the group consisting of TIM-3, LAG-3, CEACA M (e.g., CEACAM-1, CEACAM-3, or CEACAM-5), PD-L1 or PD-L2. In the present invention, the bispecific antibody molecule used in the combination is CEACAM (e.g., CE ACAM-1, CEACAM-3 and / or CEACAM-5) and LAG-3 In other embodiments, the bispecific antibody molecules used in combination bind to EACAMs (e.g., CEACAM-1, CEACAM-3 and / or CEACAM In other embodiments, the compounds used in combination bind to TIM-3. The bispecific antibody molecule binds to LAG-3 and TIM-3.

[0098] Use of combination therapy The combinations disclosed herein may be used to enhance antigen presentation, effector cell function (e.g., T cell proliferation), and / or proliferation. Increased cell proliferation, IFN-γ secretion, or cytolytic function; inhibition of regulatory T cell function against the activity of multiple cell types, including regulatory T cells, effector T cells, and NK cells Increased tumor-infiltrating lymphocytes, increased T cell receptor-mediated proliferation, and increased immune response by cancer cells In one embodiment, the PD-1 The use of inhibitors blocks, reduces, or neutralizes one or more of the activities of PD-1, resulting in immune checkpoint Such a combination can therefore be used to block or reduce the immune response in a subject. They can be used to treat or prevent disorders in which an enhanced response is desired.

[0099] Thus, in another aspect, a method of modulating an immune response in a subject is provided. The method comprises administering to a subject a combination (e.g., a combination of 1-hydroxytryptamine, 2-hydroxybenzoates ... For example, a therapeutically effective amount of an anti-PD-1 antibody molecule (e.g., a combination containing an anti-PD-1 antibody molecule) may be administered alone or in combination with one or more other drugs. In some embodiments, the antibody molecule is administered in combination with a therapeutic agent or procedure. The subject may be a mammal, e.g., a spirit animal, or a mammalian animal. a mammal, preferably a higher primate, e.g., a human (e.g., a mammal having a disorder described herein or In one embodiment, the subject is a patient who has been diagnosed with a rhesus macular degeneration (e.g., a patient at risk of having a rhesus macular degeneration). In one embodiment, the subject has a disorder described herein, e.g., In one embodiment, the subject has or is at risk of having a cancer or infectious disorder described in For example, the subject may be immunocompromised or at risk of being immunocompromised. For example, the subject may be undergoing chemotherapy treatment and are undergoing or have undergone radiation and / or radiotherapy treatment, either separately or in combination with In addition, the subject is or is at risk of being immunocompromised as a result of infection.

[0100] In some embodiments, a method for treating (e.g., reducing, preventing, or preventing progression of) a cancer or tumor in a subject is provided. The method provides a method for administering to a subject a combination (e.g., one or more of the combinations disclosed herein) of the present invention. For example, a combination comprising a therapeutically effective amount of an anti-PD-1 antibody molecule.

[0101] In certain embodiments, the cancer treated with the combination is a solid tumor, a hematological cancer (e.g., leukemia, lymphoma, myeloma (e.g., multiple myeloma) and metastatic lesions, but In one embodiment, the cancer is a solid tumor. Examples of solid tumors include malignant tumors. , e.g., sarcomas and carcinomas, e.g., lung, breast, ovarian, lymphatic system, gastrointestinal (e.g., colon), Anus, genital and urogenital tract (e.g., kidney, urothelium, bladder cells, prostate), pharynx, C NS (e.g., brain, neural or glial cells), head and neck, skin (e.g., melanoma), and pancreas Adenocarcinomas of various organs, such as those affecting colon, rectum, kidney (e.g., Renal cell carcinoma (clear cell or non-clear cell renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer (squamous cell carcinoma) adenocarcinoma, including malignant tumors such as epithelial or non-squamous non-small cell lung cancer, small intestinal cancer, and esophageal cancer. The cancer may be early stage, intermediate stage, late stage, or metastatic cancer.

[0102] In certain embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma) NSCLC or NSCLC adenocarcinoma with epithelial and / or non-squamous histology), skin cancer ( For example, Merkel cell carcinoma or melanoma (e.g., advanced melanoma), kidney cancer (e.g., kidney cancer (e.g., renal cell carcinoma), liver cancer, myeloma (e.g., multiple myeloma), prostate cancer, breast cancer (e.g., , estrogen receptor, progesterone receptor, or Her2 / neu 1, 2, or all breast cancer (e.g., triple-negative breast cancer), colorectal cancer, pancreatic cancer, head and neck cancer Cancer (e.g., head and neck squamous cell carcinoma (HNSCC), anal cancer, gastroesophageal cancer, thyroid cancer (e.g., anaplastic thyroid carcinoma), cervical cancer, neuroendocrine tumors (NETs) (e.g., atypical pulmonary carcinoid tumors) lymphoproliferative disorders (e.g., post-transplant lymphoproliferative disorders) or hematologic cancers, T-cell lymphomas lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, or leukemia (e.g., myeloid leukemia or lymphoma) leukemia).

[0103] In other embodiments, the cancer is cancer (e.g., advanced or metastatic cancer), melanoma, or lung cancer, For example, it is selected from non-small cell lung cancer.

[0104] In some embodiments, the cancer is lung cancer, e.g., non-small cell lung cancer or small cell lung cancer. In some embodiments, the non-small cell lung cancer is stage I (e.g., stage Ia or Ib). , stage II (e.g., stage IIa or IIb), stage III (e.g., stage IIIa or IIIb) or stage IV, non-small cell lung cancer.

[0105] In some embodiments, the cancer is melanoma, e.g., advanced melanoma. In another embodiment, the cancer is advanced or unresectable melanoma that has not responded to other treatments. In the present invention, the cancer is a melanoma with a BRAF mutation (e.g., a BRAF V600 mutation). In yet other embodiments, the combinations disclosed herein (e.g., anti-PD-1 antibody molecules) combinations containing BRAF inhibitors (e.g., vemurafenib or dabrafenib) Administered after treatment with an anti-CTLA-4 antibody (e.g., ipilimumab) with or without do.

[0106] In other embodiments, the cancer is associated with a viral infection, e.g., chronic viral hepatitis, or Hepatocellular carcinoma not associated with glaucoma, for example, advanced hepatocellular carcinoma.

[0107] In other embodiments, the cancer is prostate cancer, eg, advanced prostate cancer. In yet other embodiments, the cancer is a myeloma, for example, multiple myeloma.

[0108] In yet other embodiments, the cancer is a kidney cancer, e.g., a renal cell carcinoma (RCC) (e.g., a metastatic metastatic RCC, non-clear cell renal cell carcinoma (nccRCC) or clear cell renal cell carcinoma (CCRCC)) .

[0109] In one embodiment, the level of PD-L1 expression in the tumor microenvironment is increased. Alternatively or in combination, IFN-γ and / or CD8 expression in the tumor microenvironment It may increase.

[0110] In one embodiment, the subject has a high PD-L1 level or expression or a tumor-infiltrating lymphocyte. one or more of the following: lymphocyte (TIL)-positive (e.g., increased number of TILs) or both In one embodiment, the subject has or is identified as having a tumor having: Patients with or suspected to have tumors that are high in PD-L1 levels or expression and TIL+ In one embodiment, the methods described herein involve measuring PD-L1 levels or Patients with tumors with high expression or tumor-infiltrating lymphocyte (TIL)+ or both In some embodiments, the method further comprises identifying the subject based on the results of the analysis. The method described herein involves determining whether the tumor has high PD-L1 levels or expression and is TIL+. In one embodiment, the subject is identified as a TIL+ subject based on the results of the analysis. The tumor is positive for CD8 and IFN-γ. High levels of cells positive for one, two or more of L1, CD8 and / or IFN-γ In one embodiment, the subject is identified as being or has been identified as being a percentage of the total subjects. showed a high percentage of cells positive for PD-L1, CD8, and IFN-γ. Identified as being or being.

[0111] In one embodiment, the methods described herein involve targeting PD-L1, CD8, and / or I Based on the high percentage of cells positive for one, two or more FN-γ In some embodiments, the methods described herein further comprise identifying the subject based on the results of the analysis. , a high percentage of cells were positive for PD-L1, CD8, and IFN-γ. In some embodiments, the subject further comprises identifying the subject based on the presence of the antibody. Elephants were associated with one, two or more of PD-L1, CD8 and / or IFN-γ and lung cancer , e.g., squamous cell lung cancer or lung adenocarcinoma (e.g., NSCLC), head and neck cancer, squamous cell Cervical cancer, gastric cancer, esophageal cancer, thyroid cancer (e.g., anaplastic thyroid cancer), skin cancer (e.g., Merck cell carcinoma or melanoma), breast cancer (e.g., NTBC) and / or nasopharyngeal carcinoma (NPC) In some embodiments, the compounds described herein are identified as having or having one or more of the following: The method may involve the detection of one, two or more of PD-L1, CD8 and / or IFN-γ and and lung cancer, e.g., squamous cell lung cancer or lung adenocarcinoma (e.g., NSCLC), head and neck cancer, squamous Epithelial cell cervical cancer, stomach cancer, thyroid cancer (e.g., anaplastic thyroid cancer), skin cancer (e.g., Merkel cell carcinoma) cell carcinoma or melanoma), neuroendocrine tumors, breast cancer (e.g., NTBC) and / or nasopharyngeal The method further includes identifying the subject based on having one or more of the cancers.

[0112] The methods and compositions disclosed herein are useful for treating metastatic lesions associated with said cancers. .

[0113] In a further aspect, the present invention provides a method for administering to a subject a combination as described herein, e.g., a therapeutic administering to a subject a combination comprising an effective amount of an anti-PD-1 antibody molecule described herein. In one embodiment, the infectious disease is a hepatitis C virus. The disease is selected from inflammation (e.g., hepatitis C infection) or sepsis.

[0114] Still further, the present invention provides a method for administering to a subject an antibody to enhance an immune response to an antigen in the subject. (i) the antigen and (ii) a combination described herein, e.g., a therapeutically effective amount of a combination described herein administering a combination comprising an anti-PD-1 antibody molecule that is directed against the antigen in the subject. The present invention provides a method for enhancing an immune response to an antigen, such as a tumor antigen, a viral antigen, or a tumor antigen. It may be a bacterial antigen or an antigen from a pathogen.

[0115] The combinations described herein can be administered to a subject systemically (e.g., orally, parenterally, subcutaneously, intravenously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally or by inhalation or intracavitary placement), topically or can be administered by application to mucous membranes such as the nose, throat and bronchi.

[0116] Dosages and treatment regimens for the therapeutic agents disclosed herein can be determined by those skilled in the art. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 1 to 30 mg / kg, for example, about 5 to 25 mg / kg, about 10-20 mg / kg, about 1-5 mg / kg, or about 3 mg / kg by injection (e.g., intradermal) The administration schedule may be, for example, once a week for two weeks, or once a week for three weeks. In one embodiment, the anti-PD-1 antibody molecule is administered at a dose of about Administer at a dose of 10-20 mg / kg every other week.

[0117] In one embodiment, the anti-PD-1 antibody molecule is administered in a dose of about 100 mg to 600 mg, e.g., about 2 00mg to 500mg, for example, about 250mg to 450mg, about 300mg to 400mg, about 250mg ~350mg, about 350mg~450mg or about 100mg, about 200mg, about 300mg or about Administered by injection (e.g., subcutaneous or intravenous) in a dose of 400 mg (e.g., flat dose) The dosing schedule (e.g., a flat dosing schedule) may be, for example, once a week to once every two weeks, three weeks, or In one embodiment, the frequency of administration of the anti-PD-1 antibody is varied up to once every week, four weeks, five weeks, or six weeks. The molecule is administered at a dose of approximately 300 mg to 400 mg once every three weeks or once every four weeks. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 300 mg once every three weeks. In one embodiment, the anti-PD-1 antibody molecule is administered in a dose of about 400 mg every four weeks to In one embodiment, the anti-PD-1 antibody molecule is administered at a dose of about 300 mg every four weeks. In one embodiment, the anti-PD-1 antibody molecule is administered in a dose of about 400 It is administered at doses starting from 1 mg once every 3 weeks.

[0118] In certain embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 5 mg / kg or less, about 4 mg / kg or less, kg or less, about 3 mg / kg or less, about 2 mg / kg or less, about 1 mg / kg or less every other week alone or in combination (e.g., anti-LAG-3 antibody In one embodiment, the anti-PD-1 antibody molecule is administered in combination with 1 to 5 mg of / kg every other week, 1-4 mg / kg every other week, 1-3 mg / kg every other week, or 1-2 mg / kg every other week. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of 1 to 5 mg / kg every other week, 1 to 4 mg / kg every other week, or kg every other week, 1-3 mg / kg every other week, or 1-2 mg / kg every other week, alone or in combination (e.g., in combination with an anti-PD-1 antibody molecule).

[0119] Although the antibody molecules described herein are preferred for use in the methods described herein, other in place of or in combination with the anti-PD-1 antibody molecules of the present invention. It can be used.

[0120] Further combination treatments The methods and combinations described herein may also include or be used in combination with other agents or therapeutic modalities. In some embodiments, the methods described herein can be used in combination with The present invention relates to administering to a subject a combination comprising an anti-PD-1 antibody molecule described herein as a drug or therapeutic procedure. and administering the compound in combination with a technique or modality in an amount effective to treat or prevent the disorder. The anti-PD-1 antibody molecule and the agent or therapeutic procedure or modality are administered simultaneously. The anti-PD-1 antibody molecule and other therapeutic agents, procedures, Alternatively, any combination and sequence of modalities (e.g., as described herein) may be used. The antibody molecules and / or other therapeutic agents, procedures or modalities may be administered during the active or The antibody molecule can be administered during periods of remission or when the disease is less active. It can be administered before, concurrently with the treatment, after treatment or during remission of the disorder.

[0121] In some embodiments, the methods and compositions described herein are administered in combination with other antibody molecules, chemotherapy, or other therapeutic agents. , other anti-cancer therapies (e.g., targeted anti-cancer therapies, gene therapies, viral therapies, RNA therapies, bone bone marrow transplants, nanotherapy or oncolytic agents), cytotoxic agents, immune-based therapies (e.g., cytokines) immunotherapy), surgical procedures (e.g., lumpectomy or mastectomy) ) or a radiological procedure or any combination of the foregoing. The further treatment may be in the form of adjuvant or neoadjuvant treatment. In such cases, the further treatment is an enzyme inhibitor (e.g., a small molecule enzyme inhibitor) or a metastasis inhibitor. Examples of cytotoxic agents that can be administered in combination include microtubule inhibitors, topoisomerase inhibitors, and Anti-inflammatory drugs, antimetabolites, anti-mitotic agents, alkylating agents, anthracyclines, vinca alkylating agents drugs that can interfere with signal transduction pathways; drugs that promote apoptosis; and radiation (e.g., local or total body irradiation (e.g., gamma irradiation)). In other embodiments, the additional treatment is surgery or radiation or a combination thereof. In other embodiments, the additional treatment is an inhibitor of the PI3K / AKT / mTOR pathway, Therapies targeting one or more of an HSP90 inhibitor or a tubulin inhibitor.

[0122] Separately or in combination with the above combinations, the methods and compositions described herein may be used as immunomodulatory agents (e.g., activators or inhibitory molecules of costimulatory molecules, e.g., inhibitors of immune checkpoint molecules), vaccines, e.g., therapeutic cancer vaccines or cells It may include or be used in combination with one or more other forms of immunotherapy.

[0123] Non-limiting examples of the combinations disclosed herein, including combinations that include anti-PD-1 antibody molecules, include: Examples of combinations and uses include the following:

[0124] In some embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, Combinations including co-stimulatory or inhibitory molecules, e.g., co-inhibitory ligands or receptors. The compound may be administered in combination with or containing a modulator of the body.

[0125] In some embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, Combinations including, but not limited to, modulators of costimulatory molecules, e.g., agonists, may also be included. In one embodiment, the agonist of a costimulatory molecule is administered in combination with OX 40, CD2, CD27, CDS, ICAM-1, LFA-1(CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BA FFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD 160, agonists of B7-H3 or CD83 ligands (e.g., agonist antibodies or is selected from an antigen-binding fragment thereof or a soluble fusion thereof.

[0126] In some embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, The combinations include PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, and C EACAMs (e.g., CEACAM-1, CEACAM-3 and / or CEACAM -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or or an inhibitor of an inhibitory (or immune checkpoint) molecule selected from TGF-beta In one embodiment, the inhibitor comprises or is administered in combination with a soluble ligand. gand (e.g., CTLA-4-Ig) or PD-L1, PD-L2, or CTLA-4 For example, the anti-PD-1 antibody molecule can be, for example, an antibody or antibody fragment that binds to , cancer (e.g., melanoma, e.g., metastatic melanoma, lung cancer, e.g., non-small cell lung cancer or prostate and combination with an anti-CTLA-4 antibody, e.g., ipilimumab, for the treatment of cancers selected from the group consisting of: In one embodiment, the anti-PD-1 antibody molecule may be administered in combination with a BRAF inhibitor. Anti-CTLA-4 with or without (e.g., vemurafenib or dabrafenib) Administered after treatment with an antibody (e.g., ipilimumab).

[0127] In other embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, The combination includes or comprises an anti-LAG-3 antibody or antigen-binding fragment thereof. are administered in combination.

[0128] In other embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, The combination includes or comprises an anti-TIM-3 antibody or antigen-binding fragment thereof. are administered in combination.

[0129] In yet other embodiments, the combinations disclosed herein, e.g., anti-PD-1 antibody molecules, The combination comprising the anti-LAG-3 antibody and the anti-TIM-3 antibody (or antigen-binding fragments).

[0130] In other embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, Combinations including CEACAM inhibitors (e.g., CEACAM-1 and / or CEA CAM-5 inhibitors), e.g., including or in combination with anti-CEACAM antibody molecules In other embodiments, the anti-PD-1 antibody molecule is administered in combination with a CEACAM-1 inhibitor, For example, it is administered in combination with an anti-CEACAM-1 antibody molecule. The anti-PD-1 antibody molecule may be a CEACAM-5 inhibitor, e.g., an anti-CEACAM-5 antibody molecule. It is administered in combination with

[0131] The antibody combinations described herein may be used individually, e.g., by combining individual antibodies or their antigen binding They may be administered as fragments or conjugated, for example, as bispecific or trispecific antibody molecules. In one embodiment, an anti-PD-1 antibody molecule and an anti-TIM-3, anti-CEAC AM (e.g., anti-CEACAM-1, CEACAM-3 and / or anti-CEACAM- 5) or a bispecific antibody comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof is administered. In one embodiment, a combination of antibodies described herein is administered to treat cancer, e.g., The present invention is used to treat cancers (eg, solid tumors or hematological tumors) described in

[0132] In other embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, The combination may include or be administered in combination with a cytokine. The antibody may be administered as a fusion molecule to the anti-PD-1 antibody molecule or as a separate composition. In certain embodiments, the anti-PD-1 antibody inhibits one, two, three, or more cytokines. For example, the compounds may be administered in combination as a fusion molecule or as separate compositions. In embodiments, the cytokine is interleukin (IL)-1, IL-2, IL-12, The IL is selected from one, two, three or more of IL-15 or IL-21. In some embodiments, the bispecific antibody molecule has a first binding specificity to a first target (e.g., PD-1). a second binding specificity for a second target (e.g., LAG-3 or TIM-3), by interleukin (e.g., IL-12) domains, e.g., full-length IL-12 or is attached to a portion thereof. In one embodiment, the anti-PD-1 antibody molecule described herein and a cytokine combination for the treatment of cancer, e.g., a cancer described herein (e.g., a solid tumor). Used for placement.

[0133] In some embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, The combination includes antibodies specific to HLA C, e.g., killer cell immunoglobulin-like receptor agonists. containing or in combination with antibodies specific for KIR (also referred to herein as "anti-KIR antibodies"); In one embodiment, a combination of an anti-PD-1 antibody molecule and an anti-KIR antibody is administered. to treat cancer, e.g., a cancer described herein (e.g., a solid tumor, e.g., an advanced solid tumor). Used for.

[0134] In some embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, Combinations including cellular immunotherapy (e.g., Provenge® (e.g., sipuleucel T )) optionally in combination with cyclophosphamide In one embodiment, the anti-PD-1 antibody molecule, Provenge® and / or or cyclophosphamide in combination with a cancer, e.g., a cancer described herein (e.g., prostate cancer, It is used to treat adenocarcinomas, such as advanced prostate cancer.

[0135] In other embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, Combinations including vaccines, e.g., cancer vaccines (e.g., dendritic cell renal cell carcinoma (DC-RCC) In some embodiments, the vaccine comprises or is administered in combination with a The antibody may be peptide-based, DNA-based, RNA-based, or antigen-based, or a combination thereof. In some embodiments, the vaccine comprises one or more peptides, nucleic acids (e.g., , DNA or RNA), an antigen, or a combination thereof. The combination of anti-PD-1 antibody molecules and DC-RCC vaccines can be used to treat cancers, such as those described herein. cancer (e.g., kidney cancer, e.g., metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma (CCRC) C)) for the treatment of

[0136] In other embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, The combination may include or be administered in combination with an adjuvant.

[0137] In yet other embodiments, the combinations disclosed herein, e.g., anti-PD-1 antibody molecules, Combinations including chemotherapy and / or immunotherapy For example, anti-PD-1 antibody molecules can be administered alone or in combination with chemotherapy or other chemotherapy for the treatment of myeloma. or other anticancer drugs (e.g., thalidomide analogs, e.g., lenalidomide), anti-TIM- 3. Antibody, tumor antigen-pulsed dendritic cells, fusion of tumor cells and dendritic cells (e.g., electrofusion), or One or more vaccinations with immunoglobulin idiotypes produced by malignant plasma cells In one embodiment, the anti-PD-1 antibody molecule can be used in combination with an anti-TIM- 3 antibody for use in the treatment of myeloma, eg, multiple myeloma.

[0138] In some embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, Combinations including chemotherapy for the treatment of lung cancer, e.g., non-small cell lung cancer, or In one embodiment, the anti-PD-1 antibody molecule is used in combination with For standard lung, e.g., NSCLC, chemotherapy, e.g., platinum doublet therapy, In yet another embodiment, the anti-PD-1 antibody molecule is used in the treatment of advanced or metastatic cancer. Indoleamine-peptide-binding protein (IPP) is administered to subjects with NSCL cancer (e.g., patients with metastatic and recurrent NSCL cancer). Iodo 2,3-dioxygenase (IDO) inhibitors (e.g., (4E)-4-[(3-chloro-4 -fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as INCB24360), indoximod (1-methyl-D-tryptophan α-Cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol It is used in combination with other drugs such as Benzyl Alcohol (also known as NLG919).

[0139] In yet other embodiments, the combinations disclosed herein, e.g., anti-PD-1 antibody molecules, Combinations including these drugs are also used in combination with immune-based strategies (e.g., interleukin-2 or interleukin-3). -feron-α), targeting agents (e.g., monoclonal antibodies against VEGF, etc. VEGF inhibitors); such as sunitinib, sorafenib, axitinib, and pazopanib VEGF tyrosine kinase inhibitors; RNAi inhibitors; or downstream of VEGF signaling Inhibitors of mediators, such as mammalian target of rapamycin (mTOR) inhibitors, e.g. For example, it may contain or be used in combination with one or more of everolimus and temsirolimus. Any of these combinations may be used to treat kidney cancer, e.g., renal cell carcinoma (RCC) (e.g., clear cell Renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC) or metastatic RCC or liver It can be used to treat liver cancer (eg, hepatocellular carcinoma).

[0140] In some embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, The combination may include or comprise a MEK inhibitor (e.g., a MEK inhibitor described herein). In one embodiment, the combination of an anti-PD-1 antibody and a MEK inhibitor The combination is used to treat cancer (e.g., a cancer described herein). Cancers treated with the combination include melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, and In some embodiments, the cancer is selected from adenocarcinoma, pancreatic cancer, hematopoietic malignancies, or renal cell carcinoma. , BRAF mutation (e.g., BRAF V600E mutation), BRAF wild-type, KRAS wild-type or contains an activating KRAS mutation. The cancer can be early, intermediate, or late stage.

[0141] In other embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, Combinations include 1, 2, or all of oxaliplatin, leucovorin, or 5-FU ( For example, FOLFOX co-treatment) or in combination with Alternatively or in combination, the combination may further comprise a VEGF inhibitor (e.g., a VEGF inhibitor as described herein). In one embodiment, the anti-PD-1 antibody, FOLFOX, The co-treatment and combination of VEGF inhibitors can be used to treat cancer (e.g., a cancer described herein). In some embodiments, the cancer treated with the combination is melanoma, colorectal cancer, selected from non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematopoietic tumors, or renal cell carcinoma The cancer may be at an early, intermediate or late stage.

[0142] In other embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, Combinations including tyrosine kinase inhibitors (TKIs) are being investigated for the treatment of renal cell carcinoma and other solid tumors. For example, axitinib) or administered in combination therewith.

[0143] In other embodiments, the combinations disclosed herein, e.g., those comprising an anti-PD-1 antibody molecule, The combination includes a 4-1BB receptor targeting agent (e.g., 4-1BB (CD-137) ) or in combination with an antibody that stimulates signaling via In one embodiment, the anti-PD-1 antibody molecule is administered in combination with a tyrosine kinase inhibitor (e.g., axitinib) and 4-1BB receptor targeting agents. do.

[0144] The anti-PD-1 antibody molecule may be administered to a substance, e.g., a cytotoxic agent or moiety (e.g., a therapeutic drug; a radioactive Radiation-emitting compounds; molecules of plant, fungal, or bacterial origin; or biological proteins (e.g. , protein toxins) or particles (e.g., recombinant viral particles, e.g., viral coat For example, antibodies can be conjugated to α-, β-, or γ-emitters or can be bound to radioisotopes, including β- and γ-emitters.

[0145] Anti-PD-1 antibody molecules and other therapeutic agents, procedures, or modalities (e.g., as described herein) Any combination and sequence of antibody molecules and / or other therapeutic agents may be used. The procedure or modality may be administered during an active or less active phase of the disease. The antibody molecule can be administered prior to, concurrently with, or after other treatments or to alleviate the disorder. It can be administered during the solution.

[0146] Further combination treatments In certain embodiments, any of the combinations disclosed herein may be used separately or in combination with other combinations. in combination with one or more of the agents listed in Table 7.

[0147] In certain embodiments, the additional therapeutic agent is, e.g., as described herein and in Table 7. 1) Protein kinase C (PKC) inhibitors, 2) Heat shock protein 90 (HSP) 90) inhibitors, 3) phosphoinositide 3-kinase (PI3K) and / or rapamycin 4) inhibitors of cytochrome P450 (e.g., CYP17 inhibitors or or 17alpha-hydroxylase / C17-20 lyase inhibitors), 5) iron chelators 6) aromatase inhibitors, 7) p53 inhibitors, for example, p53 / Mdm2 interaction inhibitors 8) Apoptosis inducers, 9) Angiogenesis inhibitors, 10) Aldosterone synthase inhibitors 11) Smoothened (SMO) receptor inhibitor, 12) Prolactin receptor (PRLR) inhibitor 13) Wnt signaling inhibitors, 14) CDK4 / 6 inhibitors, 15) fibroblast growth factors Fibroblast growth factor receptor 2 (FGFR2) / fibroblast growth factor receptor 4 (FGFR4) inhibitor, 16) Mac phage colony-stimulating factor (M-CSF) inhibitor, 17) c-KIT, histamine release, 18) one or more inhibitors of Flt3 (e.g., FLK2 / STK1) or PKC, VEGF R-2 (e.g., FLK-1 / KDR), PDGFR beta, c-KIT, or Raf kinase 19) one or more inhibitors of phosphodiesterase C, 20) somatostatin agonists and / or growth hormone release inhibitors, 20) anaplastic lymphoma kinase (ALK) inhibitors, 21) insulin-like growth factor inhibitors 22) IGF-1 receptor (IGF-1R) inhibitor, 23) P-glycoprotein 1 inhibitor, 24) vascular endothelial cells Growth factor receptor (VEGFR) inhibitors, 24) BCR-ABL kinase inhibitors, 25) FGF R inhibitors, 26) CYP11B2 inhibitors, 27) HDM2 inhibitors, e.g., HDM2-p5 3 interaction inhibitor, 28) tyrosine kinase inhibitor, 29) c-MET inhibitor, 30) JA K inhibitors, 31) DAC inhibitors, 32) 11β-hydroxylase inhibitors, 33) IAP inhibitors 34) PIM kinase inhibitors, 35) Porcupine inhibitors, 36) BRAF, For example, inhibitors of BRAF V600E or wild-type BRAF, 37) HER3 inhibitors, 38) MEK inhibitors; or 39) lipid kinase inhibitors.

[0148] In certain embodiments, the additional therapeutic agent is Compound A8, Compound A17, Compound A23 , Compound A24, Compound A27, Compound A29, Compound A33, and Compound A13 Selected from above.

[0149] In other embodiments, the additional therapeutic agent is Compound A5, Compound A8, Compound A17, selected from one or more of Compound A23, Compound A24, Compound A29 and Compound A40 .

[0150] In other embodiments, the additional therapeutic agent is Compound A9, Compound A16, Compound A17 , Compound A21, Compound A22, Compound A25, Compound A28, Compound A48 and Compound 49.

[0151] In certain embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma) NSCLC or NSCLC adenocarcinoma with epithelial and / or non-squamous histology) or Table 7 The compounds are selected from those disclosed in the publications listed in:

[0152] Biomarkers In other embodiments, provided herein are methods for treating a subject (e.g., a cancer, e.g., a cancer-associated inflammatory disorder, e.g., a rheumatoid arthritis, ... and assessing the efficacy of the treatments (e.g., combination treatments) described herein in subjects with cancers associated with the disease. This method is a method for evaluating or monitoring the efficacy of a treatment. wherein said value is an indication of therapeutic efficacy.

[0153] In some embodiments, the therapeutic efficacy value is 1, 2, 3, 4, 5 or more of the following: , 6, 7, 8, 9 or more (e.g., all) measurements. (i) Tumor-infiltrating lymphocyte (TIL) phenotypic parameters; (ii) parameters of bone marrow cell populations; (iii) parameters of surface-expressed markers; (iv) immune response biomarker parameters; (v) parameters of systemic cytokine regulation; (vi) circulating free DNA (cfDNA) parameters; (vii) parameters of systemic immunomodulation; (viii) microbiome parameters; (ix) parameters of circulating immune cell activation markers; or (x) Circulating cytokine parameters.

[0154] In certain embodiments, TIL phenotypic parameters are measured in samples from a subject, e.g., Hematoxylin and eosin (H&E) for TIL counting in pools (e.g., tumor samples) Staining, 1, 2, 3, 4 or more of CD8, FOXP3, CD4 or CD3 (e.g. The term "antibody" includes the level or activity of a particular protein (e.g., all of the protein).

[0155] In certain embodiments, the parameters of the bone marrow cell population are measured using a sample from a subject, e.g., The levels of either CD68 or CD163 in a sample (e.g., tumor sample) Includes activity or activity.

[0156] In certain embodiments, the parameters of the surface-expressed markers are determined from a subject, e.g., 1. Expression of PD-L1, LAG-3, or TIM-3 in a sample (e.g., a tumor sample) , including two or more (eg, all) levels or activities.

[0157] In certain embodiments, the parameters of the immune response biomarkers are measured in a subject, e.g., a control. The level of one or more nucleic acid-based markers in a sample (e.g., a tumor sample) from the patient Contains a rule or sequence.

[0158] In certain embodiments, parameters of systemic cytokine regulation are measured in a subject, e.g., a subject IL-18 in a sample (e.g., a blood sample, e.g., a plasma sample) from IFN-γ, ITAC (CXCL11), IL-6, IL-10, IL-4, IL-17, IL-15 or TGF-beta 1, 2, 3, 4, 5, 6, 7, 8 or more (e.g. The term "antibody" includes the level or activity of a particular gene (e.g., all of the genes).

[0159] In certain embodiments, the cfDNA parameters are determined from a sample from a subject, e.g., one or more circulating tumor DNA ( cfDNA) molecule sequences or levels.

[0160] In certain embodiments, the parameters of systemic immunomodulation are measured by measuring the level of immune activity in a subject, e.g., serum from the subject. Activated immune cells in a sample (e.g., a blood sample, e.g., a PBMC sample), e.g., For example, this includes phenotypic characterization of CD3-expressing cells, CD8-expressing cells, or both.

[0161] In certain embodiments, the microbiome parameters are measured from a subject, e.g., sequencing or analyzing one or more genes of the microbiome in a sample (e.g., a stool sample) or expression levels.

[0162] In one embodiment, the parameter of the activation marker of circulating immune cells is in a sample (e.g., a blood sample, e.g., a plasma sample), the circulating CD8 +, HLA-DR + K i67 +, T cells, IFN-γ, IL-18 or CXCL11 (IFN-γ-induced CCK) including the level or activity of 1, 2, 3, 4, 5 or more (e.g., all) of the expressing cells .

[0163] In one embodiment, the parameter of the circulating cytokine is the level or activity of IL-6 in a sample (e.g., a blood sample, e.g., a plasma sample) from a subject, e.g., a subject . including the level or activity of IL-6 in a sample (e.g., a blood sample, e.g., a plasma sample) from a subject, e.g., a subject

[0164] In certain embodiments of any of the methods disclosed herein, the treatment is (a) an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1 (e.g., an anti-PD- 1 antibody molecule); and (b) (i) an IAP inhibitor, (S)-N-((S)-1-cyclohexyl-2-((S)-2-(4-(4 -fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl l)-2-(methylamino)propanamide (Compound A21) or a compound disclosed in U.S. Patent No. 8,552,00 3; (ii) an mTOR inhibitor, everolimus (Compound A36) or a compound disclosed in PCT Publication WO2014 / 0 85318; (iii) a DAC inhibitor, panobinostat (Compound A19) or a compound disclosed in PCT Publication WO2014 / 072493; (iv) an IL-1β inhibitor, canakinumab or a compound disclosed in PCT Publication WO2002 / 16436 ; (v) IL-17 inhibitor, CJM112 or PCT Publication No. WO2014 / 122613 the compounds disclosed in (vi) MEK inhibitor or trametinib; or (vii) EGFR inhibitor, (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino) )but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl) -2-methylisonicotinamide (compound A40) or PCT Publication WO2013 / 184 Compounds disclosed in No. 757 one or more (e.g., 2, 3, 4, or more) Includes a combination of:

[0165] In certain embodiments of any of the methods disclosed herein, measuring one or more of (i) through (x) In some embodiments, the sample is a tumor sample, Select from blood samples (e.g., plasma samples or PBMC samples) or fecal samples It is selected.

[0166] In certain embodiments of any of the methods disclosed herein, the subject is receiving treatment, e.g., a combination The patient will be assessed before, during, or after receiving treatment.

[0167] In certain embodiments of any of the methods disclosed herein, the measurements of one or more of (i) through (x) are assessing one or more profiles of gene expression, flow cytometry, or protein expression; Worth it.

[0168] In certain embodiments of any of the methods disclosed herein, in a subject or sample: Circulating CD8+, HLA-DR+Ki67+, T cells, IFN-γ, IL-18 or CX 1, 2, 3, 4, 5 or more (e.g., 1, 2, 3, 4, 5 or more) CL11 (IFN-γ-induced CCK)-expressing cells , all) and / or the presence of an increase in the level or activity of IL-6 The presence of a decrease is a positive predictor of treatment efficacy.

[0169] Alternatively or in combination with the methods disclosed herein, in response to the values: (i) administering a treatment (e.g., a combination treatment) to a subject; (ii) administering varying doses of treatment (e.g., combination treatment); (iii) changing the schedule or time course of treatment (e.g., combination treatment); (iv) treating the subject with an additional agent (e.g., a therapeutic agent described herein) (e.g., combination therapy); administered in combination with; or (v) administering another treatment (e.g., a treatment described herein) to the subject One, two, three, four or more (e.g., all) of the following may be performed.

[0170] Additional Embodiments Additional embodiments involve the use of a subject or sample (e.g., cancer cells and optionally TILs, etc.) PD-L1, CD8, or IFN-γ in a subject's sample containing immune cells; 2 or all of PD-L1, CD8, and IFN-γ or all of the values ​​of the IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL- , comparing the PD-L1, CD8 and / or IFN-γ values ​​to a reference value, e.g., a control value. The PD-L1, CD8 and / or IFN-γ values ​​may be compared with a reference value, e.g. If the reference value is greater than the reference value, the subject is administered a therapeutically effective amount of a combination described herein (e.g., (combination including an anti-PD-1 antibody described in ) optionally in combination with one or more other drugs The cancers are, for example, lung cancer (squamous cell carcinoma), lung cancer (adenocarcinoma), Head and neck cancer, cervical cancer (squamous), stomach cancer, thyroid cancer (e.g. undifferentiated thyroid cancer), skin cancer (e.g. Merkel cell carcinoma or melanoma), nasopharyngeal carcinoma, neuroendocrine tumors (e.g., atypical pulmonary carcinoma), tumor) or breast cancer, e.g., TN breast cancer, e.g., IM-TN breast cancer, In some embodiments, the cancer is ER+ breast cancer or pancreatic cancer.

[0171] Also provided are methods for treating a subject or sample (e.g., a subject sample containing cancer cells) with P Test for the presence of PD-L1, thereby identifying PD-L1 levels and controlling PD-L1 levels. and if the PD-L1 value is greater than the control value, the subject is administered a therapeutically effective amount of a compound described herein. combinations (e.g., combinations comprising an anti-PD-1 antibody described herein) can be administered as desired. and administering the compound in combination with one or more other drugs to treat cancer. The cancer is, for example, non-small cell lung cancer (NSCLC), adenocarcinoma (ACA), NSCLC, The cancer may be a cancer described herein, such as squamous cell carcinoma (SCC) or hepatocellular carcinoma (HCC).

[0172] In another aspect, the present invention provides a diagnostic antibody comprising the antibody molecule described herein and instructions for use. The present invention relates to a kit for use or treatment.

[0173] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. and are incorporated herein by reference.

[0174] Other features, objects, and advantages of the invention can be seen from the specification and drawings, and from the claims. It's obvious. [Brief explanation of the drawings]

[0175] [Figure 1]Figure 1 shows the amino acid sequences of the light and heavy chain variable regions of the murine anti-PD-1 mAb BAP049. The upper and lower sequences were derived from two independent analyses. The light and heavy chain CDR sequences based on Kabat numbering are underlined. The light and heavy chain CDR sequences based on Chothia numbering are shown in bold italics. The unpaired Cys residue at position 102 of the light chain sequence is boxed. The sequences, in order of appearance, are disclosed in SEQ ID NOs: 8, 228, 16, and 229, respectively.

[0176] [Figure 2A] Figure 2A shows the amino acid sequences of the light and heavy chain variable regions of the murine anti-PD-1 mAb BAP049 aligned with germline sequences. The top and bottom sequences are the germline (GL) and BAP049 (Mu mAb) sequences, respectively. The light and heavy chain CDR sequences based on Kabat numbering are underlined. The light and heavy chain CDR sequences based on Chothia numbering are shown in bold italics. "-" indicates identical amino acid residues. The sequences, in order of appearance, are set forth in SEQ ID NOs: 230, 8, 231, and 16, respectively.

[0177] [Figure 2B] Figure 2B shows the sequence of the mouse kappa J2 gene and the corresponding mutations in the mouse anti-PD-1 mAb BAP049. "-" indicates identical nucleotide residues. The sequences, in order of appearance, are set forth in SEQ ID NOs: 233, 232, 234, and 235, respectively.

[0178] [Figure 3]Figures 3A-3B show the competitive binding of fluorescently labeled mouse anti-PD-1 mAb BAP049 (Mu mAb) with three chimeric versions of BAP049 (Chi mAb). Experiments were performed twice, and the results are shown in Figures 3A and 3B, respectively. The three chimeric BAP049 antibodies (Chi mAb(Cys), Chi mAb(Tyr), and Chi mAb(Ser)) contain Cys, Tyr, and Ser residues at position 102 of the light chain variable region, respectively. Chi mAb(Cys), Chi mAb(Tyr), and Chi mAb(Ser) are also known as BAP049-chi, BAP049-chi-Y, and BAP049-chi-S, respectively.

[0179] [Figure 4] Figure 4 is a bar graph showing the results of FACS binding analysis of 16 humanized BAP049 clones (BAP049-hum01 to BAP049-hum16). Antibody concentrations, from left to right, are 200 ng / ml, 100 ng / ml, 50 ng / ml, 25 ng / ml, and 12.5 ng / ml for each tested mAb.

[0180] [Figure 5] Figure 5 shows the structural analysis of the humanized BAP049 clone (a, b, c, d, and e indicate different types of framework region sequences). The concentration of mAb in the sample is also shown.

[0181] [Figure 6] Figures 6A-6B show the binding affinity and specificity of the humanized BAP049 mAb as measured in a competitive binding assay using a fixed concentration of Alexa 488-labeled murine mAb BAP049, serial dilutions of the test antibody, and PD-1-expressing 300.19 cells. Experiments were performed twice, and the results are shown in Figures 6A and 6B, respectively.

[0182] [Figure 7] Figure 7 lists the ranking of humanized BAP049 clones based on FACS data, competitive binding, and structural analysis. The concentrations of mAbs in the samples are also shown.

[0183] [Figure 8] Figures 8A-8B show blockade of ligand binding to PD-1 by select humanized BAP049 clones. Blockade of PD-L1-Ig and PD-L2-Ig binding to PD-1 is shown in Figure 8A. Blockade of PD-L2-Ig binding to PD-1 is shown in Figure 8B. BAP049-hum01, BAP049-hum05, BAP049-hum08, BAP049-hum09, BAP049-hum10, and BAP049-hum11 were evaluated. Murine mAb BAP049 and a chimeric mAb with Tyr at position 102 in the light chain variable region were also included in the analysis.

[0184] [Figure 9] Figures 9A-9B show alignments of the heavy chain variable domain sequences of 16 humanized BAP049 clones and the BAP049 chimera (BAP049-chi). In Figure 9A, all sequences are shown (SEQ ID NOS: 22, 38, 38, 38, 38, 38, 38, 38, 38, 38, 50, 50, 50, 50, 82, 82, and 86, respectively, in order of appearance). In Figure 9B, only amino acid sequences that differ from the murine sequence are shown (SEQ ID NOS: 22, 38, 38, 38, 38, 38, 38, 38, 38, 38, 50, 50, 50, 50, 82, 82, and 86, respectively, in order of appearance).

[0185] [Figure 10] Figures 10A to 10B show alignments of the light chain variable domain sequences of 16 humanized BAP049 clones and the BAP049 chimera (BAP049-chi). In Figure 10A, all sequences are shown (SEQ ID NOS: 24, 66, 66, 66, 66, 70, 70, 70, 58, 62, 78, 74, 46, 46, 42, 54, and 54, respectively, in order of appearance). In Figure 10B, only amino acid sequences that differ from the murine sequence are shown (SEQ ID NOS: 24, 66, 66, 66, 66, 70, 70, 70, 58, 62, 78, 74, 46, 46, 42, 54, and 54, respectively, in order of appearance).

[0186] [Figure 11]FIG. 11 is a schematic diagram outlining antigen processing and presentation, effector cell responses, and immunosuppressive pathways targeted by the combination therapies disclosed herein.

[0187] [Figure 12] Figure 12 shows predicted C trough (C min ) concentrations across patients of various body weights receiving the same dose of an exemplary anti-PD-1 antibody molecule. A comparison of predicted mean steady-state C trough after flat / fixed dosing of two regimens of anti-PD-1 antibody molecule versus body weight is shown.

[0188] [Figure 13] Figure 13 shows observed versus model-predicted (population or individual-based) Cmin concentrations.

[0189] [Figure 14] 14A-14B show the accumulation, time course, and intra-subject variability of the model used in the pharmacokinetic analysis. Shaded areas indicate 90% prediction intervals, black lines indicate the median prediction at each time point, and black dots indicate the observed pharmacokinetic data.

[0190] [Figure 15] FIG. 15 shows the percent survival of mice implanted with MC38 cells after treatment with anti-PD-1 antibody, Compound A21, or a combination of anti-PD-1 antibody and Compound A21.

[0191] [Figure 16A] Figure 16A shows the body weights of 10 animals per group treated with vehicle, anti-mouse PD-1 antibody (10 mg / kg IV QW 4 times), panobinostat (compound A19, 10 mg / kg QOD 5 times), or the combination of panobinostat and anti-mouse PD-1 antibody.

[0192] [Figure 16B] Figure 16B shows the response of individual tumors treated with vehicle control, anti-mouse PD-1 antibody, panobinostat (compound A19), or a combination of panobinostat and anti-mouse PD-1 antibody.

[0193] [Figure 17] Figure 17 shows the percent survival of A20 lymphoma allograft-bearing mice after treatment with Compound A40, ibrutinib, anti-PD-L1 antibody, a combination of Compound A40 and anti-PD-L1 antibody, or a combination of ibrutinib and anti-PD-L1 antibody (anti-PD-L1 is shown as aPD-L1).

[0194] [Figure 18] Figure 18 shows the mean tumor volume in A20 lymphoma allograft-bearing mice after treatment with Compound A40, ibrutinib, anti-PD-L1 antibody, the combination of Compound A40 and anti-PD-L1 antibody, or the combination of ibrutinib and anti-PD-L1 antibody (anti-PD-L1 is shown as aPD-L1).

[0195] [Figure 19] Figure 19 shows the trial design for a first-in-human Phase I / II clinical trial of an exemplary anti-PD-1 antibody molecule in patients with advanced solid tumors. *At least 21 patients were required to define the MTD. Tumor assessments were performed at screening, then every 2 cycles (1 cycle = 28 days) ± 1 week from Cycle 3 Day 1 to Cycle 11 Day 1, and then every 3 cycles until disease progression per irRC or patient withdrawal. irRC, immune-related response evaluation criteria in solid tumors; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; RP2D, recommended Phase II dose; TNBC, triple-negative breast cancer.

[0196] [Figure 20] Figure 20 shows the percent change in target lesions over time for each of the radiographically evaluable patients treated with the anti-PD-1 antibody molecules in a Phase I / II clinical trial. Patients were treated with the following dosing schedules: 1 mg / kg q2w, 3 mg / kg q2w, 10 mg / kg q2w, 3 mg / kg q4w, or 5 mg / kg q4w (example lines are shown on the figure along with the dosing schedules).

[0197] [Figure 21]21A-21C show tumor assessment and immunohistochemical detection of CD8+ T lymphocytes in patients with metastatic atypical pulmonary carcinoid tumors in a phase I / II clinical trial, along with clinical responses to anti-PD-1 antibody molecules.

[0198] [Figure 21A] Figure 21A shows CT scan images demonstrating the response in a patient. The left panel shows liver metastases before antibody treatment. The center panel shows pseudoprogression of the liver in the first restaging (with significant shrinkage of the lung lesions not shown). The right panel shows the response of all lesions in the second restaging.

[0199] [Figure 21B] FIG. 21B shows the reduction in metastatic atypical pulmonary carcinoid tumor burden (% change from baseline) and individual lesions (lesion size (nm)) in patients.

[0200] [Figure 21C] Figure 21C shows an image of immunohistochemical staining showing high levels of CD8+ T lymphocytes in a tumor sample obtained from a patient during cycle 2, day 1. BL, baseline; C2D1, cycle 2, day 1.

[0201] [Figure 22A] Figure 22A shows the percent survival of mice implanted with MC38 cells after treatment with anti-PD-1 antibody, Compound A15 (once a week or daily), or a combination of anti-PD-1 antibody and Compound A15 (once a week or daily).

[0202] [Figure 22B] Figure 22B shows the mean tumor volume of mice implanted with MC38 cells after treatment with anti-PD-1 antibody, compound A15 (daily), or a combination of anti-PD-1 antibody and compound A15 (daily).

[0203] [Figure 22C]Figure 22C shows the mean tumor volume in mice implanted with MC38 cells after treatment with anti-PD-1 antibody, compound A15 (once weekly), or a combination of anti-PD-1 antibody and compound A15 (once weekly).

[0204] [Figure 23] Figure 23 shows the enhancement over time to endpoint observed in animals treated with the combination of anti-PD-L1 antibody molecules and anti-PD-1 antibodies.

[0205] Brief description of the table Table 1 shows the amino acid and nucleotide sequences of the murine, chimeric, and humanized anti-PD-1 antibody molecules. The antibody molecules are mouse mAb BAP049, chimeric mAb BA P049-chi and BAP049-chi-Y and humanized mAbs BAP049 -hum01~BAP049-hum16 and BAP049-Clone-A~BAP Contains 049-Clone-E. Amino acid and nucleotide sequences of heavy and light chain CDRs The amino acid and nucleotide sequences of the heavy and light chain variable regions and the heavy and light chain The amino acid and nucleotide sequences are shown in this table.

[0206] Table 2 shows the humanized mAbs BAP049-hum01 to BAP049-hum16 and and BAP049-Clone-A to BAP049-Clone-E heavy and light chain fragments. The amino acid and nucleotide sequences of the framework region are shown.

[0207] Table 3 shows the amino acid sequences of the constant regions of the human IgG heavy chain and the human kappa light chain.

[0208] Table 4 shows the humanized mAbs BAP049-Clone-A to BAP049-Clone-B. 1 shows the amino acid sequences of the heavy and light chain leader sequences of -E.

[0209] Table 5 shows example PK parameters based on a uniform dosing schedule.

[0210] Table 6 shows the combinations of antigen presentation (Category A), effector cell combinations (Category B), and -B) and antitumor immunosuppressive combinations (category C) .

[0211] Table 7 shows the anti-PD-1 antibody molecules described herein and other immunomodulatory agents (e.g., costimulatory one or more of: activators of immune checkpoint molecules and / or inhibitors of immune checkpoint molecules; Table 7 provides an overview of select therapeutic agents that can be administered in combination. From left to right, Table 7 lists the following second therapeutic agents: The compound names, compound structures, and patent publications disclosing the compounds are provided.

[0212] Table 8 provides, for example, a summary of the therapeutic efficacy (e.g., combination therapy) described herein. , examples of biomarkers and sample collection are shown.

[0213] Table 9 summarizes the goals and endpoints of the Phase I / II trial.

[0214] Table 10 summarizes the patient demographics and characteristics in the Phase I / II trial.

[0215] Table 11 shows patient characteristics in the Phase I / II trial.

[0216] Table 12 shows adverse events, regardless of drug-related events, in the Phase I / II clinical trial (patients Any grade occurring in ≥ 20% of cases - safety set).

[0217] Table 13 shows the best overall response (disease status using investigator's RECIST v1.1 criteria). (based on assessment of behavior). DETAILED DESCRIPTION OF THE INVENTION

[0218] Detailed Description Disclosed herein are, at least in part, methods for inhibiting programmed death 1 (PD 1) with high affinity and specificity. The antibody molecule (e.g., a humanized antibody molecule) that binds to the antibody molecule (e.g., a nucleic acid encoding the antibody molecule). Acid molecules, expression vectors, host cells and methods for producing the antibody molecules are also provided. Also provided are pharmaceutical compositions and dosage formulations comprising the anti-PD-1 antibody molecules disclosed herein: Cancerous disorders (e.g., solid and soft tissue tumors) and infectious diseases (e.g., chronic infectious disorders or or sepsis) (alone or with other agents or Therefore, compositions for detecting PD-1 can be used in combination with therapeutic modalities. and methods for treating cancer and / or infectious diseases using the anti-PD-1 antibody molecules. Disclosed herein are methods for treating various disorders. In certain embodiments, the anti-PD-1 antibody The molecule is administered or used in a flat or fixed dose.

[0219] Also disclosed herein are antibodies in the following categories: (i) antibodies that enhance antigen presentation (e.g., tumor antigen presentation); Agents that enhance dendritic cell activity or maturation, antigen uptake, or antigen processing (ii) agents that enhance effector cell responses (e.g., by enhancing one or more of the e.g., immune effector cell responses, e.g., B cell and / or T cell activation and / or recruitment) or (iii) agents that reduce tumor immunosuppression (e.g., T cell infiltration and and increased tumor cell death) In certain embodiments, the combination comprises the above therapeutic agents. The combination includes a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein). Without intending to be bound, therapeutic approaches to enhance anti-tumor immunity include those in which the immune response is , e.g., by targeting multiple components at one or more stages of the anti-tumor immune response. It is believed that when optimized, it will work more efficiently. Each of these steps is shown in Figure 21. For example, the means for activating dendritic cells and increasing cellular and humoral immunity are shown in Fig. Combinations of these strategies may result in more effective and / or prolonged therapeutic responses. do.

[0220] Additional terms are defined below and throughout the specification. The articles "a" and "an" are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. do.

[0221] The term "or" is used in conjunction with the term "and / or" unless the context clearly dictates otherwise. " and is used interchangeably therewith.

[0222] "About" and "approximately" generally refer to the amount of the quantity being measured, taking into account the nature or precision of the measurements. This means the degree of tolerance for error. An example of a tolerance is 20% of a value or range of values. Within a percentage point, typically within 10%, and more typically within 5%.

[0223] "Combination" or "in combination with" refers to the simultaneous administration of these treatments or therapeutic agents. This implies that the drug must be formulated for use and / or delivery with Although not intended, the methods of delivery are within the scope of those described herein. These may be administered simultaneously with, before, or after other additional treatments or therapeutic agents. The treatment protocols may be administered in any order. Generally, each agent is administered in a manner that is consistent with the dosage determined for that agent. These drugs are administered at a prescribed dose and / or time schedule. The additional therapeutic agents may be administered as a single composition or separately as individual compositions. It is further recognized that additional treatments used in combination generally may be used in combination. It is expected that the agents will be used at levels not exceeding the levels at which they are used individually. In some embodiments, the levels used in combination are higher than when used individually. low.

[0224] In certain embodiments, the additional therapeutic agent is administered at a therapeutic or sub-therapeutic dose. In certain embodiments, a second therapeutic agent is required to achieve inhibition, e.g., growth inhibition. The concentration of the second therapeutic agent is determined based on the amount of the first therapeutic agent administered in combination with the first therapeutic agent, e.g., an anti-PD-1 antibody molecule. In some embodiments, the inhibition, e.g., For example, the concentration of the first therapeutic agent required to achieve growth inhibition may be determined by combining the first therapeutic agent with the second therapeutic agent. When administered together, the first therapeutic agent is lower than when administered separately. In combination therapy, a second therapeutic agent is required to achieve inhibition, e.g., growth inhibition. The concentration of the second therapeutic agent is lower than the therapeutic dose of the second therapeutic agent as monotherapy, e.g., 10-20%, 2 0-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower. In some embodiments, in combination therapy, inhibition, e.g., For example, the concentration of the first therapeutic agent required to achieve growth inhibition is approximately the same as that of the first therapeutic agent as monotherapy. Lower than the therapeutic dose, e.g., 10-20%, 20-30%, 30-40%, 40-50% , 50-60%, 60-70%, 70-80% or 80-90% lower.

[0225] The terms "inhibition," "inhibitor," or "antagonist" refer to a molecule, e.g., an immune control molecule, that inhibits the activity of a specific target molecule. The activity of a checkpoint inhibitor may include a decrease in a parameter, e.g., activity. For example, at least 5%, 10%, 20%, 30%, 40% or more of PD-1 or PD-L1 activity % or more inhibition is encompassed by the term; therefore, inhibition does not have to be 100%. There's no need.

[0226] The terms "activation," "activator," or "agonist" refer to the activation of a molecule, e.g., The effects of the co-stimulatory molecules include an increase in some parameter, e.g., activity. At least a 5%, 10%, 25%, 50%, 75% or greater increase in stimulatory activity are encompassed by this term.

[0227] The term "anti-cancer effect" includes, for example, a reduction in tumor volume, a reduction in the number of cancer cells, a reduction in the number of metastases, an extension of life expectancy, including reduction in cancer cell proliferation, reduction in cancer cell survival, or amelioration of various physiological symptoms associated with the cancerous state. "Anti-cancer" refers to a biological effect that can be manifested by various means, including but not limited to: The "effect" is that the peptides, polynucleotides, cells and antibodies prevent the onset of cancer in the first place. It can also be manifested by the ability to

[0228] The term "anti-tumor effect" includes, for example, a reduction in tumor volume, a reduction in tumor cell number, a reduction in tumor cell proliferation, or This can be manifested by a variety of means, including, but not limited to, a decrease in tumor cell survival or tumor cell death. This refers to a biological effect that

[0229] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of cancers are described herein, including breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colon cancer, and the like. Including, but not limited to, rectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, etc. The terms "tumor" and "cancer" are used interchangeably herein, e.g., both The term encompasses solid and liquid tumors, e.g., generalized or circulating tumors. The term "cancer" or "tumor" includes pre-malignant and malignant cancers and tumors.

[0230] The term "antigen-presenting cell" or "APC" refers to a cell that is complexed with a major histocompatibility complex (MHC). Accessory cells (e.g., B cells, dendritic cells, etc.) that present foreign antigens on their surface T cells are immune system cells that recognize these complexes using T cell receptors (TCRs). APCs process antigens and present them to T cells.

[0231] The term "costimulatory molecule" refers to a molecule that specifically binds to a costimulatory ligand, thereby inducing T cell proliferation. Co-stimulatory responses on T cells, such as but not limited to proliferation by T cells Co-stimulatory molecules are antigen receptors or related binding partners required for an efficient immune response. Co-stimulatory molecules are cell surface molecules other than the ligands for these. F receptor protein, immunoglobulin-like protein, cytokine receptor, integrin , signaling lymphocytic activation molecule (SLAM protein), activating NK cell receptor, BT LA, Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD 30, CD40, CDS, ICAM-1, LFA-1(CD11a / CD18), 4-1B B(CD137), B7-H3, CDS, ICAM-1, ICOS(CD278), GITR , BAFFR, LIGHT, HVEM(LIGHTR), KIRDS2, SLAMF7, N Kp80(KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD 8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, IT GA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA -6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, C D11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1 , CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C , TNFR2, TRANCE / RANKL, DNAM1(CD226), SLAMF4(C D244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTA M, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4 D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD 150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTB R, LAT, GADS, SLP-76, PAG / Cbp, CD19a, and CD83 These include, but are not limited to, heterologous binding ligands.

[0232] As used herein, the term "immune effector cell" or "effector cell" refers to a cell that mediates an immune response. For example, immune effector cells are cells involved in promoting immune effector responses. Examples of T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells , natural killer (NK) cells, natural killer T (NKT) cells, mast cells and bone marrow Contains derived phagocytes.

[0233] As used herein, "immune effector" or "effector" "function" or "response" " enhances or promotes immune attack of target cells, e.g., immune effector cell function For example, an immune effector function or response may promote the killing of a target cell. This refers to the property of T cells or NK cells to stimulate or inhibit growth or proliferation. In this case, primary stimulation and costimulation are examples of immune effector functions or responses.

[0234] The term "effector function" refers to a specialized function of a cell, e.g., the effector function of a T cell. The function can be cytolytic activity or helper activity, including secretion of cytokines.

[0235] As used herein, the terms "treat" and "treatment" refer to the administration of one or more therapeutic agents. or reducing or ameliorating the progression, severity and / or duration of a disorder, e.g., a proliferative disorder. or an improvement in one or more symptoms (preferably one or more discernible symptoms) of said disorder. In embodiments, the terms "treat" and "treatment" are not necessarily patient-perceived. of at least one measurable physical parameter of a proliferative disorder, such as tumor growth, but not In another embodiment, the terms "treat" and "treatment" refer to an improvement, e.g., physical, For example, the stabilization of discernible symptoms may lead to physiological, e.g., stabilization of bodily parameters. In another embodiment, the present invention refers to inhibiting the progression of a proliferative disorder by inhibiting the proliferation of a proliferative disorder through the administration of a steroid or other anti-proliferative agent, or by inhibiting the proliferation of a proliferative disorder through the administration of a steroid or other anti-proliferative agent. In this context, the terms "treat" and "treatment" refer to the reduction or stabilization of tumor size or cancer cell number. This refers to

[0236] The compositions and methods of the present invention are directed to a specified sequence or sequences substantially identical or similar thereto. Polypeptides and nucleic acids having a sequence identical to, for example, at least 85%, 90%, or 100% of the sequence specified. In the case of amino acid sequences, the term "actual" includes sequences that are 0%, 95% or more identical. "Qualitatively identical" means that the first and second amino acid sequences share common structural domains and / or common i) identical or ii) aligned amino acid residues with a second amino acid sequence so that the amino acid sequence may have a functional activity of This refers to a first amino acid that contains a sufficient and minimum number of amino acid residues that are conservative substitutions for For example, a sequence that is at least about 85% identical to a reference sequence, e.g., a sequence provided herein. , 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 9 Amino acid sequences, including a common structural domain with 9% identity.

[0237] In the case of nucleotide sequences, the term "substantially identical" refers to a first and second nucleotide sequence encode polypeptides having a common functional activity or a common structural polypeptide The second nucleic acid sequence may be modified to encode a domain or a common functional polypeptide activity. "a" refers to a first nucleic acid sequence that contains a sufficient and minimum number of aligned nucleotides to As used herein, for example, a reference sequence, e.g., a sequence provided herein, and a sequence that is at least about 8 5%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or indicates a nucleotide sequence with 99% identity.

[0238] The term "functional variant" refers to a variant having substantially the same amino acid sequence as a naturally occurring sequence. or encoded by substantially the same nucleotide sequence as one or more of the naturally occurring sequences The term "polypeptide" refers to a polypeptide capable of having the above activity.

[0239] Homology or sequence identity between sequences (these terms are used interchangeably herein) The calculation is carried out as follows:

[0240] To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are compared using an optimal For comparison purposes, alignments are made (e.g., for optimal alignment, gaps are removed first and and a second amino acid or nucleic acid sequence can be introduced into either or both of the sequences to allow for non-homologous sequences to be used for comparison purposes. In a preferred embodiment, the length of a reference sequence alignment for comparison purposes is At least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% The amino acid residue or nucleotide at the corresponding amino acid position or nucleotide position is The sequences are then compared to determine whether a position in the first sequence matches a corresponding position in the second sequence. If the amino acid residue or nucleotide at that position is occupied by the same amino acid residue or nucleotide as (As used herein, amino acid or nucleic acid "identity" refers to amino acid or nucleic acid (equivalent to "homology").

[0241] The percent identity between two sequences can be introduced for optimal alignment of the two sequences. Considering the number of gaps needed and the length of each gap, the sequence shared by these sequences is a function of the number of identical positions.

[0242] The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences can be achieved by: Incorporated into the GAP program in the GCG software package (available at www.gcg.com) The Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm was incorporated Use Blossum 62 matrix or PAM250 matrix and gap Group weights 16, 14, 12, 10, 8, 6 or 4 and length weights 1, 2, 3, 4, 5 or is determined using 6. In yet another preferred embodiment, two nucleotide sequences The percent identity between the sequences was calculated using the GCG software package (available at www.gcg.com). The GAP program in Use 50, 60, 70 or 80 and length weights 1, 2, 3, 4, 5 or 6 to determine The particularly preferred parameter set (and the one that should be used unless otherwise specified) is Gap penalty 12, gap extension penalty 4 and frameshift gap penalty This is the Blossum 62 scoring matrix for Ti5.

[0243] The percent identity between two amino acid or nucleotide sequences can be calculated using the ALIGN program ( E. Meyers and W. Miller ((1989) CABIOS, 4:11-1) 7) algorithm, with a PAM120 weighted residue table, gap length penalty of 12, and and a gap penalty of 4.

[0244] The nucleic acid and protein sequences described herein can be used as a "query sequence" to query public Searches can be performed against databases to identify, for example, other family members or related sequences. Such searches can be performed using the method described in Altschul, et al. (1990) J. Mol. Biol. 215:403-10 using the NBLAST and XBLAST programs (version 2.0). BLAST nucleotide searches can be performed using the NBLAST program, A score of 100 and word length of 12 was used to identify nucleic acids homologous to the nucleic acid molecule of the present invention (SEQ ID NO: 1). Nucleotide sequences can be obtained. BLAST protein searches can be performed using the XBLAST program. The protein molecules of the present invention were identified using the gram, with a score of 50 and a word length of 3. Homologous amino acid sequences can be obtained. To obtain gapped alignments for comparison purposes, To do this, Gapped BLAST was performed as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402. This can be done as described. When using the BLAST and Gapped BLAST programs, Default parameters for each program (e.g., XBLAST and NBLAST) were used. See www.ncbi.nlm.nih.gov.

[0245] As used herein, the terms "low stringency, medium stringency, high stringency" and "high stringency" refer to "Hybridizes under high stringency or very high stringency conditions" refers to hybridization. This document describes the conditions for ionization and washing. Current Protocols in Molecular Biology, John Wiley & Sons, NY (1989), 6.3.1-6.3.6. Aqueous and Non-Aqueous Methods are described in that reference and either may be used. The hybridization conditions are as follows: 1) Low stringency hybridization The incubation conditions were 6× sodium chloride / sodium citrate (SSC) at approximately 45°C, followed by 0 Wash twice with 2x SSC, 0.1% SDS at least 50°C (the wash temperature is low stringency). 2) Medium stringency hybridization; lysis conditions: 6x SSC at approximately 45°C, followed by 0.2x SSC, 0.1% SDS at 60°C 3) high stringency hybridization conditions, 6x SSC about 45°C, followed by one or more washes in 0.2x SSC, 0.1% SDS at 65°C; and preferably 4) Very high stringency hybridization conditions are 0.5M sodium phosphate 1x wash in 0.2x SSC, 1% SDS at 65°C, followed by 1x wash in 0.2x SSC, 1% SDS at 65°C. Very high stringency conditions (4) are preferred, unless otherwise specified. It should be used accordingly.

[0246] The molecules of the present invention may contain additional conservative or non-essential amino acid substitutions that do not substantially affect function. It is understood that the .lambda.

[0247] The term "amino acid" refers to any amino acid, whether natural or synthetic, containing both an amino functionality and an acid functionality. It is intended to encompass all molecules that have the amino acid sequence and can be incorporated into polymers of naturally occurring amino acids. Examples of amino acids include naturally occurring amino acids, their analogs, derivatives and conjugates. amino acid analogs with variant side chains and all stereoisomers of any of the foregoing. As used herein, the term "amino acid" includes both the D- and L-optical isomers and peptides. Includes do-mimics.

[0248] A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are defined in the art. These families are characterized by basic side chains (e.g., lysine, arginine, histidine). acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycolic acid), sine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, threonine, valine, isoforms of threonine, methionine, tryptophan, beta-branched side chains (e.g., threonine, valine, isoforms of ... soleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, Contains amino acids with a histidine residue.

[0249] The terms "polypeptide," "peptide," and "protein" (if single chain) are used herein. The terms are used interchangeably herein to refer to polymers of amino acids of any length. It may be single or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The term also refers to modifications, such as disulfide bond formation, glycosylation, lipid addition, acetylation, etc. have been subjected to some other manipulation such as deprotection, phosphorylation, or conjugation with a labeling element Polypeptides can be isolated from natural sources, including eukaryotic and non-eukaryotic organisms. or can be produced by recombinant techniques from a prokaryotic host or can be the product of synthetic methods. .

[0250] The terms "nucleic acid," "nucleic acid sequence," "nucleotide sequence," "polynucleotide sequence," and The terms "polynucleotide" and "polynucleotide" are used interchangeably. Polymerization of nucleotides of any length, either nucleotides or ribonucleotides or their analogs A polynucleotide may be single-stranded or double-stranded, and if single-stranded, The polynucleotide may be a coding strand or a non-coding (antisense) strand. The nucleotides may include modified nucleotides such as nucleotides and nucleotide analogs. The sequence may be interrupted by non-nucleotide elements. The polynucleotide may be conjugated to a labeling element. The nucleic acid may be further modified after polymerization, such as by conjugation. DNA or genomic, cDNA, semi-synthetic or other non-naturally occurring or non-naturally occurring sequences. The polynucleotide may be of synthetic origin which is linked to a polynucleotide of the present invention.

[0251] As used herein, the term "isolated" refers to a substance that is free from its original or natural environment (e.g., as naturally occurring). A substance that is removed from its natural environment (e.g., its environment in nature). For example, a naturally occurring substance present in a living animal. The present polynucleotides or polypeptides are not isolated but are naturally occurring due to human intervention. The same polynucleotide or polypeptide isolated from some or all of the coexisting substances in the natural system Such a polynucleotide may be part of a vector and and / or such polynucleotides or polypeptides may be part of a composition, and, since such vectors or compositions are not part of the environment in which they naturally occur, It is still isolated.

[0252] Various aspects of this invention are further described below. Additional definitions are set forth throughout the specification.

[0253] Antigen-presenting combinations, effector cell combinations and anti-tumor immunosuppressive combinations Combination examples Antigen-presenting category (A), effector cell category (B) and antitumor immunosuppressive category Examples of combinations of therapeutic agents from two or more of the following groups are provided herein:

[0254] [Table 1]

[0255] In certain embodiments, the combination of the present invention comprises one or more of the following: A1B1, A1B2, A1B3, A1B4, A1B5, A1B6, A1B7, A1B8, A1B9, A1B10, A1B11, A1B12, A2B1, A2B2, A2B3, A2 B4, A2B5, A2B6, A2B7, A2B8, A2B9, A2B10, A2B11, A2B12, A3B1, A3B2, A3B3, A3B4, A3B5, A3B6, A3B7 , A3B8, A3B9, A3B10, A3B11, A3B12, A4B1, A4B2, A 4B3, A4B4, A4B5, A4B6, A4B7, A4B8, A4B9, A4B10, A4B11, A4B12, A5B1, A5B2, A5B3, A5B4, A5B5, A5B 6, A5B7, A5B8, A5B9, A5B10, A5B11, A5B12, A6B1, A6B2, A6B3, A6B4, A6B5, A6B6, A6B7, A6B8, A6B9, A6B10, A6B11, A6B12, A7B1, A7B2, A7B3, A7B4, A7 B5、A7B6、A7B7、A7B8、A7B9、A7B10、A7B11、A7B12 、A8B1、A8B2、A8B3、A8B4、A8B5、A8B6、A8B7、A8B8 、A8B9、A8B10、A8B11、A8B12、A9B1、A9B2、A9B3、A 9B4、A9B5、A9B6、A9B7、A9B8、A9B9、A9B10、A9B11 、A9B12、A10B1、A10B2、A10B3、A10B4、A10B5、A10 B6、A10B7、A10B8、A10B9、A10B10、A10B11、A10B1 2、A11B1、A11B2、A11B3、A11B4、A11B5、A11B6、A1 1B7、A11B8、A11B9、A11B10、A11B11、A11B12、A1C 1、A1C2、A1C3、A1C4、A1C5、A1C6、A1C7、A1C8、A1C 9、A1C10、A1C11、A1C12、A1C13、A1C14、A1C15、A1 C16、A1C17、A1C18、A1C19、A1C20、A1C21、A2C1、A 2C2、A2C3、A2C4、A2C5、A2C6、A2C7、A2C8、A2C9、A 2C10、A2C11、A2C12、A2C13、A2C14、A2C15、A2C16 、A2C17、A2C18、A2C19、A2C20、A2C21、A3C1、A3C2 、A3C3、A3C4、A3C5、A3C6、A3C7、A3C8、A3C9、A3C1 0、A3C11、A3C12、A3C13、A3C14、A3C15、A3C16、A3 C17、A3C18、A3C19、A3C20、A3C21、A4C1、A4C2、A4 C3、A4C4、A4C5、A4C6、A4C7、A4C8、A4C9、A4C10、A 4C11、A4C12、A4C13、A4C14、A4C15、A4C16、A4C17 、A4C18、A4C19、A4C20、A4C21、A5C1、A5C2、A5C3、 A5C4、A5C5、A5C6、A5C7、A5C8、A5C9、A5C10、A5C1 1、A5C12、A5C13、A5C14、A5C15、A5C16、A5C17、A5 C18、A5C19、A5C20、A5C21、A6C1、A6C2、A6C3、A6C 4、A6C5、A6C6、A6C7、A6C8、A6C9、A6C10、A6C11、A 6C12、A6C13、A6C14、A6C15、A6C16、A6C17、A6C18 、A6C19、A6C20、A6C21、A7C1、A7C2、A7C3、A7C4、A 7C5、A7C6、A7C7、A7C8、A7C9、A7C10、A7C11、A7C1 2、A7C13、A7C14、A7C15、A7C16、A7C17、A7C18、A7 C19、A7C20、A7C21、A8C1、A8C2、A8C3、A8C4、A8C5 、A8C6、A8C7、A8C8、A8C9、A8C10、A8C11、A8C12、A 8C13、A8C14、A8C15、A8C16、A8C17、A8C18、A8C19 、A8C20、A8C21、A9C1、A9C2、A9C3、A9C4、A9C5、A9 C6、A9C7、A9C8、A9C9、A9C10、A9C11、A9C12、A9C1 3、A9C14、A9C15、A9C16、A9C17、A9C18、A9C19、A9 C20、A9C21、A10C1、A10C2、A10C3、A10C4、A10C5、 A10C6、A10C7、A10C8、A10C9、A10C10、A10C11、A1 0C12、A10C13、A10C14、A10C15、A10C16、A10C17、 A10C18、A10C19、A10C20、A10C21、A11C1、A11C2、 A11C3、A11C4、A11C5、A11C6、A11C7、A11C8、A11C 9、A11C10、A11C11、A11C12、A11C13、A11C14、A11 C15、A11C16、A11C17、A11C18、A11C19、A11C20、A 11C21、B1C1、B1C2、B1C3、B1C4、B1C5、B1C6、B1C7 、B1C8、B1C9、B1C10、B1C11、B1C12、B1C13、B1C14 、B1C15、B1C16、B1C17、B1C18、B1C19、B1C20、B1C 21、B2C1、B2C2、B2C3、B2C4、B2C5、B2C6、B2C7、B2 C8、B2C9、B2C10、B2C11、B2C12、B2C13、B2C14、B2 C15、B2C16、B2C17、B2C18、B2C19、B2C20、B2C21、 B3C1、B3C2、B3C3、B3C4、B3C5、B3C6、B3C7、B3C8、 B3C9、B3C10、B3C11、B3C12、B3C13、B3C14、B3C15 、B3C16、B3C17、B3C18、B3C19、B3C20、B3C21、B4C 1、B4C2、B4C3、B4C4、B4C5、B4C6、B4C7、B4C8、B4C 9、B4C10、B4C11、B4C12、B4C13、B4C14、B4C15、B4 C16、B4C17、B4C18、B4C19、B4C20、B4C21、B5C1、B 5C2、B5C3、B5C4、B5C5、B5C6、B5C7、B5C8、B5C9、B 5C10、B5C11、B5C12、B5C13、B5C14、B5C15、B5C16 、B5C17、B5C18、B5C19、B5C20、B5C21、B6C1、B6C2 、B6C3、B6C4、B6C5、B6C6、B6C7、B6C8、B6C9、B6C1 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、A10B9C19、A10B9C20、A10B9C21、A10B10C1、A10 B10C2、A10B10C3、A10B10C4、A10B10C5、A10B10C 6、A10B10C7、A10B10C8、A10B10C9、A10B10C10、A 10B10C11、A10B10C12、A10B10C13、A10B10C14、A 10B10C15、A10B10C16、A10B10C17、A10B10C18、A 10B10C19、A10B10C20、A10B10C21、A10B11C1、A1 0B11C2、A10B11C3、A10B11C4、A10B11C5、A10B11 C6、A10B11C7、A10B11C8、A10B11C9、A10B11C10、 A10B11C11、A10B11C12、A10B11C13、A10B11C14、 A10B11C15、A10B11C16、A10B11C17、A10B11C18、 A10B11C19、A10B11C20、A10B11C21、A10B12C1、A 10B12C2、A10B12C3、A10B12C4、A10B12C5、A10B1 2C6、A10B12C7、A10B12C8、A10B12C9、A10B12C10 、A10B12C11、A10B12C12、A10B12C13、A10B12C14 、A10B12C15、A10B12C16、A10B12C17、A10B12C18 、A10B12C19、A10B12C20、A10B12C21、A11B1C1、A 11B1C2、A11B1C3、A11B1C4、A11B1C5、A11B1C6、A 11B1C7、A11B1C8、A11B1C9、A11B1C10、A11B1C11 、A11B1C12、A11B1C13、A11B1C14、A11B1C15、A11 B1C16、A11B1C17、A11B1C18、A11B1C19、A11B1C2 0、A11B1C21、A11B2C1、A11B2C2、A11B2C3、A11B2 C4、A11B2C5、A11B2C6、A11B2C7、A11B2C8、A11B2 C9、A11B2C10、A11B2C11、A11B2C12、A11B2C13、A 11B2C14、A11B2C15、A11B2C16、A11B2C17、A11B2 C18、A11B2C19、A11B2C20、A11B2C21、A11B3C1、A 11B3C2、A11B3C3、A11B3C4、A11B3C5、A11B3C6、A 11B3C7、A11B3C8、A11B3C9、A11B3C10、A11B3C11 、A11B3C12、A11B3C13、A11B3C14、A11B3C15、A11 B3C16、A11B3C17、A11B3C18、A11B3C19、A11B3C2 0、A11B3C21、A11B4C1、A11B4C2、A11B4C3、A11B4 C4、A11B4C5、A11B4C6、A11B4C7、A11B4C8、A11B4 C9、A11B4C10、A11B4C11、A11B4C12、A11B4C13、A 11B4C14、A11B4C15、A11B4C16、A11B4C17、A11B4 C18、A11B4C19、A11B4C20、A11B4C21、A11B5C1、A 11B5C2、A11B5C3、A11B5C4、A11B5C5、A11B5C6、A 11B5C7、A11B5C8、A11B5C9、A11B5C10、A11B5C11 、A11B5C12、A11B5C13、A11B5C14、A11B5C15、A11 B5C16、A11B5C17、A11B5C18、A11B5C19、A11B5C2 0、A11B5C21、A11B6C1、A11B6C2、A11B6C3、A11B6 C4、A11B6C5、A11B6C6、A11B6C7、A11B6C8、A11B6 C9、A11B6C10、A11B6C11、A11B6C12、A11B6C13、A 11B6C14、A11B6C15、A11B6C16、A11B6C17、A11B6 C18、A11B6C19、A11B6C20、A11B6C21、A11B7C1、A 11B7C2、A11B7C3、A11B7C4、A11B7C5、A11B7C6、A 11B7C7、A11B7C8、A11B7C9、A11B7C10、A11B7C11 、A11B7C12、A11B7C13、A11B7C14、A11B7C15、A11 B7C16、A11B7C17、A11B7C18、A11B7C19、A11B7C2 0、A11B7C21、A11B8C1、A11B8C2、A11B8C3、A11B8 C4、A11B8C5、A11B8C6、A11B8C7、A11B8C8、A11B8 C9、A11B8C10、A11B8C11、A11B8C12、A11B8C13、A 11B8C14、A11B8C15、A11B8C16、A11B8C17、A11B8 C18、A11B8C19、A11B8C20、A11B8C21、A11B9C1、A 11B9C2、A11B9C3、A11B9C4、A11B9C5、A11B9C6、A 11B9C7、A11B9C8、A11B9C9、A11B9C10、A11B9C11 、A11B9C12、A11B9C13、A11B9C14、A11B9C15、A11 B9C16、A11B9C17、A11B9C18、A11B9C19、A11B9C2 0、A11B9C21、A11B10C1、A11B10C2、A11B10C3、A1 1B10C4、A11B10C5、A11B10C6、A11B10C7、A11B10 C8、A11B10C9、A11B10C10、A11B10C11、A11B10C1 2、A11B10C13、A11B10C14、A11B10C15、A11B10C1 6、A11B10C17、A11B10C18、A11B10C19、A11B10C2 0、A11B10C21、A11B11C1、A11B11C2、A11B11C3、A 11B11C4、A11B11C5、A11B11C6、A11B11C7、A11B1 1C8、A11B11C9、A11B11C10、A11B11C11、A11B11C 12、A11B11C13、A11B11C14、A11B11C15、A11B11C 16、A11B11C17、A11B11C18、A11B11C19、A11B11C 20, A11B11C21, A11B12C1, A11B12C2, A11B12C3, A11B12C4, A11B12C5, A11B12C6, A11B12C7, A11B 12C8, A11B12C9, A11B12C10, A11B12C11, A11B12 C 12, A11B12C13, A11B12C14, A11B12C15, A11B12C 16, A11B12C17, A11B12C18, A11B12C19, A11B12C 20 or A11B12C21.

[0256] antibody molecule In some embodiments, the antibody molecule binds to mammalian, e.g., human, PD-1. For example, the antibody molecule may target an epitope of PD-1, e.g., a linear or conformational epitope. specifically binds to (e.g., an epitope described herein).

[0257] As used herein, the term "antibody molecule" refers to a molecule that contains at least one immunoglobulin variable domain. The term "antibody" refers to a protein, such as an immunoglobulin chain or fragment thereof, that contains a sequence. The term "antibody molecule" refers to, for example, a monoclonal antibody (a complete antibody having an immunoglobulin Fc region). In certain embodiments, the antibody molecule comprises a full-length antibody or a full-length immunoglobulin. In some embodiments, the antibody molecule comprises a full-length antibody or a full-length immunoglobulin chain. In some embodiments, the antibody may comprise an antigen-binding or functional fragment of an immunoglobulin chain. In the present invention, the antibody molecule is a multispecific antibody molecule, e.g., a molecule containing multiple immunoglobulin variable domains. wherein a first immunoglobulin variable domain sequence in said plurality comprises a first end a second immunoglobulin variable domain sequence among said plurality, said second immunoglobulin variable domain sequence having binding specificity for said target antigen; has binding specificity for a second epitope. The molecule is a bispecific antibody molecule. A bispecific antibody has specificity for no more than two antigens. A bispecific antibody molecule comprises a first immunoglobulin having binding specificity for a first epitope. a second immunoglobulin having a guanine variable domain sequence and binding specificity for a second epitope; It is characterized by a purine variable domain sequence.

[0258] In some embodiments, the antibody molecule is a monospecific antibody molecule, which binds to a single epitope. For example, multiple immunoglobulin variable domain sequences each binding to the same epitope can be used. A monospecific antibody molecule having

[0259] In some embodiments, the antibody molecule is a multispecific antibody molecule, e.g., it binds multiple immunoglobulins. a first immunoglobulin variable domain sequence in said plurality, The sequence has binding specificity for a first epitope and a second immunoglobulin variable sequence in the plurality. The domain sequence has binding specificity for a second epitope. The first and second epitopes may be located on the same antigen, e.g., the same protein (or multimeric protein). In some embodiments, the first and second epitopes overlap. In some embodiments, the first and second epitopes do not overlap. In the present invention, the first and second epitopes are located on different antigens, e.g., different proteins (or In some embodiments, the multispecific antibody is a multispecific antibody (different subunits of a multimeric protein). The molecule comprises a third, fourth, or fifth immunoglobulin variable domain. Thus, a multispecific antibody molecule may be a bispecific antibody molecule, a trispecific antibody molecule, or a tetraspecific antibody molecule. is.

[0260] In certain embodiments, the multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody molecule has specificity for no more than two antigens. a first immunoglobulin variable domain sequence having binding specificity for a second epitope; The antibody is characterized by a second immunoglobulin variable domain sequence having binding specificity for the antibody. In certain embodiments, the first and second epitopes are located on the same antigen, e.g., the same protein. In some embodiments, the first and The second epitope overlaps. In some embodiments, the first and second epitopes do not overlap. In certain embodiments, the first and second epitopes are different antigens, e.g., different In some embodiments, the proteins are different subunits of a multimeric protein. In this case, a bispecific antibody molecule comprises a heavy chain variable domain that has binding specificity for a first epitope. and a light chain variable domain sequence and a binding specificity for a second epitope. In one embodiment, the antibody comprises a heavy chain variable domain sequence and a light chain variable domain sequence. The heterologous antibody molecule comprises a half antibody having binding specificity for a first epitope and a second epitope. In some embodiments, the bispecific antibody molecule comprises a half antibody having binding specificity for one or more of the following: a half antibody or fragment thereof having binding specificity for a first epitope and a second epitope; The antibody fragments include half antibodies or fragments thereof having binding specificity for two epitopes. In an embodiment, the bispecific antibody molecule comprises a sc antibody having binding specificity for a first epitope. Fv or fragment thereof and scFv having binding specificity for a second epitope or a fragment thereof. In one embodiment, the first epitope is located in PD-1. and the second epitope is TIM-3, LAG-3, CEACAM (e.g., CEACAM -1 and / or CEACAM-5), PD-L1 or PD-L2.

[0261] In certain embodiments, antibody molecules include bispecific antibodies and single chain molecules, as well as antibody Antigen-binding fragments include Fab, F(ab')2, and Fv. For example, antibodies The molecule contains a heavy (H) chain variable domain sequence (abbreviated herein as VH) and a light (L) chain variable domain sequence. In some embodiments, the antibody molecule comprises a heavy chain and a light chain. In other examples, an antibody molecule comprises or consists of two A heavy (H) chain variable domain sequence and two light (L) chain variable domain sequences, thereby forming two antigen-binding sites, e.g., Fab, Fab', F(ab')2, Fc, Fd, Fd', Fv , single chain antibodies (e.g., scFv), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific) and chimeric (e.g., humanized) antibodies, which involve modifications of the whole antibody. or can be synthesized de novo using recombinant DNA technology. These functional antibody fragments retain the ability to selectively bind to their respective antigens or receptors. Antibodies and antibody fragments include IgG, IgA, IgM, IgD, and IgE. Any class of antibody and any subclass of antibody, including but not limited to gE The antibody molecule may be derived from any of the following classes (e.g., IgG1, IgG2, IgG3, and IgG4). The preparations may be monoclonal or polyclonal. The antibody molecules may be human, humanized, or The antibody may be, for example, an IgG1, IgG2, CDR-grafted, or in vitro generated antibody. The antibody may have a heavy chain constant region selected from IgG1, IgG2, IgG3, or IgG4. The term "immunoglobulin" (Ig) refers to a human immunoglobulin that is a globulin that binds to a human immunoglobulin (HIV) and may also have a light chain selected from the group consisting of kappa, lambda, and erythrocyte. is used interchangeably herein with the term "antibody."

[0262] Examples of antigen-binding fragments of antibody molecules include (i) VL, VH, CL and CH1 domains. (ii) a Fab fragment, which is a monovalent fragment consisting of a disulfide bridge in the hinge region; F(ab')2 fragment, a bivalent fragment containing two Fab fragments linked by a bridge (iii) an Fd fragment consisting of the VH and CH1 domains; and (iv) a single antibody fragment. an Fv fragment consisting of the VL and VH domains of the arms, and (v) a VH domain (vi) camelid or camelized variable domains; (vii) diabody (dAb) fragments; ) single-chain Fv (scFv) (e.g. Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883), (viii) single domain These antibody fragments can be obtained using conventional techniques known to those skilled in the art. These fragments are then screened for utility in the same manner as intact antibodies. do.

[0263] The term "antibody" includes intact molecules as well as functional fragments thereof. Regions may be added to modify antibody properties (e.g., Fc receptor binding, antibody glycosylation, cis- (for an increase or decrease in one or more of the following: number of tein residues, effector cell function, or complement function) , may be modified, e.g., mutated.

[0264] The antibody molecule may also be a single domain antibody. A single domain antibody has complementary determining regions. Examples include heavy chain antibodies, naturally occurring light chain antibodies, and antibodies that are part of a single domain polypeptide. antibodies lacking the nucleotide sequence, single domain antibodies derived from conventional four-chain antibodies, engineered antibodies and antibodies other than those derived from antibodies Single domain antibodies include, but are not limited to, single domain scaffolds of the following structure: The single domain antibody may be any current or future single domain antibody. Antibodies include mouse, human, camel, llama, fish, shark, goat, rabbit and bovine, According to another aspect of the present invention, the single domain Antibodies are single domain antibodies known as heavy chain antibodies that lack naturally occurring light chains. Such single domain antibodies are disclosed, for example, in WO9404678. For this reason, this variable domain from a heavy chain antibody that is naturally devoid of light chains is referred to herein as VHH or These VHs are known as nanobodies and are distinct from conventional VHs of four-chain immunoglobulins. The H molecule is found in Camelidae species, e.g. camels, llamas, dromedaries, alpacas and guanacos. Other species outside the Camelidae family naturally produce heavy chain antibodies that lack light chains. Such VHHs are within the scope of the present invention.

[0265] The VH and VL regions are separated by more conserved regions called "framework regions" (FR or FW). They are subdivided into regions of hypervariability called "complementarity determining regions" (CDRs), interspersed with regions of can.

[0266] The extent of the framework regions and CDRs has been precisely defined in a number of ways (K abat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fift h Edition, US Department of Health and Human Services, NIH Publication No. 91- 3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and the AbM definitio n used by Oxford Molecular's AbM antibody modeling software. See, generally, e. g., Protein Sequence and Structure Analysis of Antibody Variable Domains. In: An tibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verl ag, Heidelberg).

[0267] As used herein, the terms "complementarity determining region" and "CDR" refer to regions that provide antigen specificity and binding affinity. The term "antibody variable region" refers to a sequence of amino acids in an antibody variable region that provides affinity. Generally, there are three CDRs (HCDR1, HCDR2, HCDR3) and 3 CDRs (LCD) in each light chain variable region LCDR1, LCDR2, LCDR3).

[0268] The exact amino acid sequence boundaries of a CDR are defined by Kabat et al. (1991), “Sequences of Proteins eins of Immunological Interest,” 5th Ed. Public Health Service, National Institute utes of Health, Bethesda, MD ("Kabat" numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 ("Chothia" numbering scheme), As used herein, the "Chothia" number scheme can be used to determine the number of The CDRs defined by this scheme are sometimes referred to as "hypervariable loops."

[0269] For example, according to Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are 31 to 35 ( HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3). The CDR amino acid residues in the light chain variable domain (VL) are 24 to 34 (LCDR1), 5 Numbered 0-56 (LCDR2) and 89-97 (LCDR3). The CDR amino acids in H are 26-32 (HCDR1), 52-56 (HCDR2), and 9 The amino acid residues in VL are numbered 5 to 102 (HCDR3) and 26 to 32 (LC DR1), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of both Chothia and At, the CDRs are Amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) CDR3) and amino acid residues 24-34 (LCDR1), 50-56 (L It consists of CDR2) and 89 to 97 (LCDR3).

[0270] Generally, unless specifically indicated, anti-PD-1 antibody molecules include, for example, those listed in Table 1. Any combination of the above Kabat CDRs and / or Chothia hypervariable loops may be included. In certain embodiments, the following definitions apply to the anti-PD-1 antibody molecules listed in Table 1: HCDR1 and Kabat CDR1 by the combined Kabat and Chothia CDR definitions. HCCDR2-3 and LCCDR1-3 according to the CDR definition of t. A VL and a VL generally comprise three CDRs and four FRs, and are arranged from the amino terminus to the carboxy terminus as follows: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 arranged in the following order: .

[0271] As used herein, an "immunoglobulin variable domain sequence" refers to an immunoglobulin variable domain sequence. For example, the sequence may be a naturally occurring variable domain. For example, the sequence may include one, two or more It may or may not contain N-terminal or C-terminal amino acids, or the shape of the protein structure. It may contain other modifications that are compatible with the synthesis.

[0272] The term "antigen-binding site" refers to the interface that binds to a PD-1 polypeptide or its epitope. Protein (or protein mimetic) refers to the portion of an antibody molecule that contains determinants that form the The antigen-binding site generally forms an interface that binds with the PD-1 polypeptide. It contains one or more loops (of at least 4 amino acids or amino acid mimetics). The antigen-binding site of a molecule comprises at least one or two CDRs and / or hypervariable loops or more They generally contain at least 3, 4, 5 or 6 CDRs and / or hypervariable loops.

[0273] The terms "compete" or "cross-compete" are used interchangeably herein and refer to the antibody molecules that bind to anti-PD -1 antibody molecules, e.g., targets of the anti-PD-1 antibody molecules provided herein, e.g., human PD- The term "ability to interfere with binding to a target molecule" refers to the ability to interfere with binding to a target molecule. The interference with binding can be direct or indirect (e.g., antibody fragments). The mechanism of action of one antibody molecule on another antibody molecule can be through allosteric modulation of the target or the target. The degree of ability of a compound to interfere with the binding of another compound to its target, and therefore whether it can be said to compete, is determined by the competitive binding assay. Determined using, for example, a FACS assay, ELISA or BIACORE assay In certain embodiments, the competitive binding assay is a quantitative competitive assay. In certain embodiments, the first anti-PD-1 antibody molecule is selected from the group consisting of antibodies against PD-1, PD-2, PD-3, PD-4, PD-5, PD-6, PD-7, PD-8, PD-9, PD-10, PD-11, PD-12, PD-13, PD-14, PD-15, PD-16, PD-17, PD-18, PD-19, In a competitive assay described above, the binding of the first antibody molecule to the target is 10% or more. , for example, 20% or more, 30% or more, 40% or more, 50 % or more, 55% or more, 60% or more, 65% or more above, 70% or more, 75% or more, 80% or more, 85% or more or more, 90% or more, 95% or more, 98% or more, 9 If the antibody is reduced by 9% or more, it will compete with the binding of the second anti-PD-1 antibody molecule to its target. It can be said that.

[0274] As used herein, the terms "monoclonal antibody" and "monoclonal antibody composition" refer to a single antibody. A monoclonal antibody composition is a preparation of antibody molecules of a molecular composition. Monoclonal antibodies exhibit a single binding specificity and affinity for a specific target molecule. Methods that do not use chemistry or hybridoma technology (e.g., recombinant methods).

[0275] An "effectively human" protein is one that induces a neutralizing antibody response, e.g., a human anti-mouse antibody (HAMA) response. HAMA is a protein that does not induce inflammatory bowel disease. HAMA is useful, for example, in the treatment of chronic or recurrent disease states. In many situations, for example, repeated administration of antibody molecules can be problematic. MA responses are due to serum antibody clearance and also to the possibility of allergic reactions (e.g. (See LoBuglio et al., Hybridoma, 5:5117-5123 (1986)) (e.g., Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)).

[0276] The antibody molecule can be a polyclonal or monoclonal antibody. Thus, antibodies can be produced recombinantly, for example, by phage display or combinatorial methods. It can be produced by the method.

[0277] Phage display and combinatorial methods for producing antibodies are well known in the art. It is known (e.g., Ladner et al., U.S. Pat. No. 5,223,409; Kang et al., International Publication WO92 / 18619; Dower et al. WO91 / 17271; Winter et al. l. International Publication No. WO92 / 20791; Markland et al. International Publication No. WO92 / 15679 Breitling et al. International Publication No. WO93 / 01288 McCafferty et al. International Publication No. WO92 / 01047; Garrard et al. WO92 / 09690; Ladner et al. Fuchs et al. (1991) Bio / Technology 9:1370-137 2; Hay et al. (1992) Hum Antibody Hybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffths et al. (1993) EMBO J 12:725-734; Hawkins et al. (1992) J Mol Biol 226:889-896; Clackson et al. (1991) Nature 352:624-628; Gram et al. 1992) PNAS 89:3576-3580; Garrad et al. (1991) Bio / Technology 9:1373-1377; Hoogen Boom et al. (1991) Nuc Acid Res 19:4133-4137; and Barbas et al. (1991) PNAS 88: 7978-7982, the contents of which are incorporated herein by reference).

[0278] In some embodiments, the antibody is a fully human antibody (e.g., an antibody derived from a human immunoglobulin sequence). antibodies produced in mice that have been genetically engineered to produce antibodies) or non-human antibodies For example, rodent (mouse or rat), goat, primate (e.g., monkey), camel antibody. Preferably, the non-human antibody is a rodent (mouse or rat) antibody. Methods for production are known in the art.

[0279] Human monoclonal antibodies carry human immunoglobulin genes rather than the murine system These transgenic mice can be produced by immunizing them with an antigen of interest. Splenocytes from transgenic mice were used to identify epitopes specific to human proteins. Hybridomas secreting human mAbs with a specific affinity are produced (see, e.g., Wood et al. al. International Application WO91 / 00906, Kucherlapati et al. PCT Publication WO91 / 1 0741; Lonberg et al. International Application WO92 / 03918; Kay et al. International Application 9 No. 2 / 03917; Lonberg, N. et al. 1994 Nature 368:856-859; Green, LL et al. 1994 Nature Genet. 7:13-21; Morrison, SL et al. 1994 Proc. Natl. Acad. Sci. U SA 81:6851-6855; Bruggeman et al. 1993 Year Immunol 7:33-40; Tuaillon et al. 199 3 PNAS 90:3720-3724; see Bruggeman et al. 1991 Eur J Immunol 21:1323-1326).

[0280] The antibody may be a human antibody in which the variable region or a portion thereof, e.g., the CDR, is derived from a non-human organism, e.g., a rat or Chimeric, CDR-grafted and humanized antibodies may be produced in the mouse or mouse. It is within the scope of the invention to produce a non-human organism, e.g., a rat or a mouse, and then For example, the variable framework or constant regions may be modified to reduce antigenicity in humans. Antibodies modified for this purpose are within the scope of the present invention.

[0281] Chimeric antibodies can be produced by recombinant DNA techniques known in the art (Robinson et al. al., International Patent Publication No. PCT / US86 / 02269; Akira, et al., European Patent Application No. 84,187; Taniguchi, M., European Patent Application No. 171,496; Morrison et al., European Patent Application No. 173,494; Neuberger et al., International Application No. WO86 / 01533; Cabil ly et al., U.S. Patent No. 4,816,567; Cabilly et al., European Patent Application No. 125,023 No.;Better et al. (1988 Science 240:1041-1043); Liu et al. (1987) PNAS 84:3439-3 443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al. (1987) PNAS 84:214- 218; Nishimura et al., 1987, Canc. Res. 47:999-1005; Wood et al. (1985) Nature 3 14:446-449; and Shaw et al., 1988, J. Natl Cancer Inst. 80:1553-1559).

[0282] Humanized or CDR-grafted antibodies have at least one or more CDRs replaced by donor CDRs. 2, but generally all 3 recipient CDRs (of the heavy and / or light immunoglobulin chains) The antibody may have at least a portion of a non-human CDR replaced or Only a portion of the CDRs may be replaced with non-human CDRs. It is only necessary to replace the required number of CDRs. Preferably, the donor is a rodent antibody. For example, rat or mouse antibodies, the recipient may have a human framework or Generally, the immunoglobulins that provide the CDRs are The immunoglobulin that provides the framework is called the "donor" and the immunoglobulin that provides the framework is called the "acceptor." In certain embodiments, the donor immunoglobulin is non-human (e.g., rodent). The acceptor framework may be a naturally occurring (e.g., human) framework or Consensus Framework or about 85% or more thereof, preferably 90%; These are sequences that are 95%, 99% or more identical.

[0283] As used herein, the term "consensus sequence" refers to the most frequent sequence in a family of related sequences. The term "sequence" refers to the sequence formed from the amino acids (or nucleotides) that appear in a sequence (e.g., Winnaker, Fro Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family of Occupied by the most frequently occurring amino acid. If two amino acids occur equally frequently, Any of these may be included in the consensus sequence. The term "framework region" refers to a framework region in a human immunoglobulin sequence.

[0284] Antibodies can be humanized by methods known in the art (see, e.g., Morrison, SL, 1985 , Science 229:1202-1207, Oi et al., 1986, BioTechniques 4:214 and Queen et al. See US 5,585,089, US 5,693,761 and US 5,693,762. the contents of all of which are incorporated herein by reference).

[0285] Humanized or CDR-grafted antibodies can be produced by CDR-grafting or CDR-substitution, wherein In some cases, one, two, or all of the CDRs of an immunoglobulin chain can be replaced. No. 5,225,539, expressly incorporated herein by reference; Jones et al. 1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239:1534; Beidler et al. 1988 J. Immunol. 141:4053-4060; Winter US Pat. No. 5,225,539. Winter, (March 26, 1987) describes a CDR grafting method that can be used to produce the humanized antibodies of the invention. UK patent application GB2188638A filed on the same day; Winter US5,225,539), The contents of which are expressly incorporated herein by reference.

[0286] Also within the scope of the present invention are human lysates in which specific amino acids have been substituted, deleted or added. The criteria for selecting amino acids from the donor are described in US Pat. No. 5,585,089, e.g. For example, see columns 12-16 of US Pat. No. 5,585,089, the contents of which are incorporated herein by reference. Other techniques for antibody humanization are described in Pa., 2002, published December 23, 1992. dlan et al., EP519596A1.

[0287] The antibody molecule may be a single chain antibody. Single chain antibodies (scFV) may be engineered (e.g., C olcher, D. et al. (1999) Ann NY Acad Sci 880:263-80; and Reiter, Y. (1996) Cli (See Cancer Res 2:245-52.) Single-chain antibodies can be dimerized or multimerized to target the same target protein. Multivalent antibodies can be produced that have specificity for different epitopes of a protein.

[0288] In yet other embodiments, the antibody molecule is, for example, an IgG1, IgG2, IgG3, A heavy chain constant region selected from IgG4, IgM, IgA1, IgA2, IgD, and IgE. In particular, for example, IgG1, IgG2, IgG3 and IgG4 (e.g., human) heavy In other embodiments, the antibody molecule comprises a heavy chain constant region selected from: For example, a light chain constant region selected from a kappa or lambda (e.g., human) light chain constant region. The constant region is used to modify the properties of the antibody molecule (e.g., Fc receptors). binding, antibody glycosylation, number of cysteine ​​residues, effector cell function and / or complement The polypeptide can be modified, e.g., mutated, to increase or decrease one or more of its functions. In another embodiment, the antibody has effector function and can fix complement. does not recruit effector cells or fix complement. have reduced or no ability to bind to Fc receptors, e.g., Fc receptors isotype or subtype, fragment or other variant that does not support binding to For example, the Fc receptor binding region has been mutagenized or deleted.

[0289] Methods for modifying antibody constant regions are known in the art. have altered affinity for effector ligands such as FcR or the C1 component of complement The antibody may be modified by replacing at least one amino acid residue in the constant portion of the antibody with a different residue. (See, for example, EP 388,151 A1, U.S. Pat. No. 5,624,821 and See U.S. Patent No. 5,648,260, the entire contents of which are incorporated herein by reference. If similar types of modifications were applied to immunoglobulins in mice or other species, This would reduce or eliminate these functions.

[0290] Antibody molecules may be derivatized with other functional molecules (e.g., other peptides or proteins). As used herein, a "derivatized" antibody molecule is one that has been modified or conjugated. Derivatization methods include fluorescent moieties, radionucleotides, toxins, enzymes, or This includes, but is not limited to, the addition of an affinity ligand such as ribonucleotide or biotin. The antibody molecules of interest include derivatized and otherwise modified antibodies described herein, including immunoadhesion molecules. For example, antibody molecules may be used in combination with other antibodies (e.g., bispecific or bispecific antibodies). antibody), detectable agent, cytotoxic agent, drug and / or antibody or antibody portion with other molecules Proteins or peptides that can mediate binding (e.g., streptavidin core domain or to one or more other molecules (e.g., a polystidine tag) (chemical coupling, genetic fusion, non-covalent operably linked (by bond or otherwise).

[0291] One type of derivatized antibody molecule is a compound that combines the same type of antibody molecules (e.g., to produce bispecific antibodies). It is produced by cross-linking two or more antibodies (of different types or groups). is provided with an appropriate spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimide). amide ester) or homobifunctional (e.g., disuccinimidyl suberate) Such linkers include heterobifunctional linkers with two distinct reactive groups. Available from Pierce Chemical Company, Rockford, Ill.

[0292] Useful detectable agents with which the antibody molecules of the invention may be derivatized (or labeled) include fluorescent compounds. substances, various enzymes, prosthetic groups, luminescent substances, bioluminescent substances, luminescent metal atoms, e.g., Includes pium (Eu) and other lanthanides and radioactive materials (see below). Examples of agents are fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethyl ethylamine-1-naphthalenesulfonyl chloride, phycoerythrin, etc. Antibodies Also, alkaline phosphatase, horseradish peroxidase, β-galactosidase Derivatized with detectable enzymes such as acetylcholinesterase, glucose oxidase, and When an antibody is derivatized with a detectable enzyme, the enzyme produces a detectable reaction product. The detection is achieved by the addition of additional reagents used to produce the detectable agent. When radish peroxidase is present, hydrogen peroxide and diaminobenzidine The addition results in a colored reaction product that can be detected. It is also derivatized with other groups (e.g., streptavidin / biotin and avidin / biotin). For example, antibodies can be derivatized with biotin and attached to avidin or streptavidin-conjugated antibodies. Detection can be achieved by indirect measurement. Examples of suitable fluorescent substances are umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein Examples of luminescent materials include olescein, dansyl chloride, or phycoerythrin. Examples of bioluminescent substances include luciferase, luciferin, and aequoris. Includes

[0293] The labeled antibody molecules can be isolated by standard techniques such as, for example, (i) affinity chromatography or immunoprecipitation. (ii) isolating predetermined antigens by techniques; and (iii) protein abundance and expression patterns. Detect a predetermined antigen to assess (e.g., in a cell lysate or cell supernatant) (iii) as part of a clinical trial procedure, for example, to determine the efficacy of a treatment regimen The present invention has diagnostic and therapeutic applications in a number of settings, including monitoring protein levels in tissues using immunoassays. may be used experimentally and / or experimentally.

[0294] The antibody molecule may be coupled to other molecules, generally labeled or therapeutic (e.g., cytotoxic or cytostatic) Radioisotopes can be conjugated to an agent or moiety for use in diagnostic or therapeutic applications. It can be used.

[0295] The present invention provides radiolabeled antibody molecules and methods for labeling the same. In one embodiment, A method for labeling an antibody molecule is disclosed. The method comprises contacting the antibody molecule with a chelating agent, This includes producing a conjugated antibody.

[0296] As described above, the antibody molecule may be conjugated to a therapeutic agent. Other examples of therapeutic agents include taxol, cytochalasin B, gramicidin, D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincris vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxybenzoates Ithranthracindione, mitoxantrone, mithramycin, actinomycin D, 1-dehyd Doxorotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, procaine lopranolol, puromycin, maytansinoids, e.g., maytansinol (e.g., See, for example, U.S. Patent No. 5,208,020), CC-1065 (see, for example, U.S. Patent No. 5,475, 092, 5,585,499, 5,846,545) and analogs thereof Therapeutic agents include antimetabolites (e.g., methotrexate, 6-mercapto Purine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkyl anti-inflammatory drugs (e.g., mechlorethamine, thiotepa, chlorambucil, CC-1065, melphalan) Ran, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, bs fluphen, dibromomannitol, streptozocin, mitomycin C and cis- dichlorodiamineplatinum(II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin, rubicin (formerly daunomycin and doxorubicin), antibiotics (e.g., dactinoma isin (formerly actinomycin), bleomycin, mithramycin, and anthramycin anti-mitotic drugs (e.g., vincristine, vinblastine, taxanes, etc.) These include, but are not limited to, benzodiazepines (benzodiazepines, benzodiazepines, and maytansinoids).

[0297] In some embodiments, the present invention provides antibodies specific for a target disclosed herein, e.g., the PD-1 receptor. For example, the target binding molecule is an antibody molecule. The method provides a target protein comprising at least a portion of a non-human protein ( The portion is homologous (at least 70%, 75%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 30 %, 85%, 87%, 90%, 92%, 94%, 95%, 96%, 97%, 98% identical) but at least one amino acid (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8 and obtaining antibody molecules that specifically bind to the antigen, each of which differs by 9 or 10 amino acids, and then targeting the antibody molecules. The method includes assessing the effectiveness of the binding agent in modulating the activity of the protein. antibody molecule) or derivatives (e.g., humanized antibody molecules) to a human subject. It may further include:

[0298] multispecific antibody molecules In certain embodiments, the antibody molecule is a multispecific (e.g., bispecific or trispecific) antibody. Protocols for producing bispecific or heterodimeric antibody molecules are known in the art. "Knob-in-hole" means are known and are described, for example, in US Pat. No. 5,731,168; e.g. WO09 / 089004, WO06 / 106905 and WO2010 / 129304 electrostatically induced Fc pairing as described in, for example, WO07 / 110205; Main (SEED) heterodimer formation; see, for example, WO08 / 119353 and WO2011 Fab arm exchange, e.g., as described in WO2013 / 060867 and WO2013 / 061746; For example, those described in US Pat. No. 4,433,059, which contain, for example, amine-reactive groups and sulfhydryl-reactive groups, Antibody Cross-Linking to Produce Bispecific Structures Using Heterobifunctional Reagents with Reactive Groups double antibody conjugates by ligation; for example, the interchain ligation described in US Pat. No. 4,444,878 Half-antibodies (heavy-light) from different antibodies are produced by cycles of reduction and oxidation of the disulfide bonds of the Production of bispecific antibody determinants by recombination of antibody chain pairs (Fab); see, e.g., US52737 43, e.g., trifunctional antibodies, such as 3Fa cross-linked by sulfhydryl-reactive groups. b' fragments; for example, as described in US 5,534,254, biosynthetic binding proteins, e.g. For example, preferably by C-terminal tail via disulfide or amine reactive chemical cross-linking. a pair of cross-linked scFvs; for example, bifunctional antibodies, e.g., as described in US5582996; For example, leucine zippers with substituted constant domains (e.g., c-fos and c-ju n) Fab fragments with different binding specificities dimerized by Bispecific and oligospecific monovalent and oligovalent receptors, such as those described in US Pat. No. 5,918,288, e.g. For example, between the CH1 region of one antibody and the VH region of another antibody, generally with the associated light chain. VH-CH1 of two antibodies (two Fab fragments) linked by a polypeptide spacer domains; for example, bispecific DNA-antibody conjugates as described in US 5,635,602; For example, cross-linking of antibodies or Fab fragments with double-stranded fragments of DNA; Bispecific fusion proteins, such as two scFvs and a parent molecule therebetween, as described in US Pat. No. 5,637,481. An expression construct comprising an aqueous helical peptide linker and a complete constant region; e.g., US58 37242, multivalent and multispecific binding proteins, e.g., Ig heavy chain variable regions. a first domain having a binding region of an Ig light chain variable region and a second domain having a binding region of an Ig light chain variable region; Dimers of polypeptides (bispecific, trispecific, Higher order structures are also disclosed to create heterospecific or tetraspecific molecules; see, e.g., US58 37821, and further comprising a peptide spacer to the antibody hinge and CH3 regions to form bispecific / multivalent molecules a minibody that can be dimerized into a short peptide linker (e.g., 5 or 10 amino acids); linked in either orientation with or without a linker to form bispecific diabodies. VH and VL domains that can dimerize to form VH and VL domains; for example, those described in US 5,844,094 trimers and tetramers described in, for example, US Pat. No. 5,864,019; The peptide is then coupled to a C-terminal crosslinkable group further attached to the VL domain to form a scFv. VH domains (or VL domains within family members) connected by peptide bonds and scFV or bispecific FVs, as described, for example, in US Pat. No. 5,869,620. using a monoclonal antibody-type format, e.g., VH and VH linked by a peptide linker Both L domains have non- Single-chain binding polypeptides assembled into multivalent structures by covalent bonds or chemical crosslinks, e.g. Examples include, but are not limited to, multispecific and bispecific molecules and methods for producing the same. Further examples of methods are described, for example, in US5910573, US5932448, US59 No. 59083, No. US5989830, No. US6005079, No. US6239259, US6294353, US6333396, US6476198, US65116 No. 63, No. US6670453, No. US6743896, No. US6809185, US6 No. 833441, No. US7129330, No. US7183076, No. US7521056 , US7527787, US7534866, US7612181, US2002 / 004587A1, US2002 / 076406A1, US2002 / 10334 5A1, US2003 / 207346A1, US2003 / 211078A1, U S2004 / 219643A1, US2004 / 220388A1, US2004 / No. 242847A1, US2005 / 003403A1, US2005 / 004352 A1, US2005 / 069552A1, US2005 / 079170A1, US 2005 / 100543A1, US2005 / 136049A1, US2005 / 1 No. 36051A1, US2005 / 163782A1, US2005 / 266425A No. 1, US2006 / 083747A1, US2006 / 120960A1, US2 006 / 204493A1, US2006 / 263367A1, US2007 / 00 No. 4909A1, US2007 / 087381A1, US2007 / 128150A1 No., US2007 / 141049A1, US2007 / 154901A1, US20 07 / 274985A1, US2008 / 050370A1, US2008 / 069 No. 820A1, No. US2008 / 152645A1, No. US2008 / 171855A1 、US2008 / 241884A1、US2008 / 254512A1、US200 8 / 260738A1, US2009 / 130106A1, US2009 / 1489 05A1, US2009 / 155275A1, US2009 / 162359A1, US2009 / 162360A1, US2009 / 175851A1, US2009 / 175867A1, US2009 / 232811A1, US2009 / 23410 5A1, US2009 / 263392A1, US2009 / 274649A1, E No. P346087A2, No. WO00 / 06605A2, No. WO02 / 072635A2, WO04 / 081051A1, WO06 / 020258A2, WO2007 / 044 No. 887A2, No. WO2007 / 095338A2, No. WO2007 / 137760A2 , WO2008 / 119353A1, WO2009 / 021754A2, WO200 No. 9 / 068630A1, No. WO91 / 03493A1, No. WO93 / 23537A1, WO94 / 09131A1, WO94 / 12625A2, WO95 / 09917A1 No. WO96 / 37621A2, WO99 / 64460A1. The contents of the above references are incorporated herein by reference in their entirety.

[0299] In other embodiments, the anti-PD-1 antibody molecule (e.g., monospecific, bispecific, or multispecific) The antibody molecule (antibody molecule) may be a molecule that binds to another partner, e.g., a protein, e.g., one, two or more and the above cytokines, for example, as a fusion molecule, e.g., a fusion protein, by covalent bonding, e.g., In other embodiments, the fusion molecule comprises one or more proteins, e.g., In certain embodiments comprising one, two or more cytokines, the cytokines are one of interleukin (IL)-1, IL-2, IL-12, IL-15, or IL-21; In one embodiment, the bispecific antibody is an IL selected from two, three, or more. The molecule has a first binding specificity for a first target (e.g., PD-1), a second binding specificity for a second target (e.g., LAG- 3 or TIM-3), and optionally a second binding specificity for an interleukin (e.g., IL-12) domain, e.g., full-length IL-12 or a portion thereof.

[0300] "Fusion proteins" and "fusion polypeptides" refer to at least two polypeptides covalently linked together. A polypeptide having multiple portions, each of which has a different property. The properties are biological properties such as in vitro or in vivo activity. The property can be a simple chemical or physical property, such as binding to a target molecule or catalyzing a reaction. The two moieties can be joined directly by a single peptide bond or by a peptide linker. Yes, but they are in reading frame with each other.

[0301] The present invention includes isolated nucleic acid molecules encoding the antibody molecules, vectors and host cells thereof. Nucleic acid molecules include, but are not limited to, RNA, genomic DNA, and cDNA. .

[0302] Examples of drugs used in combination Described herein are agents that (i) enhance antigen (e.g., tumor antigen) presentation, (ii) enhance effector activity, and (iii) enhance tumor cell proliferation. Enhancement of receptor cell responses (e.g., B cell and / or T cell activation and / or recruitment) or (iii) a combination of one or more agents that reduce tumor immunosuppression, and compositions for treating disorders, such as hyperproliferative conditions or disorders (e.g., cancer) using In some embodiments, the combination includes a PD-1 inhibitor (e.g., a PD-1 inhibitor described herein). Examples of drugs that can be used in these combinations include: Provided here.

[0303] Examples of STING agonists In some embodiments, the combination includes a STING agonist. The combination is administered to treat cancer, e.g., a cancer described herein, e.g., a solid tumor (e.g., breast cancer, Squamous cell carcinoma, melanoma, ovarian cancer, fallopian tube cancer, peritoneal cancer, soft tissue sarcoma, esophageal cancer, head and neck cancer, endometrial cancer, cervical cancer or basal cell carcinoma), hematological tumors (e.g., leukemia (e.g., Chronic lymphocytic leukemia (CLL) or lymphoma (e.g., marginal zone B-cell lymphoma, small lymphoma) It is used to treat mycobacterial lymphoma, follicular lymphoma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. In certain embodiments, the cancer is head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC) ), skin cancer (e.g., melanoma), lung cancer (e.g., non-small cell lung cancer (NSCLC)), or breast cancer (e.g., For example, triple-negative breast cancer (TNBC).

[0304] In certain embodiments, the STING agonist is a cyclic dinucleotide, e.g., a purine dinucleotide. adenine or pyrimidine nucleobases (e.g., adenosine, guanine, uracil, thymine or In some embodiments, the cyclic dinucleotide is a cyclic dinucleotide containing a cytosine nucleobase. The nucleobases of the nucleotides may comprise the same nucleobase or different nucleobases.

[0305] In certain embodiments, the STING agonist is an adenosine or guanosine nucleoside. In certain embodiments, the STING agonist comprises one adenosine nucleobase and and one guanosine nucleobase. In certain embodiments, the STING agonist comprises two nucleobases. Contains adenosine nucleobase or two guanosine nucleobases.

[0306] In certain embodiments, the STING agonist may comprise, for example, a modified nucleobase, a modified ribonucleotide, or a In some embodiments, the dinucleotides include modified cyclic dinucleotides containing a cyclic nucleotide or modified phosphate linkage. In the present invention, the modified cyclic dinucleotide has a modified phosphate linkage, e.g., a thiophosphate Includes:

[0307] In certain embodiments, the STING agonist comprises a 2',5' or 3',5' phosphate group. cyclic dinucleotides having a cyclic bond (e.g., modified cyclic dinucleotides). In embodiments, the STING agonist has an Rp or Sp stereochemistry around the phosphate bond. The present invention also includes cyclic dinucleotides having the following chemistries (e.g., modified cyclic dinucleotides).

[0308] In certain embodiments, the STING agonist is Rp,Rp dithio 2',3' c-di -AMP (e.g., Rp,Rp-dithio c-[A(2',5')pA(3',5')p]) or In one embodiment, the STING agonist is a cyclic dinucleotide analog of , U.S. Patent Publication US2015 / 0056224 (e.g., the compound in FIG. 2c, e.g., In some embodiments, S is a compound described in TING agonists include c-[G(2',5')pG(3',5')p], its dithioribose O Substituted derivatives or PCT Publications WO2014 / 189805 and WO2014 / 189 4 of US Pat. No. 806. In one embodiment, the STING agonist is , c-[A(2',5')pA(3',5')p] or its dithioribose O-substituted derivatives, or Figure 5 in PCT Publications WO2014 / 189805 and WO2014 / 189806 In one embodiment, the STING agonist is a compound described in ',5')pA(3',5')p] or its dithioribose O-substituted derivatives or PCT publication W The compounds shown in Figure 5 of WO2014 / 189805 and WO2014 / 189806 In one embodiment, the STING agonist is 2'-O-propargyl -cyclic-[A(2',5')pA(3',5')p](2'-O-propargyl-ML-CDA) or a compound described in Figure 7 of PCT Publication WO2014 / 189806.

[0309] Other examples of STING agonists are described, for example, in PCT Publication WO2014 / 189805. and those disclosed in WO2014 / 189806 and U.S. Publication No. 2015 / 0056225. can be.

[0310] Examples of TLR agonists In some embodiments, the combinations described herein comprise a toll-like receptor (TLR) agonist. In some embodiments, the combination is administered to treat cancer, e.g., a cancer described herein, e.g., For example, solid tumors (e.g., breast cancer, squamous cell carcinoma, melanoma, ovarian cancer, fallopian tube cancer, peritoneal cancer, soft tissue cancer, tissue sarcoma, esophageal cancer, head and neck cancer, endometrial cancer, cervical cancer or basal cell carcinoma), e.g., blood tumors (e.g., leukemia (e.g., chronic lymphocytic leukemia (CLL)) or lymphoma (e.g., Marginal zone B-cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma It is used to treat Johnson & Johnson lymphoma.

[0311] TLRs were originally identified as sensors of the innate immune system that recognize microbial pathogens. TLRs are a family of immune-recognizing receptors. In humans, TLRs are TLR-1, TLR-2, and TLR-3. , TLR-3, TLR-4, TLR-5, TLR-6, ​​TLR-7, TLR-8, TLR TLR-1, -2, -4, -5, and -6 are expressed on the cell surface. TLR-3, -7 / 8 and -9 are expressed in association with the ER compartment. Cell subsets can be identified based on distinct TLR expression patterns. The "conventional" subset of dendritic cells expresses TLRs 1-8, whereas the plasmacytoid subset of dendritic cells Only TLR-7 and TLR-9 are expressed. Ligand binding to TLRs mediates inflammation and immunity. This triggers a cascade of intracellular signaling pathways that induce the production of factors involved in the stimulation. The myeloid and plasmacytoid subsets of human dendritic cells were identified as NK cells, respectively. Antigen-specific CD4 on cytoplasmic and T cells + and CD8 + T cell priming and activation results.

[0312] In certain embodiments, the TLR agonist is a TLR-1 agonist, a TLR-2 agonist, or a TLR-3 agonist. agonist, TLR-3 agonist, TLR-4 agonist, TLR-5 agonist, TLR -6 agonist, TLR-7 agonist, TLR-8 agonist, TLR-9 agonist , TLR-10 agonist, TLR-1 / 2 agonist, TLR-2 / 6 agonist or is selected from one or more TLR-7 / 8 agonists. The agonist is a TLR7 agonist.

[0313] In certain embodiments, the TLR agonist is imiquimod or 3-(2-methylpropyl) Pyr)-3,5,8-triazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4, 7,10,12-Hexaen-7-amine. Imiquimod or 3-(2-methylpropyl) Pyr)-3,5,8-triazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4, 7,10,12-Hexaen-7-amine binds to TLR-7 and / or TLR-8 and can be activated.

[0314] In one embodiment, the TLR agonist is 852A. 852A can be, for example, Inglefield et al. J Interferon Cytokine Res. 2008;28(4):253-63. 85 2A can bind to and activate TLR-7 and / or TLR-8.

[0315] In certain embodiments, the TLR agonist is Bacillus Calmette-Guerin (BCG). BCG can bind to and activate TLR-9.

[0316] In one embodiment, the TLR agonist is EMD 120108. EMD 120108 is a synthetic oligonucleotide containing phosphorothioate oligodeoxynucleotides. EMD 1201081 is a compound that inhibits, for example, monocytes / macrophages, plasma cells, It binds to TLR-9 on dendritic cells (DCs) and B cells, activates them, and mediates immune signaling. Initiating the proliferation pathway, activating B cells, and inducing T helper cell cytokine production This can be done.

[0317] In one embodiment, the TLR agonist is IMO-2055. 55 is a synthetic oligonucleotide containing unmethylated CpG dinucleotides. By mimicking the unmethylated CpG sequence in A, IMO-2055 is able to e.g. Binding to TLR-9 on monocytes / macrophages, plasmacytoid dendritic cells (DCs), and B cells They bind to and activate immune cells, initiating immune signaling pathways that activate B cells and DCs, and T It can induce helper cell cytokine production.

[0318] Other examples of TLR agonists that can be used in combination include, for example, TLR-1 / 2 agonists (e.g., Pam3Cys), TLR-2 agonists (e.g., CFA, MAL P2, Pam2Cys, FSL-1 or Hib-OMPC), TLR-3 agonists (e.g. For example, polyriboinosine:polyribocytidylic acid (poly I:C), polyadenosine-polyuri Stabilized with diamethylenediaminetetraacetic acid (polyAU), poly-L-lysine, and carboxymethylcellulose Polyinosinic-polycytidylic acid (Hiltonol®), TLR-4 agonists (e.g., Monophosphoryl lipid A (MPL), LPS, sialyl-Tn (STn), TLR-5 agonist anti-inflammatory drugs (e.g., bacterial flagellin), TLR-7 agonists (e.g., imiquimod), TLR- 7 / 8 agonists (e.g., resiquimod or loxoribine) and TLR-9 agonists (e.g., unmethylated CpG dinucleotides (CpG-ODN)).

[0319] In other embodiments, TLR agonists are used, for example, as described in WO2004060319 and and in combination with a GITR agonist as described in International Publication No. WO2014012479, Use.

[0320] Examples of VEGFR inhibitors In some embodiments, the combinations described herein include vascular endothelial growth factor (VEGF). F) receptor inhibitors (e.g., VEGFR (e.g., VEGFR-1, VEGFR-2, VE In some embodiments, the combination comprises one or more inhibitors of VEGF (e.g., GFR-3) or VEGF. The present invention relates to a cancer, e.g., a cancer described herein, e.g., a solid tumor (e.g., melanoma, breast cancer, colon cancer, Cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), kidney cancer (e.g., renal cell carcinoma), liver cancer, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer or gastric cancer), hematological tumors (e.g. It is used to treat cancer (e.g., lymphoma).

[0321] In certain embodiments, the VEGFR inhibitor is vatalanib succinate (compound A47) or or the compounds disclosed in EP296122.

[0322] In certain embodiments, the VEGFR inhibitor is VEGFR-2, PDGFRbeta, one or more inhibitors of KIT or Raf kinase C, 1-methyl-5-((2-(5-(trifluoromethyl)-2-methyl-2-propanol, (fluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4 -(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine (compound A37) or the compounds disclosed in PCT Publication WO2007 / 030377.

[0323] Other examples of VEGFR pathway inhibitors that can be used in the combinations disclosed herein include, for example, For example, bevacizumab (Avastin®), axitinib (Inlyta®); Vanillin alaninate (BMS-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl- 1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine (N-6-yloxy)propan-2-yl)2-aminopropanoate); sorafenib (N- Xavar®); pazopanib (Votrient®); sunitinib malate ( Sutent®); cediranib (AZD2171, CAS 288383-20-1); vargatef (BIBF1120 , CAS 928326-83-4); foretinib (GSK1363089); telatinib (BAY57-9352, CAS 332012- 40-5); apatinib (YN968D1, CAS 811803-05-1); imatinib (Gleevec®); Ponatinib (AP24534, CAS 943319-70-8); Tivozanib (AV951, CAS 475108-18-0); Regola Phenib (BAY73-4506, CAS 755037-03-7); Vatalanib dihydrochloride (PTK787, CAS 212141-51- 0); brivanib (BMS-540215, CAS 649735-46-6); vandetanib (Caprelsa® or or AZD6474; motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro -3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amine

[0033] -3-pyridinecarboxamide, as described in PCT Publication No. WO 02 / 066470; Dovitinib (TKI258, CAS 852433-84-2); Linifanib (ABT869, CAS 796967-16-3); Bozantinib (XL184, CAS 849217-68-1); Lestaurtinib (CAS 111358-88-4); N-[5 -[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl] -4-Piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-Amino No-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazine N-(3,4-dichloro-2-phenyl-5-yl)methyl)piperidin-3-ol (BMS690514); -fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2 -Methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647 , CAS 781613-23-8);4-methyl-3-[[1-methyl-6-(3-pyridinyl)-1H- Pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)furan [phenyl]-benzamide (BHG712, CAS 940310-85-0); aflibercept (Eylea (registered) ) and endostatin (ENDOSTAR®).

[0324] Examples of anti-VEGF antibodies that can be used in the combinations disclosed herein include, for example, Presta Recombinant humanized anti-VEGF produced by NIH et al. (1997) Cancer Res. 57:4593-4599 Monoclonal antibody, produced by hybridoma ATCC HB 10709 A monoclonal antibody that binds to the same epitope as the monoclonal anti-VEGF antibody A4.6.1 In certain embodiments, the anti-VEGF antibody is rhuMAb VEGF or Bevacizumab (BV), also known as Avastin®, is a mutant human I gG1 framework region and mouse that blocks binding of human VEGF to its receptor Contains antigen-binding complementarity-determining regions from anti-hVEGF monoclonal antibody A.4.6.1. Vacizumab and other humanized anti-VEGF antibodies are disclosed in U.S. Patent No. 6,412,264, issued February 26, 2005. ,884,87. Additional antibodies are described in PCT Publication WO 2005 / 012 359, G6 or B20 series described in PCT Publication WO2005 / 044853 and antibodies (e.g., G6-31, B20-4.1), the contents of which are incorporated herein by reference. For further antibodies, see U.S. Pat. No. 7,060,269. No. 6,582,959, 6,703,020, 6,054,297, WO98 / 453 No. 32, No. WO96 / 30046, No. WO94 / 10202, No. EP0666868B1 , U.S. Patent Application Publication Nos. 2006 / 009360, 2005 / 0186208, 2003 Nos. / 0206899, 2003 / 0190317, 2003 / 0203409 and 2005 / 0112126; and Popkov et al, Journal of Immunological Methods 288: 149-164 (2004). Other antibodies contain residues F17, M18, D19, Y21 , Y25, Q89, 191, Kl01, El03, and C104, or residue F1 Functional DNA fragments of human VEGF containing 7, Y21, Q22, Y25, D63, 183, and Q89 Includes those that bind to epitopes.

[0325] Examples of c-MET inhibitors In certain embodiments, the combinations described herein include a c-MET inhibitor. In embodiments, the combination is administered to a patient suffering from a cancer, e.g., a cancer described herein, e.g., a solid tumor (e.g., For example, non-small cell lung cancer, pancreatic cancer, liver cancer, thyroid cancer (e.g., anaplastic thyroid cancer), brain tumors ( glioblastoma), kidney cancer (e.g., renal cell carcinoma), or head and neck cancer (e.g., squamous cell carcinoma) In one embodiment, the cancer is liver cancer, e.g., hepatocellular carcinoma (HCC). HCC) (e.g., c-MET-expressing HCC).

[0326] In certain embodiments, the c-MET inhibitor is compound A17 or U.S. Pat. No. 7,767, 675 and 8,420,645. c-MET, receptor tyrosine Kinases are overexpressed or mutated in many tumor cell types and regulate tumor cell proliferation, survival, invasion, and metastasis. c-MET plays an important role in tumor angiogenesis and tumor vasculogenesis. Cells of tumor cells that overexpress or express constitutively activated c-MET protein It can induce cell death.

[0327] In one embodiment, the c-MET inhibitor is JNJ-38877605. J-38877605 is an orally available, small molecule c-MET inhibitor. 8877605 selectively binds to c-MET, thereby inhibiting c-MET phosphorylation. , which disrupts the c-Met signaling pathway.

[0328] In one embodiment, the c-Met inhibitor is AMG 208. AMG 208 AMG 208 is a selective small molecule c-MET inhibitor. inhibits the dependent and ligand-independent activation of c- This can lead to cell growth inhibition in tumors that overexpress Met.

[0329] In one embodiment, the c-Met inhibitor is AMG 337. AMG 337 AMG 337 is an orally bioavailable c-MET inhibitor. selectively binds to c-MET, thereby disrupting the c-MET signaling pathway.

[0330] In one embodiment, the c-Met inhibitor is LY2801653. LY2801653 is an orally available, small molecule c-MET inhibitor. It selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and inhibiting c-Met signaling. It interferes with the signal transmission pathway.

[0331] In one embodiment, the c-Met inhibitor is MSC2156119J. 2156119J is an orally bioavailable c-MET inhibitor. MSC21 56119J selectively binds to c-MET, which inhibits c-MET phosphorylation and -Interfering with Met-mediated signaling pathways.

[0332] In one embodiment, the c-MET inhibitor is capmatinib. Also known as INCB028060. Capmatinib is an orally bioavailable Capmatinib is a c-MET inhibitor. It selectively binds to c-MET, thereby inhibiting c- It inhibits MET phosphorylation and disrupts the c-Met signaling pathway.

[0333] In one embodiment, the c-MET inhibitor is crizotinib. Also known as PF-02341066. Crizotinib inhibits receptor tyrosine kinase inhibitors Transduction of ALK and c-Met / hepatocyte growth factor receptor (HGFR) Crizotinib is an orally available aminopyridine-based inhibitor that inhibits ATP-competitive It binds to and inhibits ALK kinase and ALK fusion proteins. Nib inhibits c-Met kinase and disrupts the c-Met signaling pathway. This drug inhibits tumor cell growth.

[0334] In one embodiment, the c-MET inhibitor is golvatinib. Orally bioavailable dual kinase c- Golvatinib is a MET and VEGFR-2 inhibitor. -2 binds to and inhibits the activity of both receptor tyrosine kinases, which is thought to be a key factor in the overexpression of these receptors. The present invention can inhibit tumor cell proliferation and survival of tumor cells.

[0335] In one embodiment, the c-MET inhibitor is tivantinib. Also known as ARQ 197, tivantinib is an orally bioavailable small molecule Tivantinib is a c-MET inhibitor. It binds to the c-MET protein and inhibits c-Met disrupts the signaling pathway, which can be achieved by overexpressing or constitutively expressing the c-MET protein. It can induce cell death in tumor cells that express activated c-Met protein.

[0336] Examples of TGF-β inhibitors In some embodiments, the combinations described herein include transforming growth factors In some embodiments, the combination is used to treat cancer, e.g., Cancers described herein, e.g., solid tumors (e.g., brain tumors (e.g., gliomas), melanomas, renal tumors, liver cancer (e.g., renal cell carcinoma), pleural malignant mesothelioma (e.g., recurrent pleural malignant mesothelioma) or breast cancer (e.g., In some embodiments, the cancer is colorectal cancer (e.g., metastatic breast cancer). , microsatellite stable colorectal cancer (MSS CRC), liver cancer (e.g., hepatocellular carcinoma), Lung cancer (e.g., non-small cell lung cancer (HSCLC)), breast cancer (e.g., triple-negative breast cancer (TN) BC), TGF-β-expressing cancer, pancreatic cancer, prostate cancer, or kidney cancer (e.g., renal cell carcinoma) will be done.

[0337] TGF-β is a stimulator of, for example, bone morphogenetic proteins (BMPs), growth and differentiation factors, activins, and inhibins. In certain embodiments, the TGF-β inhibitors described herein include one or more isoforms of TGF-β. form (e.g., one, two, or all of TGF-β1, TGF-β2, or TGF-β3) It can bind to and / or inhibit.

[0338] Under normal conditions, TGF-β maintains homeostasis and stimulates the proliferation of epithelial, endothelial, neuronal, and hematopoietic cell lines. They limit proliferation of the cells, for example, by inducing antiproliferative and apoptotic responses. The canonical and non-canonical signaling pathways involve the cellular response to TGF-β. Activation of the canonical pathway may mediate the antiproliferative effects of TGF-β. Non-canonical TGF-β pathway may involve additional intracellular pathways, such as mitogen-activated protein kinase (MAPK), Sphatidylinositol 3-kinase / protein kinase B, Rho-like GTPase (Tian et al. Cell Signal. 2011; 23(6):951-62; Blobe et al. N Engl J Me d. 2000; 342(18):1350-8), thereby promoting epithelial-mesenchymal transition (EMT) and / or cell motility. Adjust.

[0339] Alterations in the TGF-β signaling pathway have been implicated in a variety of human diseases, including cancer, cardiovascular disease, fibrosis, It is associated with reproductive disorders and wound healing. Without intending to be bound by theory, in some embodiments In this context, the role of TGF-β in cancer depends on the tumor context (e.g., tumor stage and genetic It is thought that this depends on the genetic alterations and / or cellular context. For example, in the later stages of cancer, TG F-β has various functions, such as promoting tumor growth (e.g., inducing EMT), blocking anti-tumor immune responses, and inhibiting tumor-associated Increased fibrosis or enhanced angiogenesis may modulate cancer-related processes (Wakefield and Hill, 2004). In one embodiment, the TGF- Combinations containing beta-blockers are used to treat late stage, metastatic or advanced cancer.

[0340] Preclinical evidence indicates that TGF-β plays an important role in immune regulation (Wojtowicz-P Invest New Drugs. 2003; 21(1):21-32; Yang et al. Trends Immunol. 2010; 31(6 TGF-β mediates several mechanisms, including the Th2 immune response in the T helper balance. Shift toward a novel type: inhibition of antitumor Th1-type responses and M1-type macrophages ;Cytotoxic CD8 + Suppression of T lymphocyte (CTL), NK lymphocyte and dendritic cell function, C D4 + CD25+ T regulatory cell production; or immunosuppressive cytokines (e.g., IL1 0 or VEGF), proinflammatory cytokines (e.g., IL6, TNFα, or IL1) secretion of β-lactamase and its tumor-promoting activity mediated by the production of reactive oxygen species (ROS) with genotoxic activity The promotion of M2-type macrophages with γ-β downregulates the host immune response (Y ang et al. Trends Immunol. 2010; 31(6):220-7; Truty and Urrutia Pancreatology. 2 007; 7(5-6):423-35; Achyut et al Gastroenterology. 2011; 141(4):1167-78).

[0341] In one embodiment, the TGF-β inhibitor is fresolimumab (CAS Registry Number: 948564-73-6). Fresolimumab is also known as GC1008. Mab is a human monoclonal antibody that binds to and inhibits TGF-beta isoforms 1, 2, and 3. It is a clonal antibody.

[0342] The heavy chain of fresolimumab has the amino acid sequence QVQLVQSGAEVKKPGSSVKVSCKASGYTFSSNVISWVRQAPG QGLEWMGVIPIVDIANYAQRFKGRVTITADESTSTTYMELSSLRSEDTAVYYCASTLGLVLDAMDYWGQGTLVTVSSAS TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT CNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLS LSLGK (SEQ ID NO: 238). The light chain of fresolimumab has the amino acid sequence ETVLTQSPGTLSL SPGERATLSCRASQSLGSSYLAWYQQKPGQAPRLLIYGASSRAPGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYA DSPITFGQGTRLEIKRTVAAPSVFIFPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (sequence number 239).

[0343] Fresolimumab is described, for example, in WO2006 / 086469 and US Pat. No. 8,383,780. and US 8,591,901.

[0344] In one embodiment, the TGF-β inhibitor is XOMA 089. XOMA 089 is also known as XPA.42.089. XOMA 089 inhibits TGF-beta1 and a fully human monoclonal antibody that specifically binds to and neutralizes the two ligands.

[0345] The heavy chain variable region of XOMA 089 has the amino acid sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSY AISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGLWEVRALPSVYWG QGTLVTVSS (SEQ ID NO: 240) (described in WO2012 / 167143 as SEQ ID NO: 6) The light chain variable region of XOMA 089 has the amino acid sequence SYELTQPPSVSVAPGQTARITCGANDI GSKSVHWYQQKAGQAPVLVVSEDIIRPSGIPERISGSNSGNTATLTISRVEAGDEADYYCQVWDRDSDQYVFGTGTKVTV LG (SEQ ID NO: 241) (described as SEQ ID NO: 8 in WO2012 / 167143).

[0346] XOMA 089 binds to human TGF-β isoforms with high affinity. XOMA 089 binds TGF-β1 and TGF-β2 with high affinity, and TGF-β3 In Biacore assays, it binds to human TGF-β to a lesser extent. OMA 089 K D 14.6 pM for TGF-β1, 67.3 pM for TGF-β2, and 948 pM for TGF-β3. Considering the high affinity binding to all three TGF-β isoforms Thus, in certain embodiments, XOMA 089 is used in the methods described herein for the treatment of XOMA 089. XOMA 089 is predicted to bind to TGF-β1, 2, and 3 at levels comparable to those of the IL-1 receptor agonist. It cross-reacts with cynomolgus monkey TGF-β and exhibits functional activity in vitro and in vivo. , rodents, and cynomolgus monkeys are suitable species for toxicity testing.

[0347] In one embodiment, the combination includes an inhibitor of PD-1 (e.g., an inhibitor described herein). PD-1 antibody molecule) and a TGF-β inhibitor (e.g., a TGF-β inhibitor described herein) Includes:

[0348] Without intending to be bound by theory, in certain embodiments, PD-1 immunotherapy Resistance to TGF-β is mediated by, for example, TGF-β signaling and TGF-β-dependent processes, such as Regarding the presence of transcriptional signatures, including genes linked to wound healing or angiogenesis (Hugo et al. Cell. 2016; 165(1):35-44). In one embodiment, TGF-β blockade broadens the therapeutic window for therapies that inhibit the PD-1 / PD-L1 axis. -β inhibitors can be used to inhibit, for example, the tumor microenvironment, e.g., angiogenesis, fibrosis, or effector T Modulation of factors that influence cell recruitment may influence the clinical benefit of PD-1 immunotherapy (Yang et al. Trends Immunol. 2010; 31(6):220-7; Wakefield and Hill Nat Rev Cance r. 2013; 13(5):328-41; Truty and Urrutia Pancreatology. 2007; 7(5-6):423-35).

[0349] Without intending to be bound by theory, in one embodiment, PD-1 and TGF-β receptors and components of the antitumor immune cycle that express both PD-1 and TGF-β receptors It is also thought that the number of cells may propagate non-redundant cell signals. For example, spontaneous prostate cancer In a mouse model of TGFBRII, a dominant-negative form or expression of TGFBRII in T cells The use of TGF-β production suppression by steroids slows tum...

Claims

1. For the treatment of cancer in a subject, a dose of about 300 mg to 400 mg is administered once every three weeks or once every four weeks.

1. An anti-PD-1 antibody molecule for use comprising: (a) the VHCDR1 amino acid sequence of SEQ ID NO:4, the VHCDR2 amino acid sequence of SEQ ID NO:5, and and a heavy chain variable region (VH) comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and The VLCDR1 amino acid sequence of SEQ ID NO:13, the VLCDR2 amino acid sequence of SEQ ID NO:14 and the sequence a light chain variable region (VL) comprising the VLCDR3 amino acid sequence of number 33; (b) the VHCDR1 amino acid sequence of SEQ ID NO:1; the VHCDR2 amino acid sequence of SEQ ID NO:2; and a VH comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and a VLCD comprising the VLCD of SEQ ID NO:

10. The R1 amino acid sequence, the VLCDR2 amino acid sequence of SEQ ID NO: 11 and the VL VL comprising a CDR3 amino acid sequence; (c) a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5 VH comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and VL comprising the VHCDR3 amino acid sequence of SEQ ID NO:13 The CDR1 amino acid sequence of SEQ ID NO:14, the VLCDR2 amino acid sequence of SEQ ID NO:33 or a VL comprising a VLCDR3 amino acid sequence; (d) the VHCDR1 amino acid sequence of SEQ ID NO:224; VH comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and VL comprising the VHCDR3 amino acid sequence of SEQ ID NO:

10. The CDR1 amino acid sequence of SEQ ID NO:11, the VLCDR2 amino acid sequence of SEQ ID NO:32 VL comprising the VLCDR3 amino acid sequence An anti-PD-1 antibody molecule comprising:

2. A method of treating cancer in a subject, comprising administering to the subject about 300 mg to 4 mg of an anti-PD-1 antibody molecule. 00 mg once every 3 weeks or once every 4 weeks, Body molecules (a) the VHCDR1 amino acid sequence of SEQ ID NO:4, the VHCDR2 amino acid sequence of SEQ ID NO:5, and and a heavy chain variable region (VH) comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and The VLCDR1 amino acid sequence of SEQ ID NO:13, the VLCDR2 amino acid sequence of SEQ ID NO:14 and the sequence a light chain variable region (VL) comprising the VLCDR3 amino acid sequence of number 33; (b) the VHCDR1 amino acid sequence of SEQ ID NO:1; the VHCDR2 amino acid sequence of SEQ ID NO:2; and a VH comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and a VLCD comprising the VLCD of SEQ ID NO:

10. The R1 amino acid sequence, the VLCDR2 amino acid sequence of SEQ ID NO: 11 and the VL VL comprising a CDR3 amino acid sequence; (c) a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5 VH comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and VL comprising the VHCDR3 amino acid sequence of SEQ ID NO:13 The CDR1 amino acid sequence of SEQ ID NO:14, the VLCDR2 amino acid sequence of SEQ ID NO:33 or a VL comprising a VLCDR3 amino acid sequence; (d) the VHCDR1 amino acid sequence of SEQ ID NO:224; VH comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and VL comprising the VHCDR3 amino acid sequence of SEQ ID NO:

10. The CDR1 amino acid sequence of SEQ ID NO:11, the VLCDR2 amino acid sequence of SEQ ID NO:32 VL comprising the VLCDR3 amino acid sequence A method comprising:

3. Anti-PD-1 antibody molecules fall into the following categories: (i) STING agonist, TLR agonist, A2AR antagonist, tumor lytic Virus, TIM-3 modulator, vascular endothelial growth factor receptor (VEGFR) inhibitor, c-Met inhibitors, TGF-β inhibitors, IDO / TDO inhibitors, vaccines or An agent that enhances tumor antigen presentation selected from one or more of three specific cell engagers ； (ii) GITR agonist, PD-L1 inhibitor, IAP (Inhibitor of Apoptosis Protein) Inhibitors, EGFR (Epidermal Growth Factor Receptor) inhibitors, target of rapamycin ( mTOR) inhibitors, IL-15 or variants thereof, CTLA-4 inhibitors, CD3 and and a bispecific antibody molecule that binds to a tumor antigen, a CD40 agonist, an OX40 agonist, or an agent that enhances an effector cell response selected from one or more CD27 agonists; or (iii) GITR agonist, PD-L1, LAG-3, TIM-3 or CTLA-4 Inhibitors of immune checkpoint molecules selected from one or more of CSF-1 / 1R inhibitors, I L-17 inhibitor, IL-1β inhibitor, CXCR2 inhibitor, PI3Kγ or PI3Kδ inhibitors, BAFF-R inhibitors, MALT-1 / BTK inhibitors, JAK inhibitors, CRTH2 inhibitors, VEGFR inhibitors, IL-15 or variants thereof, CTLA-4 inhibitors, I DO / TDO inhibitors, A2AR antagonists, TGF-β inhibitors or PFKFB3 inhibitors A drug for reducing tumor immunosuppression selected from one or more of the following inhibitors: In combination with one or more therapeutic agents selected from one, two or all of (i) to (iii) 3. The antibody molecule for use according to claim 1 or the method according to claim 2,

4. The method according to claim 1 or 3, wherein the anti-PD-1 antibody molecule is administered at a dose of about 300 mg once every three weeks.

4. An antibody molecule for the above-mentioned use or the method according to claim 2 or 3.

5. The method according to claim 1 or 3, wherein the anti-PD-1 antibody molecule is administered at a dose of about 400 mg once every 4 weeks.

4. An antibody molecule for the above-mentioned use or the method according to claim 2 or 3.

6. Anti-PD-1 antibody molecule (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 42 a light chain variable domain comprising the sequence; (b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 66 a light chain variable domain comprising the sequence; (d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 70 a light chain variable domain comprising the sequence; (d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and the amino acid sequence of SEQ ID NO: 70 a light chain variable domain comprising the sequence; (e) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 46 a light chain variable domain comprising the sequence; (f) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and the amino acid sequence of SEQ ID NO: 46 a light chain variable domain comprising the sequence; (g) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and the amino acid sequence of SEQ ID NO:

54. a light chain variable domain comprising the sequence; (h) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO:

54. a light chain variable domain comprising the sequence; (i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 58 a light chain variable domain comprising the sequence; (j) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 62 a light chain variable domain comprising the sequence; (k) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and the amino acid sequence of SEQ ID NO: 66 a light chain variable domain comprising the sequence; (l) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 74 a light chain variable domain comprising the sequence; (m) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 78 a light chain variable domain comprising the sequence; (n) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 and the amino acid sequence of SEQ ID NO: 70 a light chain variable domain comprising the sequence; (o) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 and the amino acid sequence of SEQ ID NO: 66 a light chain variable domain comprising the sequence; or (p) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 86 and the amino acid sequence of SEQ ID NO: 66 A light chain variable domain comprising the sequence The antibody molecule for use according to any one of claims 1 or 3 to 5 or claims 2 to 5, 5. A method according to any one of claims 1 to 5.

7. For the use according to any one of claims 1 or 3 to 6, wherein the cancer is a solid tumor or a blood cancer. or the method according to any one of claims 2 to 6.

8. Cancers include lung cancer, kidney cancer, liver cancer, myeloma, prostate cancer, breast cancer, colorectal cancer (CRC), gastric cancer, and pancreatic cancer. Pancreatic cancer, thyroid cancer, neuroendocrine tumors (NETs), ovarian cancer, fallopian tube cancer, lymphoma, leukemia, myelodysplastic syndromes The method according to claim 1 or 3 to 7, wherein the cancer is selected from the group consisting of myelofibrosis syndrome (MDS) and metastatic lesions of these cancers. An antibody molecule for the use according to any one of claims 2 to 7 or a method according to any one of claims 2 to 7.

9. The antibody molecule of claim 8, wherein the skin cancer is Merkel cell carcinoma or melanoma.

8. The method according to claim 8.

10. Breast cancer is triple-negative breast cancer (TNBC), HER2-negative breast cancer, or ER+ breast cancer 9. The antibody molecule of claim 8 or the method of claim 8, which is

11. The antibody molecule of claim 8 or the method of claim 8, wherein the renal cancer is renal cell carcinoma.

12. The renal cell carcinoma is clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC).

12. An antibody molecule according to claim 11 or a method according to claim 11.

13. 9. The antibody molecule of claim 8, wherein the thyroid cancer is anaplastic thyroid cancer (ATC). The method according to

14. Neuroendocrine tumors (NETs) are atypical pulmonary carcinoid tumors or tumors of the pancreas or gastrointestinal (GI) tract.

9. The antibody molecule of claim 8 or the method of claim 8, wherein the NET is pulmonary NET.

15. The antibody molecule of claim 8, wherein the lung cancer is non-small cell lung cancer (NSCLC). The method described.

16. The NSCLC is squamous NSCLC, non-squamous NSCLC, or NSCLC adenocarcinoma.

16. An antibody molecule according to claim 15 or a method according to claim 15.

17. Colorectal cancer (CRC) is classified as microsatellite instability high (MSI high CRC) or The antibody of claim 8 is a microsatellite stable colorectal cancer (MSS CRC). The molecule or the method of claim 8.

18. The antibody molecule of claim 8, wherein the leukemia is acute myeloid leukemia (AML). The method according to

19. The acute myeloid leukemia (AML) is relapsed or refractory AML or de novo AML.

19. The antibody molecule of claim 18 or the method of claim 18.

20. The antibody molecule of claim 8, wherein the myelodysplastic syndrome (MDS) is high-risk MDS. The method according to claim 8.

21. The antibody molecule of claim 8 or the method of claim 8, wherein the liver cancer is hepatocellular carcinoma.

22. The antibody molecule of claim 8 or the method of claim 8, wherein the gastric cancer is EBV+ gastric cancer.

23. The antibody molecule of claim 8 or the antibody molecule of claim 8, wherein the lymphoma is non-Hodgkin's lymphoma. Method of posting.

24. The anti-PD-1 antibody molecule is used in combination with an IAP inhibitor according to claims 1 or 3-2.

3. An antibody molecule for use according to any one of claims 2 to 23 or a method according to any one of claims 2 to 23.

25. The anti-PD-1 antibody molecule is used in combination with an mTOR inhibitor according to claims 1 or 3 to 23 or a method according to any of claims 2 to 23 for use. 。

26. The anti-PD-1 antibody molecule is used in combination with a DAC inhibitor according to claims 1 or 3-2.

3. An antibody molecule for use according to any one of claims 2 to 23 or a method according to any one of claims 2 to 23.

27. 1 or 3, wherein the anti-PD-1 antibody molecule is used in combination with an IL-1β inhibitor. An antibody molecule for use according to any one of claims 2 to 23 or a method according to any one of claims 2 to 23. Law.

28. 1 or 3, wherein the anti-PD-1 antibody molecule is used in combination with an IL-17 inhibitor. An antibody molecule for use according to any one of claims 2 to 23 or a method according to any one of claims 2 to 23. Law.

29. The anti-PD-1 antibody molecule is used in combination with a MEK inhibitor according to claims 1 or 3-2.

3. An antibody molecule for use according to any one of claims 2 to 23 or a method according to any one of claims 2 to 23.

30. Claim 1 or 3, wherein the anti-PD-1 antibody molecule is used in combination with an EGFR inhibitor. An antibody molecule for use according to any one of claims 2 to 23 or a method according to any one of claims 2 to 23. Law.

31. Any of claims 24 to 30, wherein the combination is used for the treatment of colorectal cancer, lung cancer or breast cancer. An antibody molecule for the use according to any one of claims 24 to 30 or a method according to any one of claims 24 to 30.

32. 32. The antibody molecule of claim 31 for use according to claim 31, wherein the lung cancer is NSCLC. The method according to

33. The antibody molecule for use according to claim 31, wherein the breast cancer is NTBC. The method described.

34. The CSF-1 / 1R binding agent is used in combination with an anti-PD-1 antibody molecule. or 3 to 23, or an antibody molecule for the use according to any of claims 2 to 23. Method of posting.

35. 35. The method of claim 34 for the treatment of brain cancer, breast cancer or pancreatic cancer. The antibody molecule or the method of claim 34.

36. 36. The antibody molecule or antibody for use according to claim 35, wherein the brain tumor is glioblastoma multiforme (GBM). Or the method of claim 35.

37. The antibody molecule for use according to claim 35, wherein the breast cancer is NTBC, or the antibody molecule for use according to claim 35, The method described.

38. The anti-PD-1 antibody molecule is 6-phosphofructo-2-kinase / fructose-2,6-bis 1 or 3, in combination with an inhibitor of phosphatase 3 (PFKFB3). An antibody molecule for use according to any one of claims 2 to 23 or a method according to any one of claims 2 to 23. Law.

39. 3. The combination is used to treat ovarian cancer, fallopian tube cancer, or colorectal cancer (CRC).

8. An antibody molecule for use as described in claim 8 or a method according to claim 38.

40. The anti-PD-1 antibody molecule is used in combination with a chemotherapeutic agent, and optionally the chemotherapeutic agent is The antibody molecule for use according to any one of claims 1 or 3 to 23, which is paclitaxel. Or a method according to any one of claims 2 to 23.

41. 41. The antibody molecule of claim 40 for use in the treatment of breast cancer.

40. The method according to claim 40.

42. 42. The antibody molecule or method of claim 41, wherein the breast cancer is a HER2-negative breast cancer. The method according to claim 41.

43. The anti-PD-1 antibody molecule is administered in combination with a BRAF inhibitor and a MEK inhibitor. An antibody molecule for use according to any of claims 1 or 3 to 23 or according to claims 2 to 23 Any method described herein.

44. 44. The antibody molecule or the antibody according to claim 43 for use in the treatment of skin cancer.

44. The method according to claim 43.

45. 45. The antibody molecule for use according to claim 44, or the antibody molecule for use according to claim 44, wherein the skin cancer is melanoma. The method described.

46. 1 or 3, wherein the anti-PD-1 antibody molecule is administered in combination with a TGF-β inhibitor. An antibody molecule for use according to any one of claims 2 to 23 or a method according to any one of claims 2 to 23. Law.

47. For use in the treatment of pancreatic cancer, colorectal cancer, lung cancer, breast cancer, liver cancer, prostate cancer or kidney cancer.

47. An antibody molecule for use as claimed in claim 46 or a method according to claim 46.

48. 4. The method of claim 3, wherein the colorectal cancer is microsatellite-stable colorectal cancer (MSS-CRC).

7. An antibody molecule for use as claimed in claim 7 or a method according to claim 47.

49. 48. The antibody molecule for use according to claim 47, wherein the lung cancer is NSCLC. The method according to

50. 48. The antibody molecule for use according to claim 47, wherein the breast cancer is TNBC, or The method described.

51. 48. The antibody molecule for use according to claim 47, wherein the liver cancer is hepatocellular carcinoma. The method according to

52. 48. The antibody molecule or claim for use according to claim 47, wherein the renal cancer is clear cell renal cell carcinoma.

48. The method according to claim 47.

53. 10. The method of claim 1, wherein the anti-PD-1 antibody molecule is administered in combination with an inhibitor of PD-L1. 3 to 23 or an antibody molecule according to any one of claims 2 to 23 for use according to any one of claims 2 to 23. method.

54. 54. The use according to claim 53 for the treatment of lung cancer, breast cancer, uterine cancer or thyroid cancer. or the method of claim 53.

55. 55. The antibody molecule for use according to claim 54, wherein the lung cancer is NSCLC. The method according to

56. 55. The antibody molecule for use according to claim 54, wherein the breast cancer is TNBC. The method described.

57. 55. The antibody molecule for use according to claim 54 or claim 5, wherein the uterine cancer is endometrial cancer.

5. The method according to claim 4.

58. 55. The antibody molecule or antibody for use according to claim 54, wherein the thyroid cancer is anaplastic thyroid cancer. The method of claim 54.

59. The anti-PD-1 antibody molecule is administered in combination with a methylation inhibitor according to claims 1 or 3 to 5. 23 or a method according to any of claims 2 to 23 for use. 。

60. 60. The antibody for use according to claim 59, wherein the combination further comprises an inhibitor of TIM-3. The molecule or the method of claim 59.

61. 59. The combination is used to treat leukemia or myelodysplastic syndrome (MDS). or 60. An antibody molecule for use as claimed in claim 59 or 60, or a method according to claim 59 or 60.

62. 62. The antibody molecule for use according to claim 61, wherein the leukemia is acute myeloid leukemia (AML). Or the method of claim 61.

63. 62. The antibody molecule or claim for use according to claim 61, wherein the MDS is high-risk MDS. Item 62. The method according to item 61.

64. 10. The method of claim 1, wherein the anti-PD-1 antibody molecule is administered in combination with a second PD-1 inhibitor. 3 to 63 or an antibody molecule according to any one of claims 2 to 63 for use. method.

65. Anti-PD-12 for use at a dose of about 300 mg to 400 mg once every 3 weeks or once every 4 weeks A pharmaceutical composition or dosage formulation comprising an anti-PD-1 antibody molecule, (a) the VHCDR1 amino acid sequence of SEQ ID NO:4, the VHCDR2 amino acid sequence of SEQ ID NO:5, and and a heavy chain variable region (VH) comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and The VLCDR1 amino acid sequence of SEQ ID NO:13, the VLCDR2 amino acid sequence of SEQ ID NO:14 and the sequence a light chain variable region (VL) comprising the VLCDR3 amino acid sequence of number 33; (b) the VHCDR1 amino acid sequence of SEQ ID NO:1; the VHCDR2 amino acid sequence of SEQ ID NO:2; and a VH comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and a VLCD comprising the VLCD of SEQ ID NO:

10. The R1 amino acid sequence, the VLCDR2 amino acid sequence of SEQ ID NO: 11 and the VL VL comprising a CDR3 amino acid sequence; (c) a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5 VH comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and VL comprising the VHCDR3 amino acid sequence of SEQ ID NO:13 The CDR1 amino acid sequence of SEQ ID NO:14, the VLCDR2 amino acid sequence of SEQ ID NO:33 or a VL comprising a VLCDR3 amino acid sequence; (d) the VHCDR1 amino acid sequence of SEQ ID NO:224; VH comprising the VHCDR3 amino acid sequence of SEQ ID NO:3; and VL comprising the VHCDR3 amino acid sequence of SEQ ID NO:

10. The CDR1 amino acid sequence of SEQ ID NO:11, the VLCDR2 amino acid sequence of SEQ ID NO:32 VL comprising the VLCDR3 amino acid sequence A pharmaceutical composition or dosage formulation comprising:

66. 66. The pharmaceutical composition or dosage form of claim 65, wherein the dose is about 300 mg once every three weeks. 。

67. 66. The pharmaceutical composition or dosage form of claim 65, wherein the dose is about 400 mg once every four weeks. 。

68. Anti-PD-1 antibody molecule (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 42 a light chain variable domain comprising the sequence; (b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 66 a light chain variable domain comprising the sequence; (d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 70 a light chain variable domain comprising the sequence; (d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and the amino acid sequence of SEQ ID NO: 70 a light chain variable domain comprising the sequence; (e) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 46 a light chain variable domain comprising the sequence; (f) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and the amino acid sequence of SEQ ID NO: 46 a light chain variable domain comprising the sequence; (g) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and the amino acid sequence of SEQ ID NO:

54. a light chain variable domain comprising the sequence; (h) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO:

54. a light chain variable domain comprising the sequence; (i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 58 a light chain variable domain comprising the sequence; (j) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 62 a light chain variable domain comprising the sequence; (k) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and the amino acid sequence of SEQ ID NO: 66 a light chain variable domain comprising the sequence; (l) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 74 a light chain variable domain comprising the sequence; (m) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and the amino acid sequence of SEQ ID NO: 78 a light chain variable domain comprising the sequence; (n) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 and the amino acid sequence of SEQ ID NO: 70 a light chain variable domain comprising the sequence; (o) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 and the amino acid sequence of SEQ ID NO: 66 a light chain variable domain comprising the sequence; or (p) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 86 and the amino acid sequence of SEQ ID NO: 66 A light chain variable domain comprising the sequence 68. The pharmaceutical composition or dosage form of any of claims 65 to 67, comprising:

69. A pharmaceutical composition or method according to any one of claims 65 to 68 for use in the treatment of cancer. formulation.

70. Cancers include lung cancer, kidney cancer, liver cancer, myeloma, prostate cancer, breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, Adenocarcinoma, neuroendocrine tumor (NET), ovarian cancer, fallopian tube cancer, lymphoma, leukemia, myelodysplastic syndrome 70. The pharmaceutical composition according to claim 69, wherein the compound is selected from the group consisting of MDS and metastatic lesions of these cancers. or dosage form.

71. 71. The pharmaceutical composition or dosage form of claim 70, wherein the skin cancer is Merkel cell carcinoma or melanoma. Prescribed formulation.

72. Breast cancer is triple-negative breast cancer (TNBC), HER2-negative breast cancer, or ER+ breast cancer.

71. The pharmaceutical composition or dosage formulation of claim 70.

73. 71. The pharmaceutical composition or dosage formulation of claim 70, wherein the renal cancer is renal cell carcinoma.

74. The renal cell carcinoma is clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC).

74. The pharmaceutical composition or dosage formulation of claim 73.

75. 71. The pharmaceutical composition or administration of claim 70, wherein the thyroid cancer is anaplastic thyroid cancer (ATC). formulation.

76. Neuroendocrine tumors (NETs) are atypical pulmonary carcinoid tumors or tumors of the pancreas or gastrointestinal (GI) tract.

71. The pharmaceutical composition or dosage formulation of claim 70, wherein the NET is in the lung.

77. 71. The pharmaceutical composition or dosage form of claim 70, wherein the lung cancer is non-small cell lung cancer (NSCLC). Agent.

78. The NSCLC is squamous NSCLC, non-squamous NSCLC, or NSCLC adenocarcinoma.

78. The pharmaceutical composition or dosage formulation of claim 77.

79. Colorectal cancer (CRC) is classified as microsatellite instability high (MSI high CRC) or The method of claim 70, wherein the patient has microsatellite stable colorectal cancer (MSS CRC). Pharmaceutical compositions or dosage forms.

80. 71. The pharmaceutical composition or administration of claim 70, wherein the leukemia is acute myeloid leukemia (AML). formulation.

81. The acute myeloid leukemia (AML) is relapsed or refractory AML or de novo AML. Item 80. A pharmaceutical composition or dosage form according to item 80.

82. The pharmaceutical composition according to claim 70, wherein the myelodysplastic syndrome (MDS) is high-risk MDS. or dosage form.

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