Combination therapy comprising anti-angiogenesis agents and ox40 binding agonists

Abstract

The invention provides compositions and methods for treating cancers. The method comprises administering an anti-angiogenesis agent and an OX40 binding agonist.

What is claimed is: 
     
         1 . A method for treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of an anti-angiogenesis agent and an OX40 binding agonist. 
     
     
         2 . The method of  claim 1 , wherein the anti-angiogenesis agent is selected from the group consisting of an anti-VEGFR2 antibody; an anti-VEGFR1 antibody; a VEGF-trap; a bispecific VEGF antibody; a bispecific antibody comprising a combination of two arms selected from the group consisting of an anti-VEGF arm, an anti-VEGFR1 arm, and an anti-VEGFR2 arm; an anti-VEGF-A antibody; an anti-VEGFB antibody; an anti-VEGFC antibody; an anti-VEGFD antibody; a nonpeptide small molecule VEGF antagonist; an anti-PDGFR inhibitor; and a native angiogenesis inhibitor. 
     
     
         3 . The method of  claim 2 , wherein the anti-angiogenesis agent is selected from the group consisting of ramucirumab, tanibirumab, aflibercept, icrucumab, ziv-aflibercept, MP-0250, vanucizumab, sevacizumab, VGX-100, pazopanib, axitinib, vandetanib, stivarga, cabozantinib, lenvatinib, nintedanib, orantinib, telatinib, dovitinig, cediranib, motesanib, sulfatinib, apatinib, foretinib, famitinib, imatinib, and tivozanib. 
     
     
         4 . The method of  claim 1 , wherein the anti-angiogenesis agent is an anti-angiogenesis antibody. 
     
     
         5 . The method of  claim 4 , wherein the anti-angiogenesis antibody is a monoclonal antibody. 
     
     
         6 . The method of  claim 4  or  claim 5 , wherein the anti-angiogenesis antibody is a human or humanized antibody. 
     
     
         7 . The method of  claim 1 , wherein the anti-angiogenesis agent is a VEGF antagonist. 
     
     
         8 . The method of  claim 7 , wherein the VEGF antagonist reduces the expression level or biological activity of VEGF by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. 
     
     
         9 . The method of  claim 8 , wherein the VEGF is VEGF (8-109), VEGF (1-109), or VEGF 165 . 
     
     
         10 . The method of  claim 7 , wherein the VEGF antagonist increases MHC class II expression on dendritic cells as compared to MHC class II expression on dendritic cells prior to treatment with the VEGF antagonist. 
     
     
         11 . The method of  claim 7 , wherein the VEGF antagonist increases OX40L expression on dendritic cells as compared to OX40L expression on dendritic cells prior to treatment with the VEGF antagonist. 
     
     
         12 . The method of  claim 10  or  claim 11 , wherein the dendritic cells are myeloid dendritic cells. 
     
     
         13 . The method of  claim 10  or  claim 11 , wherein the dendritic cells are non-myeloid dendritic cells. 
     
     
         14 . The method of  claim 7 , wherein the VEGF antagonist comprises a soluble VEGF receptor or a soluble VEGF receptor fragment that specifically binds to VEGF. 
     
     
         15 . The method of  claim 7 , wherein the VEGF antagonist is a chimeric VEGF receptor protein. 
     
     
         16 . The method of  claim 7 , wherein the VEGF antagonist is administered by gene therapy. 
     
     
         17 . The method of  claim 7 , wherein the VEGF antagonist is an anti-VEGF antibody. 
     
     
         18 . The method of  claim 17 , wherein the anti-VEGF antibody is a human or humanized antibody. 
     
     
         19 . The method of  claim 17 , wherein the anti-VEGF antibody binds to the A4.6.1 epitope. 
     
     
         20 . The method of  claim 17 , wherein the anti-VEGF antibody binds to a functional epitope comprising residues F17, M18, D19, Y21, Y25, Q89, 191, K01, E103, and C104 of human VEGF. 
     
     
         21 . The method of  claim 17 , wherein the anti-VEGF antibody binds to a functional epitope comprising residues F17, Y21, Q22, Y25, D63, 183, and Q89 of human VEGF. 
     
     
         22 . The method of  claim 17 , wherein the anti-VEGF antibody is a G6 series antibody. 
     
     
         23 . The method of  claim 17 , wherein the anti-VEGF antibody is a B20 series antibody. 
     
     
         24 . The method of  claim 17 , wherein the anti-VEGF antibody is a monoclonal anti-VEGF antibody. 
     
     
         25 . The method of  claim 24 , wherein the monoclonal anti-VEGF antibody is bevacizumab. 
     
     
         26 . The method of  claim 17 , wherein the anti-VEGF antibody comprises a light chain variable region comprising the amino acid sequence of DIQMTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP GKAPKVLIYF TSSLHSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSTVPWTFGQ GTKVEIKR. (SEQ ID NO:214). 
     
     
         27 . The method of  claim 17 , wherein the anti-VEGF antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGG LVQPGGSLRL SCAASGYTFT NYGMNWVRQA PGKGLEWVGW INTYTGEPTY AADFKRRFTF SLDTSKSTAY LQMNSLRAED TAVYYCAKYP HYYGSSHWYF DVWGQGTLVT VSS (SEQ ID NO:215). 
     
     
         28 . The method of  claim 17 , wherein the anti-VEGF antibody comprises a light chain variable region comprising the amino acid sequence of DIQMTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP GKAPKVLIYF TSSLHSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSTVPWTFGQ GTKVEIKR. (SEQ ID NO:214) and a heavy chain variable region comprising the amino acid sequence of EVQLVESGGG LVQPGGSLRL SCAASGYTFT NYGMNWVRQA PGKGLEWVGW INTYTGEPTY AADFKRRFTF SLDTSKSTAY LQMNSLRAED TAVYYCAKYP HYYGSSHWYF DVWGQGTLVT VSS (SEQ ID NO:215). 
     
     
         29 . The method of  claim 17 , wherein the anti-VEGF antibody comprises one, two, three, four, five, or six hypervariable region (HVR) sequences of bevacizumab. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein the OX40 binding agonist is selected from the group consisting of an OX40 agonist antibody, an OX40L agonist fragment, an OX40 oligomeric receptor, and an OX40 immunoadhesin. 
     
     
         31 . The method of any one of  claims 1 - 30 , wherein the OX40 binding agonist is a trimeric OX40L-Fc protein. 
     
     
         32 . The method of any one of  claims 1 - 30 , wherein the OX40 binding agonist is an OX40L agonist fragment comprising one or more extracellular domains of OX40L. 
     
     
         33 . The method of any one of  claims 1 - 30 , wherein the OX40 binding agonist is an OX40 agonist antibody that binds human OX40. 
     
     
         34 . The method of  claim 33 , wherein the OX40 agonist antibody is a full-length human IgG1 antibody. 
     
     
         35 . The method of  claim 33 , wherein the OX40 agonist antibody depletes cells that express human OX40. 
     
     
         36 . The method of  claim 35 , wherein the cells are CD4+ effector T cells. 
     
     
         37 . The method of  claim 35 , wherein the cells are Treg cells. 
     
     
         38 . The method of any one of  claims 35 - 37 , wherein the depleting is by ADCC and/or phagocytosis. 
     
     
         39 . The method of  claim 38 , wherein the depleting is by ADCC. 
     
     
         40 . The method of  claim 33 , wherein the OX40 agonist antibody binds human OX40 with an affinity of less than or equal to about 0.45 nM. 
     
     
         41 . The method of  claim 40 , wherein the OX40 agonist antibody binds human OX40 with an affinity of less than or equal to about 0.4 nM. 
     
     
         42 . The method of  claim 40  or  claim 41 , wherein OX40 agonist antibody binding affinity is determined using radioimmunoassay. 
     
     
         43 . The method of  claim 33 , wherein binding to human OX40 has an EC50 of less than or equal to 0.2 ug/ml. 
     
     
         44 . The method of  claim 33 , wherein binding to human OX40 has an EC50 of less than or equal to 0.3 ug/ml. 
     
     
         45 . The method of any one of  claims 33 - 44 , wherein the OX40 agonist antibody increases CD4+ effector T cell proliferation and/or increasing cytokine production by the CD4+ effector T cell as compared to proliferation and/or cytokine production prior to treatment with anti-human OX40 agonist antibody. 
     
     
         46 . The method of  claim 45 , wherein the cytokine is gamma interferon. 
     
     
         47 . The method of any one of  claims 33 - 46 , wherein the OX40 agonist antibody increases memory T cell proliferation and/or increasing cytokine production by the memory cell. 
     
     
         48 . The method of  claim 47 , wherein the cytokine is gamma interferon. 
     
     
         49 . The method of any one of  claims 33 - 48 , wherein the OX40 agonist antibody inhibits Treg function. 
     
     
         50 . The method of  claim 49 , wherein the OX40 agonist antibody inhibits Treg suppression of effector T cell function. 
     
     
         51 . The method of  claim 50 , wherein effector T cell function is effector T cell proliferation and/or cytokine production. 
     
     
         52 . The method of  claim 50  or  claim 51 , wherein the effector T cell is a CD4+ effector T cell. 
     
     
         53 . The method of any one of  claims 33 - 52 , wherein the OX40 agonist antibody increases OX40 signal transduction in a target cell that expresses OX40. 
     
     
         54 . The method of  claim 53 , wherein OX40 signal transduction is detected by monitoring NFkB downstream signaling. 
     
     
         55 . The method of any one of  claims 33 - 54 , wherein the OX40 agonist antibody is stable after treatment at 40° C. for two weeks. 
     
     
         56 . The method of any one of  claims 33 - 55 , wherein the OX40 agonist antibody comprises a variant IgG1 Fc polypeptide comprising a mutation that eliminates binding to human effector cells, and wherein the antibody has diminished activity relative to an anti-human OX40 agonist antibody comprising a native sequence IgG1 Fc portion. 
     
     
         57 . The method of  claim 56 , wherein the OX40 agonist antibody comprises a variant Fc portion comprising a DANA mutation. 
     
     
         58 . The method of any one of  claims 33 - 57 , wherein OX40 agonist antibody cross-linking is required for anti-human OX40 agonist antibody function. 
     
     
         59 . The method of any one of  claims 33 - 58 , the OX40 agonist antibody comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 2, 8 or 9, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3, 10, 11, 12, 13 or 14, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 4, 15, or 19; and (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 7, 22, 23, 24, 25, 26, 27, or 28. 
     
     
         60 . The method of  claim 59 , wherein the OX40 agonist antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence of SEQ ID NO:7. 
     
     
         61 . The method of  claim 59 , wherein the OX40 agonist antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence of SEQ ID NO:26. 
     
     
         62 . The method of  claim 59 , wherein the OX40 agonist antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence of SEQ ID NO:27. 
     
     
         63 . The method of any one of  claims 33 - 62 , wherein the OX40 agonist antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 108, 114, 116, 233, or 234. 
     
     
         64 . The method of any one of  claims 33 - 63 , wherein the OX40 agonist antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 109, 115 or 117. 
     
     
         65 . The method of any one of  claims 33 - 64 , wherein the OX40 agonist antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:56. 
     
     
         66 . The method of  claim 65 , wherein the OX40 agonist VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to human OX40. 
     
     
         67 . The method of  claim 65  or  claim 66 , wherein a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:56. 
     
     
         68 . The method of any one of  claims 65 - 67 , wherein the OX40 agonist VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4. 
     
     
         69 . The method of any one of  claims 33 - 68 , wherein the OX40 agonist antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:57. 
     
     
         70 . The method of  claim 69 , wherein the OX40 agonist VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to human OX40. 
     
     
         71 . The method of  claim 69  or  70 , wherein a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 57. 
     
     
         72 . The method of any one of  claims 69 - 71 , wherein the OX40 agonist VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7. 
     
     
         73 . The method of any one of  claims 33 - 72 , wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 56. 
     
     
         74 . The method of any one of  claims 33 - 72 , wherein the OX40 agonist antibody comprises a VL sequence of SEQ ID NO: 57. 
     
     
         75 . The method of any one of  claims 33 - 72 , wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO:56 and a VL sequence of SEQ ID NO: 57. 
     
     
         76 . The method of any one of  claims 33 - 72 , wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 94. 
     
     
         77 . The method of any one of  claims 33 - 72 , wherein the OX40 agonist antibody comprises a VL sequence of SEQ ID NO: 95. 
     
     
         78 . The method of any one of  claims 33 - 72 , wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO:94 and a VL sequence of SEQ ID NO: 95. 
     
     
         79 . The method of any one of  claims 33 - 72 , wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 96. 
     
     
         80 . The method of any one of  claims 33 - 72 , wherein the OX40 agonist antibody comprises a VL sequence of SEQ ID NO: 97. 
     
     
         81 . The method of any one of  claims 33 - 72 , wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO:96 and a VL sequence of SEQ ID NO: 97. 
     
     
         82 . The method of  claim 33 , wherein the OX40 agonist antibody is MEDI6469, MEDI0562, or MEDI6383. 
     
     
         83 . The method of any one of  claims 1 - 82 , wherein the cancer is lung cancer, glioblastoma, cervical cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, fallopian tube cancer, peritoneal cancer, kidney cancer, renal cancer, non-Hodgkins lymphoma, prostate cancer, pancreatic cancer, soft-tissue sarcoma, kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, mesothelioma, multiple myeloma, non-small cell lung cancer, neuroblastoma, melanoma, gastric cancer, or liver cancer. 
     
     
         84 . The method of any one of  claims 1 - 82 , wherein the cancer is a gynecologic cancer. 
     
     
         85 . The method of any one of  claims 1 - 84 , wherein the cancer is advanced, refractory, recurrent, chemotherapy-resistant, and/or platinum-resistant. 
     
     
         86 . The method of any one of  claims 1 - 85 , wherein the individual has cancer or has been diagnosed with cancer. 
     
     
         87 . The method of any one of  claims 1 - 86 , wherein the treatment results in a sustained response in the individual after cessation of the treatment. 
     
     
         88 . The method of any one of  claims 1 - 87 , wherein the OX40 binding agonist is administered before the anti-angiogenesis agent, simultaneous with the anti-angiogenesis agent, or after the anti-angiogenesis agent. 
     
     
         89 . The method of any one of  claims 1 - 88 , wherein the individual is a human. 
     
     
         90 . The method of any one of  claims 1 - 89 , wherein the anti-angiogenesis agent and/or the OX40 binding agonist are administered intravenously, intramuscularly, subcutaneously, intracerobrospinally, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intra-articularly, intrasynovially, or intranasally. 
     
     
         91 . The method of any one of  claims 1 - 90 , further comprising administering a chemotherapeutic agent for treating or delaying progression of cancer. 
     
     
         92 . Use of an anti-angiogenesis agent in the manufacture of a medicament for treating or delaying progression of cancer in an individual, wherein the medicament comprises the anti-angiogenesis agent and an optional pharmaceutically acceptable carrier, and wherein the treatment comprises administration of the medicament in combination with a composition comprising an OX40 binding agonist and an optional pharmaceutically acceptable carrier. 
     
     
         93 . Use of an OX40 binding agonist in the manufacture of a medicament for treating or delaying progression of cancer in an individual, wherein the medicament comprises the OX40 binding agonist and an optional pharmaceutically acceptable carrier, and wherein the treatment comprises administration of the medicament in combination with a composition comprising an anti-angiogenesis agent and an optional pharmaceutically acceptable carrier. 
     
     
         94 . A composition comprising an anti-angiogenesis agent and an optional pharmaceutically acceptable carrier for use in treating or delaying progression of cancer in an individual, wherein the treatment comprises administration of said composition in combination with a second composition, wherein the second composition comprises OX40 binding agonist and an optional pharmaceutically acceptable carrier. 
     
     
         95 . A composition comprising an OX40 binding agonist and an optional pharmaceutically acceptable carrier for use in treating or delaying progression of cancer in an individual, wherein the treatment comprises administration of said composition in combination with a second composition, wherein the second composition comprises an anti-angiogenesis agent and an optional pharmaceutically acceptable carrier. 
     
     
         96 . A kit comprising a medicament comprising an anti-angiogenesis agent and an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administration of the medicament in combination with a composition comprising an OX40 binding agonist and an optional pharmaceutically acceptable carrier for treating or delaying progression of cancer in an individual. 
     
     
         97 . A kit comprising a first medicament comprising an anti-angiogenesis agent and an optional pharmaceutically acceptable carrier, and a second medicament comprising an OX40 binding agonist and an optional pharmaceutically acceptable carrier. 
     
     
         98 . The kit of  claim 97 , wherein the kit further comprises a package insert comprising instructions for administration of the first medicament and the second medicament for treating or delaying progression of cancer in an individual. 
     
     
         99 . A kit comprising a medicament comprising an OX40 binding agonist and an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administration of the medicament in combination with a composition comprising an anti-angiogenesis agent and an optional pharmaceutically acceptable carrier for treating or delaying progression of cancer in an individual.