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.

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 , 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 11 , wherein the dendritic cells are myeloid dendritic cells. 
     
     
         13 . The method of  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, K101, 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  claim 1 , 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  claim 1 , wherein the OX40 binding agonist is a trimeric OX40L-Fc protein. 
     
     
         32 . The method of  claim 1 , wherein the OX40 binding agonist is an OX40L agonist fragment comprising one or more extracellular domains of OX40L. 
     
     
         33 . The method of  claim 1 , 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  claim 35 , 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 , 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  claim 33 , 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  claim 33 , 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  claim 33 , 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 , wherein the effector T cell is a CD4+ effector T cell. 
     
     
         53 . The method of  claim 33 , 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  claim 33 , wherein the OX40 agonist antibody is stable after treatment at 40° C. for two weeks. 
     
     
         56 . The method of  claim 33 , 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  claim 33 , wherein OX40 agonist antibody cross-linking is required for anti-human OX40 agonist antibody function. 
     
     
         59 . The method of  claim 33 , 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  claim 33 , 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  claim 33 , 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  claim 33 , 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, 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 , 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  claim 65 , 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  claim 33 , 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, 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 , 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  claim 69 , 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  claim 33 , wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 56. 
     
     
         74 . The method of  claim 33 , wherein the OX40 agonist antibody comprises a VL sequence of SEQ ID NO: 57. 
     
     
         75 . The method of  claim 33 , 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  claim 33 , wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 94. 
     
     
         77 . The method of  claim 33 , wherein the OX40 agonist antibody comprises a VL sequence of SEQ ID NO: 95. 
     
     
         78 . The method of  claim 33 , 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  claim 33 , wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 96. 
     
     
         80 . The method of  claim 33 , wherein the OX40 agonist antibody comprises a VL sequence of SEQ ID NO: 97. 
     
     
         81 . The method of  claim 33 , 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  claim 1 , 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  claim 1 , wherein the cancer is a gynecologic cancer. 
     
     
         85 . The method of  claim 1 , wherein the cancer is advanced, refractory, recurrent, chemotherapy-resistant, and/or platinum-resistant. 
     
     
         86 . The method of  claim 1 , wherein the individual has cancer or has been diagnosed with cancer. 
     
     
         87 . The method of  claim 1 , wherein the treatment results in a sustained response in the individual after cessation of the treatment. 
     
     
         88 . The method of  claim 1 , 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  claim 1 , wherein the individual is a human. 
     
     
         90 . The method of  claim 1 , 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  claim 1 , further comprising administering a chemotherapeutic agent for treating or delaying progression of cancer. 
     
     
         92 - 95 . (canceled) 
     
     
         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.