Enhancing the therapeutic activity of immune checkpoint inhibitor

Abstract

The present invention provides antagonists and methods of use thereof in the treatment of cancer and abnormal immune suppression diseases.

We claim: 
     
         1 . A method of treating cancer in a subject comprising,
 identifying a subject that has been diagnosed with cancer;   administering an immune checkpoint inhibitor; and   administering an antagonist of collagen or a fragment thereof,   thereby treating cancer in said subject.   
     
     
         2 . The method of  claim 1 , wherein the immune checkpoint inhibitor comprises an inhibitor of CTLA-4, PD-1, PDL-1, Lag3, LAIR1, or LAIR2 
     
     
         3 . The method of  claim 1 , wherein said inhibitor of PDL-1 comprises a PDL-1 antibody. 
     
     
         4 . The method of  claim 1 , wherein said antagonist of collagen or a fragment thereof enhances anti-tumor activity of the immune checkpoint inhibitor. 
     
     
         5 . The method of  claim 1 , further comprising inhibiting an inflammatory condition, wherein said inflammatory condition comprises dermatitis, pneumonitis, or colitis. 
     
     
         6 . The method of  claim 1 , wherein the collagen comprises collagen type-I, collagen type II, collagen type III, or collagen type-IV. 
     
     
         7 . The method of  claim 6 , wherein the antagonist of collagen type-IV or a fragment thereof comprises an antagonist of the XL313 cryptic collagen epitope or an antagonist of the HU177 cryptic collagen epitope. 
     
     
         8 . The method of  claim 7 , wherein the antagonist of the XL313 cryptic collagen epitope comprises an antibody that binds a cryptic RGDKGE (SEQ ID NO: 1)-containing collagen epitope or wherein the antagonist of the HU177 cryptic collagen epitope comprises an antibody that binds a cryptic CPGFPGFC (SEQ ID NO: 16)-containing collagen epitope. 
     
     
         9 . The method of  claim 8 , wherein the antibody comprises a monoclonal antibody. 
     
     
         10 . The method of  claim 9 , wherein said monoclonal antibody comprises an XL313 monoclonal antibody or an HU177 monoclonal antibody. 
     
     
         11 . The method of  claim 1 , wherein the subject is a human. 
     
     
         12 . The method of  claim 1 , further comprising administering a chemotherapy agent. 
     
     
         13 . The method of  claim 1 , wherein the cancer is selected from the group comprising of melanoma, central nervous system (CNS) cancer, CNS germ cell tumor, lung cancer, leukemia, multiple myeloma, renal cancer, malignant glioma, medulloblatoma, breast cancer, ovarian cancer, prostate cancer, bladder cancer, fibrosarcoma, pancreatic cancer, gastric cancer, head and neck cancer, colorectal cancer. For example, a cancer cell is derived from a solid cancer or hematological cancer. The hematological cancer is, e.g., a leukemia or a lymphoma. A leukemia is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), or acute monocytic leukemia (AMoL). A lymphoma is follicular lymphoma, Hodgkin's lymphoma (e.g., Nodular sclerosing subtype, mixed-cellularity subtype, lymphocyte-rich subtype, or lymphocyte depleted subtype), or Non-Hodgkin's lymphoma. Exemplary solid cancers include but are not limited to melanoma (e.g., unresectable, metastatic melanoma), renal cancer (e.g., renal cell carcinoma), prostate cancer (e.g., metastatic castration resistant prostate cancer), ovarian cancer (e.g., epithelial ovarian cancer, such as metastatic epithelial ovarian cancer), breast cancer (e.g., triple negative breast cancer), and lung cancer (e.g., non-small cell lung cancer). 
     
     
         14 . The method of  claim 1 , wherein said immune checkpoint inhibitor is administered at a dose of 0.01-10 mg/kg bodyweight, and wherein said antagonist of collagen is administered at a dose of 0.01-25 mg/kg bodyweight. 
     
     
         15 . The method of  claim 1 , wherein said composition is administered once per hour, or wherein said composition is administered once every two weeks for 4 to 6 weeks. 
     
     
         16 . A method of treating a disease characterized by abnormal immune suppression in a subject comprising,
 identifying a subject that has been diagnosed with a disease characterized by abnormal immune suppression;   administering an immune checkpoint inhibitor; and   administering an antagonist of an integrin,   thereby treating in said subject.   
     
     
         17 . The method of  claim 16 , wherein the immune checkpoint inhibitor comprises an inhibitor of CTLA-4, PD-1, PDL-1, Lag3, LAIR1, or LAIR2. 
     
     
         18 . The method of  claim 16 , wherein said immune checkpoint inhibitor comprises a CTLA-4 antibody, a PD-1 antibody, a PDL-1 antibody, a Lag3 antibody, a LAIR1 antibody or a LAIR2 antibody. 
     
     
         19 . The method of  claim 18 , wherein the integrin comprises integrin αvβ3. 
     
     
         20 . The method of  claim 19 , wherein said antagonist of integrin αvβ3 comprises an antibody targeting αvβ3 binding RGDKGE (SEQ ID NO: 1)-containing collagen epitope. 
     
     
         21 . The method of  claim 18 , wherein the integrin comprises integrin α10β1. 
     
     
         22 . The method of  claim 21 , wherein said antagonist of integrin α10β1 comprises an antibody targeting α10β1 binding CPGFPGFC (SEQ ID NO: 16)-containing collagen epitope. 
     
     
         23 . The method of  claim 16 , wherein the subject is a human. 
     
     
         24 . The method of  claim 16 , further comprising administering a chemotherapy agent. 
     
     
         25 . The method of  claim 16 , wherein the disease characterized by abnormal immune suppression comprises Type I diabetes, lupus, psoriasis, scleroderma, hemolytic anemia, vasculitis, Graves' disease, rheumatoid arthritis, multiple sclerosis, Hashimoto's thyroiditis, Myasthenia gravis, and vasculitis. 
     
     
         26 . The method of  claim 16 , wherein said immune checkpoint inhibitor is administered at a dose of 0.01-10 mg/kg bodyweight, and wherein said antagonist of an integrin is administered at a dose of 0.01-25 mg/kg bodyweight. 
     
     
         27 . The method of  claim 16 , wherein said composition is administered once per hour, or wherein said composition is administered once every two weeks for 4 to 6 weeks. 
     
     
         28 . A method of treating a disease characterized by an overactive immune response in a subject comprising,
 identifying a subject that has been diagnosed with an overactive immune response; and   administering a peptide comprising collagen or a fragment thereof,   thereby treating an overactive immune response in said subject.   
     
     
         29 . The method of  claim 28 , wherein said overactive immune response comprises an autoimmune disease. 
     
     
         30 . The method of  claim 28 , wherein the collagen comprises collagen type-I, collagen type II, collagen type III, or collagen type-IV. 
     
     
         31 . The method of  claim 28 , wherein the peptide comprises RGDKGE (SEQ ID NO: 1) or CPGFPGFC (SEQ ID NO: 16). 
     
     
         32 . The method of  claim 28 , wherein the subject is a human. 
     
     
         33 . The method of  claim 28 , wherein said autoimmune disease comprises Graves' disease, Hashimoto's thyroiditis, Systemic lups erythematosus (lupus), Type 1 diabetes, multiple sclerosis or rheumatoid arthritis. 
     
     
         34 . A method for healing a wound in a subject comprising,
 identifying a subject with a wound; and   administering a peptide comprising collagen or a fragment thereof to said wound,   thereby healing said wound in said subject.   
     
     
         35 . The method of  claim 34 , wherein the collagen comprises collagen type-I, collagen type II, collagen type III, or collagen type-IV. 
     
     
         36 . The method of  claim 34 , wherein the peptide comprises RGDKGE (SEQ ID NO: 1) or CPGFPGFC (SEQ ID NO: 16). 
     
     
         37 . The method of  claim 34 , wherein the subject is a human.