US 20150307617A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0307617 A1 DU et al. (43) Pub. Date: Oct. 29, 2015
(54) ANTI-OX40ANTIBODIES AND METHODS OF cation No. 62/080,171, filed on Nov. 14, 2014, provi USE sional application No. 62/113,345, filed on Feb. 6, 2015. (71) Applicant: Genentech, Inc., South San Francisco, CA (US) Publication Classification (72) Inventors: Changchun DU, South San Francisco, (51) Int. Cl. CA (US); Jeong Kim, San Francisco, C07K 6/28 (2006.01) CA (US); Jing Zhu, Moraga, CA (US); A 6LX39/395 (2006.01) Jack Bevers, III, San Mateo, CA (US); C07K 6/30 (2006.01) Kevin Walsh, Walnut Creek, CA (US); A647/48 (2006.01) Patricia De Almeida, Pleasant Hill, CA A6II 45/06 (2006.01) (US); James Andya, Millbrae, CA (US); (52) U.S. Cl. Ye Shen, Daly City, CA (US) CPC ...... C07K 16/2878 (2013.01); A61K 47/48561 2013.O1): 46 IK 47/48.384 (2013.O1): 46II (73) Assignee: Genentech, Inc., South San Francisco, isi, 38-6. C07K 6/30 38. A61 K CA (US) 39/39558 (2013.01); A61 K39/3955 (2013.01); C07K 16/3069 (2013.01); C07K 2317/92 (21) Appl. No.: 14/673,792 (2013.01); C07K 2317/75 (2013.01); C07K 1-1. 2317/71 (2013.01); C07K 2317/56 (2013.01); (22)22) FileFiled: Marar, 30,5U, 2015 C07K 2317/51 (2013.01);s C07K 2317/515s Related U.S. Application Data (2013.01); A61K 2039/505 (2013.01) (60) Provisional application No. 61/973,193, filed on Mar. (57) ABSTRACT 31, 2014, provisional application No. 61/989,448, filed on May 6, 2014, provisional application No. The invention provides anti-OX40 antibodies and methods of 62/073,873, filed on Oct. 31, 2014, provisional appli using the same. Patent Application Publication Oct. 29, 2015 Sheet 1 of 39 US 2015/0307617 A1
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Nos. 61/973,193, filed Mar. 31, cial effects of combining bevacizumab with standard chemo 2014: 61/989,448, filed May 6, 2014; 62/073,873, filed Oct. therapeutic regimens (see, e.g., Saltz et al., 2008, J. Clin. 31, 2014; 62/080,171, filed Nov. 14, 2014; and 62/113,345, Oncol., 26:2013-2019; Yang et al., 2008, Clin. Cancer Res., filed Feb. 6, 2015; each of which is incorporated herein by 14:5893-5899: Hurwitz et al., 2004, N. Engl. J. Med., 350: reference in its entirety. 2335-2342). However, as in previous studies of angiogenesis inhibitors, some of these phase-III studies have shown that a portion of patients experience incomplete response to the SEQUENCE LISTING addition of bevacizumab to their chemotherapeutic regimens. 0002 The content of the following submission on ASCII Accordingly, there is a need for methods of identifying those text file is incorporated herein by reference in its entirety: a patients that are likely to respond or have an improved computer readable form (CRF) of the Sequence Listing (file response to not only angiogenesis inhibitors (e.g., bevaci name: 146392029100SEQLIST.txt, date recorded: Mar. 30, Zumab) alone, but also combination therapies comprising 2015, size: 191 KB). angiogenesis inhibitors (e.g., bevacizumab). 0009. Accordingly, there is a need for combination thera FIELD OF THE INVENTION pies that may increase the efficacy of anti-angiogenic cancer 0003. The present invention relates to anti-OX40 antibod therapy. Combination therapies may increase responsiveness ies and methods of using the same. in patients that show incomplete response and/or further increase responsiveness in patients that do respond to anti BACKGROUND angiogenic cancer therapy. 0010 All references cited herein, including patent appli 0004 OX40 (also known as CD34, TNFRSF4 and cations and publications, are incorporated by reference in ACT35) is a member of the tumor necrosis factor receptor superfamily. OX40 is not constitutively expressed on naive T their entirety. cells, but is induced after engagement of the T cell receptor SUMMARY (TCR). The ligand for OX40, OX40L, is predominantly expressed on antigen presenting cells. OX40 is highly 0011. In one aspect, provided are isolated antibodies that expressed by activated CD4+ T cells, activated CD8+ T cells, bind to human OX40. memory T cells, and regulatory T cells. OX40 signaling can 0012. In another aspect, provided are anti-human OX40 provide costimulatory signals to CD4 and CD8 T cells, lead agonist antibodies wherein the antibody is a depleting anti ing to enhanced cell proliferation, Survival, effector function body. In another aspect, provided are anti-human OX40 ago and migration. OX40 signaling also enhances memory T cell nist antibodies wherein the antibody depletes cells that development and function. express human OX40 in vitro and binds human OX40 with an 0005 Regulatory T cells (Treg) cells are highly enriched affinity of less than or equal to about 1 nM. In some embodi in tumors and tumor draining lymph nodes derived from ments, the antibodies deplete CD4+ effector T cells. In some multiple cancer indications, including melanoma, NSCLC, embodiments the antibodies deplete regulatory T cells (Treg). renal, ovarian, colon, pancreatic, hepatocellular, and breast In some embodiments, the depleting is by ADCC and/or cancer. In a Subset of these indications, increased intratu phagocytosis. In some embodiments, the depleting is by moral T reg cell densities are associated with poor patient ADCC prognosis, Suggesting that these cells play an important role 0013. In another aspect, provided are anti-human OX40 in Suppressing antitumor immunity. OX40 positive tumor agonistantibodies that bind human OX40 with an affinity of infiltrating lymphocytes have been described. less than or equal to about 0.45 nM. In some embodiments, 0006. It is clear that there continues to be a need for agents the antibody binds human OX40 with an affinity of less than that have clinical attributes that are optimal for development or equal to about 0.4 nM. In some embodiments, antibody as therapeutic agents. The invention described herein meets binding affinity is determined using radioimmunoassay. In this need and provides other benefits. some embodiments, the antibody binds human OX40 and 0007 Bevacizumab (Avastin R) is a recombinant human cynomolgus OX40. In some embodiments, binding to human ized monoclonal IgG1 antibody that specifically binds to and and cynomolgus OX40 is determined using a FACS assay. In blocks the biological effects of VEGF. Bevacizumab has been some embodiments, binding to human OX40 has an EC50 of approved in Europe for the treatment of the advanced stages less than or equal to 0.2ug/ml. In some embodiments, binding of six common types of cancer: colorectal cancer, breast to human OX40 has an EC50 of less than or equal to 0.3 ug/ml cancer, non-Small cell lung cancer (NSCLC), ovarian cancer, or lower. In some embodiments, binding to cynomolgus cervical cancer, and kidney cancer, which collectively cause OX40 has an EC50 of less than or equal to 1.5ug/ml. In some over 2.5 million deaths each year. In the United States, beva embodiments, binding to cynomolgus OX40 has an EC50 of cizumab was the first anti-angiogenesis therapy approved by less than or equal to 1.4 ug/ml. the FDA, and it is now approved for the treatment of six tumor 0014. In another aspect, the invention provides anti-hu types: colorectal cancer, NSCLC, brain cancer (glioblas man OX40 agonist antibodies that increase (are capable of toma), kidney cancer (renal cell carcinoma), ovarian cancer, increasing) CD4+ effector T cell proliferation and/or increas and cervical cancer. Over half a million patients have been ing cytokine production by the CD4+ effector T cell as com treated with bevacizumab so far, and a comprehensive clinical pared to proliferation and/or cytokine production prior to US 2015/0307617 A1 Oct. 29, 2015 treatment with anti-human OX40 agonist antibody. In some amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 embodiments, the cytokine is gamma interferon. comprising an amino acid sequence selected from SEQ ID 0015. In another aspect, the invention provides anti-hu NO:7. man OX40 agonist antibodies that increase (are capable of 0023. In another aspect, provided are anti-human OX40 increasing) memory T cell proliferation and/or increasing agonistantibodies, wherein the antibody comprises (a) HVR cytokine production by the memory cell. In some embodi H1 comprising the amino acid sequence of SEQID NO:2; (b) ments, the cytokine is gamma interferon. HVR-H2 comprising the amino acid sequence of SEQ ID 0016. In another aspect, the invention provides anti-hu NO:3; (c) HVR-H3 comprising the amino acid sequence of man OX40 agonist that inhibit (are capable of inhibiting) Treg SEQ ID NO:4; (d) HVR-L1 comprising the amino acid function. In some embodiments, the antibodies inhibit Treg sequence of SEQ ID NO:5; (e) HVR-L2 comprising the suppression of effector T cell function. In some embodi amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 ments, effector T cell function is effector T cell proliferation comprising an amino acid sequence selected from SEQ ID and/or cytokine production. In some embodiments, the effec NO:26. tor T cell is a CD4+ effector T cell. 0024. In another aspect, provided are anti-human OX40 0017. In another aspect, the invention provides anti-hu agonistantibodies, wherein the antibody comprises (a) HVR man OX40 agonist antibodies that increase (are capable of H1 comprising the amino acid sequence of SEQID NO:2; (b) increasing) OX40 signal transduction in a target cell that HVR-H2 comprising the amino acid sequence of SEQ ID expresses OX40. In some embodiments, OX40 signal trans NO:3; (c) HVR-H3 comprising the amino acid sequence of duction is detected by monitoring NFkB downstream signal SEQ ID NO:4; (d) HVR-L1 comprising the amino acid ing (e.g., in the OX40 expressing cell, e.g., CD4+ effector T sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 cell, CD8+ effector T cell, CD4+ memory T cell). comprising an amino acid sequence selected from SEQ ID 0018. In another aspect, provided are anti-human OX40 NO:27. agonistantibodies that are stable after treatment at 40°C. for 0025. In another aspect, provided are anti-human OX40 two weeks. agonist antibodies, wherein the antibody comprises a heavy 0019. In another aspect, provided are anti-human OX40 chain variable domain (VH) sequence having at least 90%, agonistantibodies, wherein the antibodies comprise a variant 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% IgG1 Fc polypeptide comprising a mutation that eliminates sequence identity to the amino acid sequence of SEQ ID binding to human effector cells, wherein the antibodies have NO:56, 58,60, 62, 64, 66, 68,70, 72, 74,76, 78,80, 82,84, 86, diminished activity relative to anti-human OX40 agonistanti 88,90, 92,94, 96, 98, 100, 108, 114, 116, 233, or 234. bodies comprising native sequence IgG1 Fc portion. In some 0026. In another aspect, provided are anti-human OX40 embodiments, the antibodies comprise a variant Fc portion agonistantibodies, wherein the antibody comprises, wherein comprising a mutation that eliminates binding to FcR (e.g., a the antibody comprises a light chain variable domain (VL) DANA or N297G mutation). In some embodiments, the activ having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, ity is one or more of increasing CD4+ effector T cell prolif 98%, 99%, or 100% sequence identity to the amino acid eration and/or cytokine production, increasing CD4+ sequence of SEQID NO:57, 59, 61,63, 65, 67, 69,71, 73,75, memory T cell proliferation and/or cytokine production, and/ 77,79, 81, 83, 85, 87, 89,91, 93, 95, 97,99, 101, 109, 115 or or depleting cells by ADCC and/or phagocytosis. 117. 0020. In another aspect, provided are anti-human OX40 0027. In another aspect, provided are anti-human OX40 agonist antibodies, wherein antibody cross-linking is agonist antibodies, wherein the antibody comprises a heavy required for anti-human OX40 agonist antibody function. In chain variable domain (VH) sequence having at least 90%, Some embodiments, anti-human OX40 agonist antibody 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% function is one or more of increasing CD4+ effector T cell sequence identity to the amino acid sequence of SEQ ID proliferation and/or cytokine production, increasing CD4+ NO:56. In some embodiments, the VH sequence having at memory T cell proliferation and/or cytokine production, and/ least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or or depleting cells by ADCC and/or phagocytosis. 99% identity contains substitutions (e.g., conservative substi 0021. In another aspect, provided are anti-human OX40 tutions), insertions, or deletions relative to the reference agonistantibodies, wherein the antibody comprises (a) a VH sequence, but an anti-human OX40 agonist antibody com domain comprising (i) HVR-H1 comprising the amino acid prising that sequence retains the ability to bind to human sequence of SEQID NO: 2, 8 or 9, (ii) HVR-H2 comprising OX40. In some embodiments, total of 1 to 10 amino acids the amino acid sequence of SEQID NO: 3, 10, 11, 12, 13 or have been substituted, inserted and/or deleted in SEQ ID 14, and (iii) HVR-H3 comprising an amino acid sequence NO:56. In some embodiments, the VH comprises one, two or selected from SEQ ID NO: 4, 15, or 19; and (iv) HVR-L1 three HVRs selected from: (a) HVR-H1 comprising the comprising the amino acid sequence of SEQ ID NO:5, (v) amino acid sequence of SEQID NO:2, (b) HVR-H2 compris HVR-L2 comprising the amino acid sequence of SEQ ID ing the amino acid sequence of SEQID NO:3, and (c) HVR NO:6, and (vi) HVR-L3 comprising the amino acid sequence H3 comprising the amino acid sequence of SEQID NO:4. of SEQID NO: 7, 22, 23, 24, 25, 26, 27, or 28. 0028. In another aspect, provided are anti-human OX40 0022. In another aspect, provided are anti-human OX40 agonist antibodies, wherein the antibody comprises a light agonistantibodies, wherein the antibody comprises (a) HVR chain variable domain (VL) having at least 90%, 91%, 92%, H1 comprising the amino acid sequence of SEQID NO:2; (b) 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence HVR-H2 comprising the amino acid sequence of SEQ ID identity to the amino acid sequence of SEQ ID NO:57. In NO:3; (c) HVR-H3 comprising the amino acid sequence of some embodiments, the VL sequence having at least 90%, SEQ ID NO:4; (d) HVR-L1 comprising the amino acid 91%, 92%.93%, 94%, 95%,96%.97%, 98%, or 99% identity sequence of SEQ ID NO:5; (e) HVR-L2 comprising the contains Substitutions (e.g., conservative substitutions), US 2015/0307617 A1 Oct. 29, 2015 insertions, or deletions relative to the reference sequence, but 0046. In some embodiments of any of the antibodies of the an anti-human OX40 agonist antibody comprising that invention, the antibody is a naked antibody. sequence retains the ability to bind to human OX40. In some 0047. In another aspect, provided are isolated nucleic embodiments, a total of 1 to 10 amino acids have been sub acids encoding any of the anti-human OX40 antibodies (e.g., stituted, inserted and/or deleted in SEQID NO: 57. In some agonistantibodies) provided herein. embodiments, the VL comprises one, two or three HVRs 0048. In another aspect, provided are host cells compris selected from (a) HVR-L1 comprising the amino acid ing the nucleic acid encoding any of the anti-human OX40 sequence of SEQ ID NO:5; (b) HVR-L2 comprising the antibodies (e.g., agonist antibodies) provided herein. amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 0049. In another aspect, provided are methods of produc comprising the amino acid sequence of SEQID NO:7. ing an antibody comprising culturing the host cell so that the 0029. In another aspect, provided are anti-human OX40 antibody is produced. In some embodiments, the methods agonistantibodies comprising a VH sequence of SEQID NO: further comprise recovering the antibody from the host cell. 56. 0050. In another aspect, provided are immunoconjugates 0030. In another aspect, provided are anti-human OX40 comprising any of the anti-human OX40 antibodies (e.g., agonistantibodies comprising a VL sequence of SEQID NO: agonistantibodies) provided herein and a cytotoxic agent. 57. 0051. In another aspect, provided are pharmaceutical for 0031. In another aspect, provided are anti-human OX40 mulations comprising any of the anti-human OX40 antibod agonist antibodies comprising a VH sequence of SEQ ID ies (e.g., agonist antibodies) provided herein and a pharma NO:56 and a VL sequence of SEQID NO: 57. ceutically acceptable carrier. In some embodiments, the 0032. In another aspect, provided are anti-human OX40 pharmaceutical formulation comprises (a) any of the anti agonistantibodies comprising a VH sequence of SEQID NO: human OX40 agonist antibodies described herein at a con 94. centration between about 10 mg/mL and about 100 mg/mL, 0033. In another aspect, provided are anti-human OX40 (b) a polysorbate, wherein the polysorbate concentration is agonistantibodies comprising a VL sequence of SEQID NO: about 0.02% to about 0.06%; (c) ahistidine buffer at about pH 95. 5.0 to about pH 6.0; and (d) a saccharide, wherein the sac 0034. In another aspect, provided are anti-human OX40 charide concentration is about 120 mM to about 320 mM. In agonist antibodies comprising a VH sequence of SEQ ID some embodiments, the histidine buffer is at pH 5.0 to 6.0. In NO:94 and a VL sequence of SEQID NO: 95. Some embodiments, the saccharide is sucrose. In some 0035. In another aspect, provided are anti-human OX40 embodiments, the pharmaceutical formulation comprises (a) agonistantibodies comprising a VH sequence of SEQID NO: any of the anti-human OX40 agonist antibodies described 96. herein, (b) polysorbate 20, wherein the polysorbate concen 0036. In another aspect, provided are anti-human OX40 tration is about 0.02%; (c) a histidine acetate buffer at pH 6.0: agonistantibodies comprising a VL sequence of SEQID NO: and (d) Sucrose, wherein the Sucrose concentration is about 97. 320 mM. In some embodiments, the pharmaceutical formu 0037. In another aspect, provided are anti-human OX40 lation comprises (a) any of the anti-human OX40 agonist agonist antibodies comprising a VH sequence of SEQ ID antibodies described herein, (b) polysorbate 20, wherein the NO:96 and a VL sequence of SEQID NO: 97. polysorbate concentration is about 0.02%; (c) a histidine 0038. In another aspect, provided are anti-human OX40 acetate buffer at pH 5.5; and (d) sucrose, wherein the sucrose agonistantibodies comprising a VH sequence of SEQID NO: concentration is about 240 mM. In some embodiments, the 18O. pharmaceutical formulation comprises (a) any of the anti 0039. In another aspect, provided are anti-human OX40 human OX40 agonist antibodies described herein, (b) agonistantibodies comprising a VL sequence of SEQID NO: polysorbate 20, wherein the polysorbate concentration is 179. about 0.04%; (c) a histidine acetate buffer at pH 6.0; and (d) sucrose, wherein the sucrose concentration is about 120 mM. 0040. In another aspect, provided are anti-human OX40 In some embodiments, the pharmaceutical formulation com agonist antibodies comprising a VH sequence of SEQ ID prises (a) any of the anti-human OX40 agonist antibodies NO:180 and a VL sequence of SEQID NO: 179. described herein, (b) polysorbate 40, wherein the polysorbate 0041. In another aspect, provided are anti-human OX40 concentration is about 0.04%; (c) a histidine acetate buffer at agonistantibodies comprising a VH sequence of SEQID NO: pH 5.0; and (d) Sucrose, wherein the Sucrose concentration is 182. about 240 mM. In some embodiments, the pharmaceutical 0042. In another aspect, provided are anti-human OX40 formulation comprises (a) any of the anti-human OX40 ago agonistantibodies comprising a VL sequence of SEQID NO: nistantibodies described herein, (b) polysorbate 40, wherein 181. the polysorbate concentration is about 0.04%; (c) a histidine 0043. In another aspect, provided are anti-human OX40 acetate buffer at pH 6.0; and (d) sucrose, wherein the sucrose agonist antibodies comprising a VH sequence of SEQ ID concentration is about 120 mM. In some embodiments, the NO:182 and a VL sequence of SEQID NO: 181. antibody of the formulation comprises (a) a VH domain com 0044. In some embodiments of any of the antibodies of the prising (i) HVR-H1 comprising the amino acid sequence of invention, the antibody is a full length human IgG1 antibody. SEQ ID NO: 2, 8 or 9, (ii) HVR-H2 comprising the amino 0045. In some embodiments of any of the antibodies of the acid sequence of SEQID NO: 3, 10, 11, 12, 13 or 14, and (iii) invention, the antibody is a human antibody. In some embodi HVR-H3 comprising an amino acid sequence selected from ments of any of the antibodies of the invention, the antibody SEQ ID NO: 4, 15, or 19; and (iv) HVR-L1 comprising the is a humanized antibody. In some embodiments of any of the amino acid sequence of SEQID NO:5, (v) HVR-L2 compris antibodies of the invention, the antibody is a chimeric anti ing the amino acid sequence of SEQID NO:6, and (vi) HVR body. L3 comprising the amino acid sequence of SEQID NO: 7, 22. US 2015/0307617 A1 Oct. 29, 2015 23, 24, 25, 26, 27, or 28. In some embodiments, the antibody ability to bind to human OX40. In some embodiments, a total of the formulation comprises (a) HVR-H1 comprising the of 1 to 10 amino acids have been substituted, inserted and/or amino acid sequence of SEQ ID NO:2; (b) HVR-H2 com deleted in SEQ ID NO: 57. In some embodiments, the VL prising the amino acid sequence of SEQID NO:3; (c) HVR comprises one, two or three HVRs selected from (a) HVR-L1 H3 comprising the amino acid sequence of SEQID NO:4; (d) comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L1 comprising the amino acid sequence of SEQ ID HVR-L2 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of NO:6; and (c) HVR-L3 comprising the amino acid sequence SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid of SEQID NO:7. In some embodiments, the antibody of the formulation comprises a VH sequence of SEQID NO: 56. In sequence selected from SEQ ID NO:7. In some embodi some embodiments, the antibody of the formulation com ments, the antibody of the formulation comprises (a) HVR prises a VL sequence of SEQ ID NO: 57. In some embodi H1 comprising the amino acid sequence of SEQID NO:2; (b) ments, the antibody of the formulation comprises a VH HVR-H2 comprising the amino acid sequence of SEQ ID sequence of SEQID NO:56 and a VL sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of NO: 57. In some embodiments, the antibody of the formula SEQ ID NO:4; (d) HVR-L1 comprising the amino acid tion comprises a VH sequence of SEQ ID NO: 94. In some sequence of SEQ ID NO:5; (e) HVR-L2 comprising the embodiments, the antibody of the formulation comprises a amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 VL sequence of SEQID NO: 95. In some embodiments, the comprising an amino acid sequence selected from SEQ ID antibody of the formulation comprises aVH sequence of SEQ NO:26. In some embodiments, the antibody of the formula ID NO:94 and a VL sequence of SEQ ID NO: 95. In some tion comprises (a) HVR-H1 comprising the amino acid embodiments, the antibody of the formulation comprises a sequence of SEQ ID NO:2; (b) HVR-H2 comprising the VH sequence of SEQID NO: 96. In some embodiments, the amino acid sequence of SEQID NO:3; (c) HVR-H3 compris antibody of the formulation comprises aVL sequence of SEQ ing the amino acid sequence of SEQID NO:4; (d) HVR-L1 ID NO: 97. In some embodiments, the antibody of the for comprising the amino acid sequence of SEQ ID NO:5; (e) mulation comprises a VH sequence of SEQID NO:96 and a HVR-L2 comprising the amino acid sequence of SEQ ID VL sequence of SEQID NO: 97. In some embodiments, the NO:6; and (f) HVR-L3 comprising an amino acid sequence antibody of the formulation comprises aVH sequence of SEQ selected from SEQ ID NO:27. In some embodiments, the ID NO: 180. In some embodiments, the antibody of the for antibody of the formulation comprises a heavy chain variable mulation comprises a VL sequence of SEQID NO: 179. In domain (VH) sequence having at least 90%, 91%, 92%, 93%, some embodiments, the antibody of the formulation com 94%. 95%,96%.97%.98%, 99%, or 100% sequence identity prises a VH sequence of SEQID NO:180 and a VL sequence to the amino acid sequence of SEQID NO:56, 58, 60, 62, 64. of SEQID NO: 179. In some embodiments, the antibody of 66, 68,70, 72, 74,76, 78,80, 82,84, 86, 88,90, 92,94, 96, 98, the formulation comprises a VH sequence of SEQ ID NO: 100, 108, 114, 116, 233, or 234. In some embodiments, the 182. In some embodiments, the antibody of the formulation antibody of the formulation comprises a light chain variable comprises a VL sequence of SEQ ID NO: 181. In some domain (VL) having at least 90%, 91%, 92%, 93%, 94%, embodiments, the antibody of the formulation comprises a 95%,96%.97%, 98%.99%, or 100% sequence identity to the VH sequence of SEQID NO:182 and a VL sequence of SEQ amino acid sequence of SEQIDNO:57, 59, 61,63, 65, 67, 69, ID NO: 181. 71, 73, 75, 77, 79, 81, 83, 85, 87, 89,91, 93, 95, 97,99, 101, 109, 115 or 117. In some embodiments, the antibody of the 0052. In another aspect, an anti-human OXO agonistanti formulation comprises a heavy chain variable domain (VH) bodies provided herein is for use as a medicament. sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 0053. In another aspect, an anti-human OXO agonistanti 96%, 97%, 98%, 99%, or 100% sequence identity to the body provided herein is for use in treating cancer. amino acid sequence of SEQ ID NO:56. In some embodi 0054. In another aspect, an anti-human OXO agonistanti ments, the VH sequence having at least 90%, 91%, 92%, body provided herein is for use in one or more of inhibiting 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains Treg function (e.g., inhibiting the Suppressive function of Substitutions (e.g., conservative Substitutions), insertions, or Tregs), killing OX40 expressing cells (e.g., cells that express deletions relative to the reference sequence, but an anti-hu high levels of OX40), increasing effector T cell function man OX40 agonistantibody comprising that sequence retains and/or increasing memory T cell function, decrease tumor the ability to bind to human OX40. In some embodiments, immunity, enhance T cell function and/or depleting OX-40 total of 1 to 10 amino acids have been substituted, inserted expressing cells. and/or deleted in SEQID NO:56. In some embodiments, the 0055. In another aspect, provided is use of an anti-human VH comprises one, two or three HVRs selected from: (a) OXO agonistantibody provided herein in the manufacture of HVR-H1 comprising the amino acid sequence of SEQ ID a medicament for treatment of cancer. NO:2, (b) HVR-H2 comprising the amino acid sequence of 0056. In another aspect, provided is use of an anti-human SEQID NO:3, and (c) HVR-H3 comprising the amino acid OXO agonistantibody provided herein in the manufacture of sequence of SEQ ID NO:4. In some embodiments, the anti a medicament for one or more of inhibiting Treg function body of the formulation comprises a light chain variable (e.g., inhibiting the Suppressive function of Tregs), killing domain (VL) having at least 90%, 91%, 92%, 93%, 94%, OX40 expressing cells (e.g., cells that express high levels of 95%,96%.97%, 98%.99%, or 100% sequence identity to the OX40), increasing effector T cell function and/or increasing amino acid sequence of SEQ ID NO:57. In some embodi memory T cell function, decrease tumor immunity, enhance T ments, the VL sequence having at least 90%, 91%, 92%.93%, cell function and/or depleting OX-40 expressing cells. 94%. 95%, 96%, 97%, 98%, or 99% identity contains substi 0057. In another aspect, provided are methods of treating tutions (e.g., conservative Substitutions), insertions, or dele an individual having cancer comprising administering to the tions relative to the reference sequence, but an anti-human individual an effective amount of any of the anti-human OX40 agonistantibody comprising that sequence retains the OX40 agonist antibodies provided herein. In some embodi US 2015/0307617 A1 Oct. 29, 2015 ments, the methods further comprise administering an addi herein is a kit comprising a medicament comprising an OX40 tional therapeutic agent. In some embodiments, the additional binding agonist and an optional pharmaceutically acceptable therapeutic agent comprises a chemotherapeutic agent. In carrier, and a package insert comprising instructions for Some embodiments, the additional therapeutic agent com administration of the medicament in combination with a com prises a PD-1 axis binding antagonist. position comprising an anti-angiogenesis agent and an 0058. In another aspect, provided are methods of diagno optional pharmaceutically acceptable carrier for treating or sis or detection using any of the anti-human OX40 antibodies delaying progression of cancer in an individual. disclosed herein. 0064. In some embodiments, the anti-angiogenesis agent 0059. In another aspect, provided are kits or articles of is selected from the group consisting of an anti-VEGFR2 manufacture comprising any of the anti-human OX40 anti antibody; an anti-VEGFR1 antibody; a VEGF-trap; a bispe bodies disclosed herein. cific VEGF antibody; a bispecific antibody comprising a 0060. In one aspect, provided herein is a method for treat combination of two arms selected from the group consisting ing or delaying progression of cancer in an individual com of an anti-VEGF arm, an anti-VEGFR1 arm, and an anti prising administering to the individual an effective amount of VEGFR2 arm; an anti-VEGF-A antibody; an anti-VEGFB an anti-angiogenesis agent and an OX40 binding agonist. antibody; an anti-VEGFC antibody; an anti-VEGFD anti 0061. In another aspect, provided herein is a use of an body; a nonpeptide Small molecule VEGF antagonist; an anti-angiogenesis agent in the manufacture of a medicament anti-PDGFR inhibitor; and a native angiogenesis inhibitor. In for treating or delaying progression of cancer in an individual, Some embodiments, the anti-angiogenesis agent is selected wherein the medicament comprises the anti-angiogenesis from the group consisting of ramucirumab, tanibirumab, agent and an optional pharmaceutically acceptable carrier, aflibercept, icrucumab, Ziv-aflibercept, MP-0250, Vanuci and wherein the treatment comprises administration of the Zumab, sevacizumab, VGX-100, pazopanib, axitinib, vandet medicament in combination with a composition comprising anib, stivarga, cabozantinib, lenvatinib, nintedanib, orantinib, an OX40 binding agonist and an optional pharmaceutically telatinib, dovitinig, cediranib, motesanib, Sulfatinib, apatinib, acceptable carrier. Further provided herein is a use of an foretinib, famitinib, imatinib, and tivoZanib. OX40 binding agonist in the manufacture of a medicament 0065. In some embodiments, the anti-angiogenesis agent for treating or delaying progression of cancer in an individual, is an anti-angiogenesis antibody. In some embodiments, the wherein the medicament comprises the OX40 binding ago anti-angiogenesis antibody is a monoclonal antibody. In nist and an optional pharmaceutically acceptable carrier, and Some embodiments, the anti-angiogenesis antibody is a wherein the treatment comprises administration of the medi human or humanized antibody. In some embodiments, the cament in combination with a composition comprising an anti-angiogenesis agent is a VEGF antagonist. In some anti-angiogenesis agent and an optional pharmaceutically embodiments, the VEGF antagonist reduces the expression acceptable carrier. level or biological activity of VEGF by at least 10%, 20%, 0062. In still another aspect, provided herein is a compo 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodi sition comprising an anti-angiogenesis agent and an optional ments, the VEGF is VEGF (8-109), VEGF (1-109), or pharmaceutically acceptable carrier for use in treating or VEGFs. In some embodiments, the VEGF antagonist delaying progression of cancer in an individual, wherein the increases MHC class II expression on dendritic cells as com treatment comprises administration of said composition in pared to MHC class II expression on dendritic cells prior to combination with a second composition, wherein the second treatment with the VEGFantagonist. In some embodiments, composition comprises OX40 binding agonist and an the VEGF antagonist increases OX40L expression on den optional pharmaceutically acceptable carrier. Further pro dritic cells as compared to OX40L expression on dendritic vided herein is a composition comprising an OX40 binding cells prior to treatment with the VEGF antagonist. In some agonist and an optional pharmaceutically acceptable carrier embodiments, the dendritic cells are myeloid dendritic cells. for use in treating or delaying progression of cancer in an In some embodiments, the dendritic cells are non-myeloid individual, wherein the treatment comprises administration dendritic cells. In some embodiments, the VEGF antagonist of said composition in combination with a second composi comprises a soluble VEGF receptor or a soluble VEGF recep tion, wherein the second composition comprises an anti-an tor fragment that specifically binds to VEGF. In some giogenesis agent and an optional pharmaceutically accept embodiments, the VEGF antagonist is a chimeric VEGF able carrier. receptor protein. In some embodiments, the VEGFantagonist 0063. In yet another aspect, provided herein is a kitcom is administered by gene therapy. prising a medicament comprising an anti-angiogenesis agent 0066. In some embodiments, the VEGF antagonist is an and an optional pharmaceutically acceptable carrier, and a anti-VEGF antibody. In some embodiments, the anti-VEGF package insert comprising instructions for administration of antibody is a human or humanized antibody. In some embodi the medicament in combination with a composition compris ments, the anti-VEGF antibody binds to the A4.6.1 epitope. ing an OX40 binding agonist and an optional pharmaceuti In some embodiments, the anti-VEGF antibody binds to a cally acceptable carrier for treating ordelaying progression of functional epitope comprising residues F17, M18, D19,Y21, cancer in an individual. Further provided here is a kit com Y25, Q89, 191, K101, E103, and C104 of human VEGF. In prising a first medicament comprising an anti-angiogenesis some embodiments, the anti-VEGF antibody binds to a func agent and an optional pharmaceutically acceptable carrier, tional epitope comprising residues F17,Y21, Q22, Y25, D63, and a second medicament comprising an OX40 binding ago 183, and Q89 of human VEGF. In some embodiments, the nist and an optional pharmaceutically acceptable carrier. In anti-VEGF antibody is a G6 series antibody. In some embodi Some embodiments, the kit further comprises a package insert ments, the anti-VEGF antibody is a B20 series antibody. In comprising instructions for administration of the first medi some embodiments, the anti-VEGF antibody is a monoclonal cament and the second medicament for treating or delaying anti-VEGF antibody. In some embodiments, the monoclonal progression of cancer in an individual. Still further provided anti-VEGF antibody is bevacizumab. In some embodiments, US 2015/0307617 A1 Oct. 29, 2015 the anti-VEGF antibody comprises a light chain variable an OX40L agonist fragment comprising one or more extra region comprising the amino acid sequence of cellular domains of OX40L. In some embodiments, the OX40 DIQMTQSPSS LSASVGDRVT ITCSASQDIS NYLNW binding agonist is an OX40 agonist antibody that binds YQQKP GKAPKVLIYF TSSLHSGVPS RFSGSGSGTD human OX40. In some embodiments, the OX40 agonist anti FTLTISSLQP EDFATYYCQQ YSTVPWTFGQ body depletes cells that express human OX40. In some GTKVEIKR. (SEQID NO:214). In some embodiments, the embodiments, the OX40 agonist antibody depletes cells that anti-VEGF antibody comprises a heavy chain variable region express human OX40 in vitro. In some embodiments, the comprising the amino acid sequence of EVOLVESGGG cells are CD4+ effector T cells. In some embodiments, the LVQPGGSLRL SCAASGYTFT NYGMNWVRQA PGK cells are Treg cells. In some embodiments, the depleting is by GLEWVGW INTYTGEPTY AADFKRRFTF ADCC and/or phagocytosis. In some embodiments, the SLDTSKSTAY LQMNSLRAED TAVYYCAKYP depleting is by ADCC. In some embodiments, the OX40 HYYGSSHWYF DVWGQGTLVT VSS (SEQID NO:215). agonist antibody binds human OX40 with an affinity of less In some embodiments, the anti-VEGF antibody comprises a than or equal to about 1 nM. In some embodiments, the OX40 light chain variable region comprising the amino acid agonist antibody depletes cells that express human OX40 in sequence of DIQMTQSPSS LSASVGDRVT ITCSASQDIS vitro and binds human OX40 with an affinity of less than or NYLNWYQQKP GKAPKVLIYF TSSLHSGVPS equal to about 1 nM. In some embodiments, the OX40 agonist RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT antibody binds human OX40 with an affinity of less than or FGQ GTKVEIKR. (SEQ ID NO:214) and a heavy chain equal to about 0.45 nM. In some embodiments, the OX40 variable region comprising the amino acid sequence of agonist antibody binds human OX40 with an affinity of less EVQLVESGGG LVOPGGSLRL SCAASGYTFT NYGM than or equal to about 0.4 nM. In some embodiments, OX40 NWVRQA PGKGLEWVGW INTYTGEPTY AAD agonist antibody binding affinity is determined using radio FKRRFTF SLDTSKSTAY LOMNSLRAED TAVYY immunoassay. In some embodiments, binding to human CAKYP HYYGSSHWYF DVWGQGTLVT VSS (SEQ ID OX40 has an EC50 of less than or equal to 0.2 ug/ml. In some NO:215). In some embodiments, the anti-VEGF antibody embodiments, binding to human OX40 has an EC50 of less comprises one, two, three, four, five, or six hyperVariable than or equal to 0.3 ug/ml. In some embodiments, the OX40 region (HVR) sequences of bevacizumab. In some embodi agonistantibody increases CD4+ effector T cell proliferation ments, the anti-VEGF antibody comprises one, two, three, and/or increasing cytokine production by the CD4+ effector T four, five, or six hypervariable region (HVR) sequences of cell as compared to proliferation and/or cytokine production selected from (a) HVR-H1 comprising the amino acid prior to treatment with anti-human OX40 agonistantibody. In sequence of GYTFTNYGMN (SEQID NO:216); (b) HVR Some embodiments, the cytokine is gamma interferon. In H2 comprising the amino acid sequence of WINTYT Some embodiments, the OX40 agonist antibody increases GEPTYAADFKR (SEQID NO:217); (c) HVR-H3 compris memory T cell proliferation and/or increasing cytokine pro ing the amino acid sequence ofYPHYYGSSHWYFDV (SEQ duction by the memory cell. In some embodiments, the cytok ID NO:218); (d) HVR-L1 comprising the amino acid ine is gamma interferon. In some embodiments, the OX40 sequence of SASQDISNYLN (SEQID NO:219); (e) HVR agonist antibody inhibits Treg function. In some embodi L2 comprising the amino acid sequence of FTSSLHS (SEQ ments, the OX40 agonist antibody inhibits Treg Suppression ID NO:220); and (f) HVR-L3 comprising the amino acid of effector T cell function. In some embodiments, effector T sequence of QQYSTVPWT (SEQ ID NO:221). In some cell function is effector T cell proliferation and/or cytokine embodiments, the anti-VEGF antibody comprises one, two, production. In some embodiments, the effector T cell is a three, four, five, or six hypervariable region (HVR) sequences CD4+ effector T cell. In some embodiments, the OX40 ago of an antibody described in U.S. Pat. No. 6,884.879. In some nist antibody increases OX40 signal transduction in a target embodiments, the anti-VEGF antibody comprises one, two, cell that expresses OX40. In some embodiments, OX40 signal or three hypervariable region (HVR) sequences of a light transduction is detected by monitoring NFkB downstream chain variable region comprising the following amino acid signaling. In some embodiments, the OX40 agonistantibody sequence: DIQMTQSPSS LSASVGDRVT ITCSASQDIS is stable after treatment at 40° C. for two weeks. In some NYLNWYQQKP GKAPKVLIYF TSSLHSGVPS embodiments, the OX40agonistantibody comprises a variant RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT IgG1 Fc polypeptide comprising a mutation that eliminates FGQ GTKVEIKR. (SEQ ID NO:214) and/or one, two, or binding to human effector cells, and wherein the antibody has three hypervariable region (HVR) sequences of a heavy chain diminished activity relative to an anti-human OX40 agonist variable region comprising the following amino acid antibody comprising a native sequence IgG1 Fc portion. In sequence: EVOLVESGGG LVOPGGSLRLSCAASGYTFT Some embodiments, the OX40 agonist antibody comprises a NYGMNWVRQAPGKGLEWVG WINTYTGEPTY AAD variant Fc portion comprising a DANA mutation. In some FKRRFTF SLDTSKSTAY LOMNSLRAED TAVYY embodiments, OX40 agonist antibody cross-linking is CAKYP HYYGSSHWYF DVWGQGTLVT VSS (SEQ ID required for anti-human OX40 agonist antibody function. In NO:215). In some embodiments, the anti-VEGF antibody Some embodiments, the OX40 agonistantibody comprises (a) comprises one, two, three, four, five, or six hyperVariable a VH domain comprising (i) HVR-H1 comprising the amino region (HVR) sequences of bevacizumab. acid sequence of SEQ ID NO: 2, 8 or 9, (ii) HVR-H2 com 0067. In some embodiments, the OX40 binding agonist prising the amino acid sequence of SEQID NO:3, 10, 11, 12, for use in conjunction with an anti-angiogenesis agent is 13 or 14, and (iii) HVR-H3 comprising an amino acid selected from the group consisting of an OX40 agonist anti sequence selected from SEQ ID NO: 4, 15, or 19; and (iv) body, an OX40L agonist fragment, an OX40 oligomeric HVR-L1 comprising the amino acid sequence of SEQ ID receptor, and an OX40 immunoadhesin. In some embodi NO:5, (v) HVR-L2 comprising the amino acid sequence of ments, the OX40 binding agonist is a trimeric OX40L-Fc SEQID NO:6, and (vi) HVR-L3 comprising the amino acid protein. In some embodiments, the OX40 binding agonist is sequence of SEQID NO: 7, 22, 23, 24, 25, 26, 27, or 28. In US 2015/0307617 A1 Oct. 29, 2015 Some embodiments, the OX40 agonistantibody comprises (a) of 1 to 10 amino acids have been substituted, inserted and/or HVR-H1 comprising the amino acid sequence of SEQ ID deleted in SEQID NO: 57. In some embodiments, the OX40 NO:2; (b) HVR-H2 comprising the amino acid sequence of agonist VL comprises one, two or three HVRs selected from SEQ ID NO:3; (c) HVR-H3 comprising the amino acid (a) HVR-L1 comprising the amino acid sequence of SEQID sequence of SEQ ID NO:4; (d) HVR-L1 comprising the NO:5; (b) HVR-L2 comprising the amino acid sequence of amino acid sequence of SEQID NO:5; (e) HVR-L2 compris SEQID NO:6; and (c) HVR-L3 comprising the amino acid ing the amino acid sequence of SEQID NO:6; and (f) HVR sequence of SEQID NO:7. In some embodiments, the OX40 L3 comprising an amino acid sequence of SEQID NO:7. In agonistantibody comprises a VH sequence of SEQ ID NO: Some embodiments, the OX40 agonistantibody comprises (a) 56. In some embodiments, the OX40 agonist antibody com prises a VL sequence of SEQ ID NO: 57. In some embodi HVR-H1 comprising the amino acid sequence of SEQ ID ments, the OX40 agonist antibody comprises a VHSequence NO:2; (b) HVR-H2 comprising the amino acid sequence of of SEQID NO:56 and a VL sequence of SEQID NO: 57. In SEQ ID NO:3; (c) HVR-H3 comprising the amino acid Some embodiments, the OX40 agonist antibody comprises a sequence of SEQ ID NO:4; (d) HVR-L1 comprising the VH sequence of SEQID NO: 94. In some embodiments, the amino acid sequence of SEQID NO:5; (e) HVR-L2 compris OX40 agonistantibody comprises a VL sequence of SEQID ing the amino acid sequence of SEQID NO:6; and (f) HVR NO: 95. In some embodiments, the OX40 agonist antibody L3 comprising an amino acid sequence of SEQID NO:26. In comprises a VH sequence of SEQ ID NO:94 and a VL Some embodiments, the OX40 agonistantibody comprises (a) sequence of SEQ ID NO: 95. In some embodiments, the HVR-H1 comprising the amino acid sequence of SEQ ID OX40 agonist antibody comprises aVH sequence of SEQID NO:2; (b) HVR-H2 comprising the amino acid sequence of NO: 96. In some embodiments, the OX40 agonist antibody SEQ ID NO:3; (c) HVR-H3 comprising the amino acid comprises a VL sequence of SEQ ID NO: 97. In some sequence of SEQ ID NO:4; (d) HVR-L1 comprising the embodiments, the OX40 agonist antibody comprises a VH amino acid sequence of SEQID NO:5; (e) HVR-L2 compris sequence of SEQID NO:96 and a VL sequence of SEQ ID ing the amino acid sequence of SEQID NO:6; and (f) HVR NO: 97. In some embodiments, the OX40 agonistantibody is L3 comprising an amino acid sequence of SEQID NO:27. In MEDI6469, MEDIO562, or MEDI6383. Some embodiments, the OX40 agonist antibody comprises a 0068. In some embodiments, the cancer is lung cancer, heavy chain variable domain (VH) sequence having at least glioblastoma, cervical cancer, ovarian cancer, breast cancer, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or colon cancer, colorectal cancer, fallopian tube cancer, perito 100% sequence identity to the amino acid sequence of SEQ neal cancer, kidney cancer, renal cancer, non-Hodgkins lym IDNO:56,58,60, 62,64,66, 68,70, 72, 74,76,78,80, 82,84, phoma, prostate cancer, pancreatic cancer, soft-tissue sar 86, 88,90, 92,94, 96, 98, 100, 108, 114, 116, 233, or 234. In coma, kaposi's sarcoma, carcinoid carcinoma, head and neck Some embodiments, the OX40 agonist antibody comprises a cancer, mesothelioma, multiple myeloma, non-Small cell light chain variable domain (VL) having at least 90%, 91%, lung cancer, neuroblastoma, melanoma, gastric cancer, or 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% liver cancer. In some embodiments, the cancer is a gyneco sequence identity to the amino acid sequence of SEQ ID logic cancer. In some embodiments, the cancer is advanced, NO:57, 59,61,63,65, 67, 69,71, 73,75, 77, 79,81, 83,85, 87, refractory, recurrent, chemotherapy-resistant, and/or plati 89,91, 93, 95, 97,99, 101, 109, 115 or 117. In some embodi num-resistant. In some embodiments the individual has can ments, the OX40 agonist antibody comprises a heavy chain cer or has been diagnosed with cancer. In some embodiments, variable domain (VH) sequence having at least 90%, 91%, the treatment results in a Sustained response in the individual 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% after cessation of the treatment. In some embodiments, the sequence identity to the amino acid sequence of SEQ ID OX40 binding agonist is administered before the anti-angio NO:56. In some embodiments, the OX40 agonist VH genesis agent, simultaneous with the anti-angiogenesis agent, sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, or after the anti-angiogenesis agent. In some embodiments, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., the individual is a human. In some embodiments, the anti conservative Substitutions), insertions, or deletions relative to angiogenesis agent and/or the OX40 binding agonist are the reference sequence, but an anti-human OX40 agonist administered intravenously, intramuscularly, Subcutane antibody comprising that sequence retains the ability to bind ously, intracerebrospinally, topically, orally, transdermally, to human OX40. In some embodiments, a total of 1 to 10 intraperitoneally, intraorbitally, by implantation, by inhala amino acids have been substituted, inserted and/or deleted in tion, intrathecally, intraventricularly, intra-articularly intra SEQID NO:56. In some embodiments, the OX40 agonist VH synovially, or intranasally. In some embodiments, the method comprises one, two or three HVRs selected from: (a) HVR further comprises administering a chemotherapeutic agent H1 comprising the amino acid sequence of SEQID NO:2, (b) HVR-H2 comprising the amino acid sequence of SEQ ID for treating or delaying progression of cancer. NO:3, and (c) HVR-H3 comprising the amino acid sequence 0069. It is to be understood that one, some, or all of the of SEQ ID NO:4. In some embodiments, the OX40 agonist properties of the various embodiments described herein may antibody comprises a light chain variable domain (VL) hav be combined to form other embodiments of the present inven ing at least 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, tion. These and other aspects of the invention will become 98%, 99%, or 100% sequence identity to the amino acid apparent to one of skill in the art. These and other embodi sequence of SEQID NO:57. In some embodiments, the OX40 ments of the invention are further described by the detailed agonist VL sequence having at least 90%, 91%, 92%, 93%, description that follows. 94%. 95%, 96%, 97%, 98%, or 99% identity contains substi BRIEF DESCRIPTION OF THE FIGURES tutions (e.g., conservative Substitutions), insertions, or dele tions relative to the reference sequence, but an anti-human (0070 FIG. 1: Humanized OX40 antibody variants were OX40 agonistantibody comprising that sequence retains the analyzed by FACS to evaluate antibody binding to huOX40 ability to bind to human OX40. In some embodiments, a total expressed on the surface of Hut 78 cells. US 2015/0307617 A1 Oct. 29, 2015 (0071 FIG. 2: OX40 agonistantibody 1A7.gr. 1 bound with I0086 FIG. 13: Pharmacokinetics (PK) of 1A7:gr1 dosed high affinity to human and cynomolgus monkey T cells. at 1 mg/kg or 10 mg/kg in SCID mice. 0072 FIGS. 3A and 3B: (FIG. 3A) Mab 1A7.gr. 1 had no I0087 FIGS. 14A and 14B: Administration of 1A7gr1 in effect on T cell proliferation in the absence of crosslinking cynomolgus monkeys resulted in minimal or transient Increasing concentration of mab 1A7.gr. 1 costimulated increases in c-reactive protein (CRP). (FIG. 14A) CRP levels CD4+ memory T cell proliferation in response to anti-CD3 over time observed in monkeys given 0 mg/kg or 0.01 mg/kg crosslinking. The calculated EC50 for the costimulatory doses. (FIG. 14B) CRP levels over time observed in monkeys effect of mab1A7.gr. 1 was 9.96 ng/mL (n=2). (FIG. 3B) given 0.3 mg/kg or 10 mg/kg doses. Increasing concentrations of mab 1A7.gr. 1 costimulated I0088 FIGS. 15A and 15B: Administration of 1A7gr1 in CD4+ memory T cell production of interferon gamma in cynomolgus monkeys resulted in minimal or transient response to anti-CD3 crosslinking. increases in a mixed subset of cytokines. (FIG.15A) Levels of 0073 FIG. 4A: In the presence of plate-bound anti-CD3, pro-inflammatory cytokines IL6 and MCP1 over time. (FIG. plate-bound mab 1A7 costimulated effector T cell prolifera 15B) Levels of anti-inflammatory cytokines IL 10 and IL1 ra tion. By contrast, costimulatory activity was abrogated when over time. In FIGS. 15A and 15B, individual monkeys in the mab 1A7 was provided in soluble form in the presence of 10 mg/kg dose group that demonstrated transient increases in plate-bound anti-CD3, to a similar level as that observed with cytokine levels are labeled with arrows. a plate-bound isotype control antibody in the presence of I0089 FIGS. 16A and 16B: Exposure of cynomolgus mon plate-bound anti-CD3. keys to 1A7.gr1 was confirmed by serum PK and peripheral 0074 FIG.4B: MAb 1A7 gr. 1 harboring the N297G muta receptor occupancy. (FIG. 16A) Serum PK of monkeys tion failed to costimulate Teff cell proliferation. By contrast, administered 0.01, 0.3, or 10 mg/kg of 1A7:gr1. (FIG. 16B) wild type (un-mutated) mab 1A7 gr.1 costimulated anti-CD3 OX40 receptor occupancy on peripheral CD4+ T cells over induced Teff cell proliferation. time in monkeys administered 0.01, 0.3, or 10 mg/kg of 0075 FIG. 5: Treatment with OX40 agonist antibody 1A7.gr1. inhibited Treg cell-mediated suppression of naive CD4+ T (0090 FIG. 17: Pharmacokinetics (PK) of 1A7:gr1 dosed cells. Naive CD4+ T cell (Tn) when cultured alone were at 0.5, 5, or 30 mg/kg in cynomolgus monkeys. inhibited by the addition of Treg cells and an isotype control (0091 FIG. 18: OX40 receptor occupancy over time in antibody. Treg cell mediated inhibition of native CD4+ T cell monkeys administered 0, 0.5, 5, or 30 mg/kg of 1A7.gr1. proliferation was abrogated in cultures containing anti-OX40 Arrows indicate days on which samples were obtained. antibody, mab 1A7.gr1. The data represented the average of 3 0092 FIG. 19: MCP-1 levels overtime in monkeys admin independent experiments. istered 0,0.5, 5, or 30 mg/kg of 1A7:gr1. 0076 FIG. 6: Treatment with mab 1A7.gr. 1 impaired the (0093 FIG. 20: No significant activation or proliferation of Suppressive function of Treg cells. peripheral T cells was observed in monkeys administered 0. 0.077 FIGS. 7A and 7B: (FIG. 7A) Treatment with mab 0.5, 5, or 30 mg/kg of 1A7:gr1. 1A7.gr. 1 induced ADCC of OX40-expressing T cells. (FIG. (0094 FIG.21 shows the efficacy of different treatments on 7B) Treatment with mab A7.gr1 (IgG1) induced greater inhibiting tumor growth in a CT26 tumor model. Average ADCC of OX40-expressing CD4+ T cells compared to level tumor Volumes (y-axis) over time (X-axis) are plotted for each of ADCC induced by mab 1A7:gr1 (IgG4). experimental group. Experimental groups were anti-OX40 0078 FIGS. 8A and 8B: BT474-human OX40 transgenic and anti-GP120 treatment (pluses), anti-GP120 treatment clones expressed different levels of human OX40. FIG. 8A, (circles), anti-VEGF and anti-GP120 treatment (triangles), low OX40 expressing BT474 cells. FIG. 8B, high OX40 and anti-VEGF and anti-OX40 treatment (Xs). expressing BT474 cells. 0095 FIGS. 22A-22D track tumor volumes from indi 0079 FIG. 9: Treatment with OX40 agonist antibody vidual mice over time in the following treatment groups: induced antibody dependent cell-mediated phagocytosis of anti-GP120 (control; FIG. 22A), anti-VEGF+anti-GP120 cell lines expressing human OX40, and level of antibody (FIG. 22B), anti-OX40+anti-GP120 (FIG. 22C), and anti dependent cell-mediated phagocytosis was sensitive to level VEGF+anti-OX40 (FIG. 22D). Solid black and dashed and of OX40 expression in the target cells. dotted lines represent tumors from individual mice within 0080 FIG. 10: Treatment with OX40 agonist antibody each experimental group. Solid black lines represent mice 1A7.gr1 induced ADCC in OX40-expressing cells. that remained alive at the termination of the experiment, and 0081 FIGS. 11A-I: Amino acid sequences of variable dashed and dotted lines represent mice that were euthanized regions of anti-OX40 antibodies. Heavy chain HVR-H1, -H2, prior to experiment termination due to tumor ulceration or and-H3, and light chain HVR-L1, -L2, and -L3 sequences are tumor size exceeding 2000 mm. Evenly dashed lines depict marked. Amino acid positions are numbered according to the the average tumor Volume over time in mice that received Kabat numbering system as described herein. anti-GP120 alone (as labeled by arrows). Unevenly dashed I0082 FIG. 12 A: Anti-human OX40 mab 1A7 gr1 bound to lines are representative of the average tumor Volume over Hut78-hCX40 cells in a dose dependent fashion, with 70% of time within each experimental group (as labeled by arrows). maximum binding observed at about 200 ng/mL of antibody Percentages in top left corner of each individual graph are '% (indicated by the dotted square). tumor growth inhibition (TGI), as judged against mice that I0083 FIG. 12B: OX40L-flag demonstrated dose depen received anti-GP120 alone. dent binding to Hut?8-hCX40 cells. 0096 FIGS. 23A and 23B show increased intratumoral I0084 FIG. 12C: Binding of anti-human OX40 mab 1A7. dendritic cell activation following anti-VEGF treatment in a gr. 1 to Hut 78-hCX40 cells decreased as the concentration of CT26 tumor model. FIG. 23A shows increased activation of OX40L-flag increased. myeloid dendritic cells (CD1 lb+). FIG. 23B shows increased I0085 FIG. 12D: Presence of control DR5-flag had no activation of non-myeloid dendritic cells (CD11b-). Aster impact on mab 1A7.gr.1 binding. isks indicate statistical significance determined using a Stu US 2015/0307617 A1 Oct. 29, 2015 dent's t-test, assuming unequal variance and a significance changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, level of 0.05 (* indicates p<0.05). 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to DETAILED DESCRIPTION OF EMBODIMENTS the VL human immunoglobulin framework sequence or OF THE INVENTION human consensus framework sequence. 0097. In one aspect, provided herein are isolated antibod 0105. “Affinity” refers to the strength of the sum total of ies that bind to human OX40 (e.g., anti-human OX40 agonist noncovalent interactions between a single binding site of a antibodies wherein the antibody depletes cells that express molecule (e.g., an antibody) and its binding partner (e.g., an human OX40 in vitro and binds human OX40 with an affinity antigen). Unless indicated otherwise, as used herein, "bind of less than or equal to about 1 nM), as well as methods of ing affinity” refers to intrinsic binding affinity which reflects production, methods of use, formulations and other compo a 1:1 interaction between members of a binding pair (e.g., sitions, and kits or articles of manufacture related thereto. antibody and antigen). The affinity of a molecule X for its 0098. In another aspect, provided herein are methods, partner Y can generally be represented by the dissociation compositions and uses for treating or delaying progression of constant (Kd). Affinity can be measured by common methods cancer in an individual comprising administering an effective known in the art, including those described herein. Specific amount of an anti-angiogenesis agent and an OX40 binding illustrative and exemplary embodiments for measuring bind agonist. ing affinity are described in the following. 010.6 An “agonist antibody, as used herein, is an anti I. DEFINITIONS body which activates a biological activity of the antigen it 0099. The term “dysfunction” in the context of immune binds. dysfunction, refers to a state of reduced immune responsive 0107 An “anti-angiogenic agent” refers to a compound ness to antigenic stimulation. which blocks, or interferes with to some degree, the develop 0100. The term "dysfunctional', as used herein, also ment of blood vessels. An anti-angiogenic agent may, for includes refractory or unresponsive to antigen recognition, instance, be a small molecule or antibody that binds to a specifically, impaired capacity to translate antigen recogni growth factor or growth factor receptor involved in promoting tion into downstream T-cell effector functions, such as pro angiogenesis. In one embodiment, an anti-angiogenic agentis liferation, cytokine production (e.g., gamma interferon) and/ an antibody that binds to vascular endothelial growth factor or target cell killing. (VEGF), such as bevacizumab (AVASTIN). 0101. “Enhancing T cell function” means to induce, cause 0.108 “Antibody-dependent cell-mediated cytotoxicity' or stimulate an effector or memory T cell to have a renewed, or ADCC refers to a form of cytotoxicity in which secreted Sustained or amplified biological function. Examples of immunoglobulin bound onto Fc receptors (FcRs) present on enhancing T-cell function include: increased secretion of certain cytotoxic cells (e.g. NK cells, neutrophils, and mac Y-interferon from CD8+ effector T cells, increased secretion rophages) enable these cytotoxic effector cells to bind spe of Y-interferon from CD4+ memory and/or effector T-cells, cifically to an antigen-bearing target cell and Subsequently increased proliferation of CD4+ effector and/or memory T kill the target cell with cytotoxins. The primary cells for cells, increased proliferation of CD8+ effector T-cells, mediating ADCC, NK cells, express FcyRIII only, whereas increased antigen responsiveness (e.g., clearance), relative to monocytes express FcyRI, FcyRII, and FcyRIII. FcR expres such levels before the intervention. In one embodiment, the sion on hematopoietic cells is Summarized in Table 3 on page level of enhancement is at least 50%, alternatively 60%, 70%, 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 80%, 90%, 100%, 120%, 150%, 200%. The manner of mea (1991). To assess ADCC activity of a molecule of interest, an Suring this enhancement is known to one of ordinary skill in in vitro ADCC assay, such as that described in U.S. Pat. No. the art. 5,500,362 or 5,821,337 or U.S. Pat. No. 6,737,056 (Presta), 0102 “Tumor immunity” refers to the process in which may be performed. Useful effector cells for such assays tumors evade immune recognition and clearance. Thus, as a include PBMC and NK cells. Alternatively, or additionally, therapeutic concept, tumor immunity is “treated when Such ADCC activity of the molecule of interest may be assessed in evasion is attenuated, and the tumors are recognized and Vivo, e.g., in an animal model Such as that disclosed in Clynes attacked by the immune system. Examples of tumor recogni et al. PNAS (USA) 95:652-656 (1998). An exemplary assay tion include tumor binding, tumor shrinkage and tumor clear for assessing ADCC activity is provided in the examples aCC. herein. 0103 “Immunogenicity” refers to the ability of a particu 0109. The terms “anti-OX40 antibody” and “an antibody lar Substance to provoke an immune response. Tumors are that binds to OX40” refer to an antibody that is capable of immunogenic and enhancing tumor immunogenicity aids in binding OX40 with sufficient affinity such that the antibody is the clearance of the tumor cells by the immune response. useful as a diagnostic and/or therapeutic agent in targeting 0104. An “acceptor human framework” for the purposes OX40. In one embodiment, the extent of binding of an anti herein is a framework comprising the amino acid sequence of OX40 antibody to an unrelated, non-OX40 protein is less than a light chain variable domain (VL) framework or a heavy about 10% of the binding of the antibody to OX40 as mea chain variable domain (VH) framework derived from a Sured, e.g., by a radioimmunoassay (RIA). In certain embodi human immunoglobulin framework or a human consensus ments, an antibody that binds to OX40 has a dissociation framework, as defined below. An acceptor human framework constant (Kd) of s1 LM, s100 nM, is 10 nM, s1 nM. s.0.1 nM. "derived from a human immunoglobulin framework or a s0.01 nM. ors0.001 nM (e.g. 10 Morless, e.g. from 10M human consensus framework may comprise the same amino to 10'M, e.g., from 10M to 10' M). In certain embodi acid sequence thereof, or it may contain amino acid sequence ments, an anti-OX40 antibody binds to an epitope of OX40 changes. In some embodiments, the number of amino acid that is conserved among OX40 from different species. US 2015/0307617 A1 Oct. 29, 2015 0110. As use herein, the term “binds”, “specifically binds 0118. The terms “cancer and "cancerous” refer to or to” or is “specific for refers to measurable and reproducible describe the physiological condition in mammals that is typi interactions such as binding between a target and an antibody, cally characterized by unregulated cell growth. Examples of which is determinative of the presence of the target in the cancer include but are not limited to, carcinoma, lymphoma, presence of a heterogeneous population of molecules includ blastoma, sarcoma, and leukemia or lymphoid malignancies. ing biological molecules. For example, an antibody that binds More particular examples of Such cancers include, but not to or specifically binds to a target (which can be an epitope) is limited to, squamous cell cancer (e.g., epithelial squamous an antibody that binds this target with greater affinity, avidity, cell cancer), lung cancer including Small-cell lung cancer, more readily, and/or with greater duration than it binds to non-Small cell lung cancer, adenocarcinoma of the lung and other targets. In one embodiment, the extent of binding of an squamous carcinoma of the lung, cancer of the peritoneum, antibody to an unrelated target is less than about 10% of the hepatocellular cancer, gastric or stomach cancer including binding of the antibody to the target as measured, e.g., by a gastrointestinal cancer and gastrointestinal stromal cancer, radioimmunoassay (RIA). In certain embodiments, an anti pancreatic cancer, glioblastoma, cervical cancer, ovarian can body that specifically binds to a target has a dissociation cer, liver cancer, bladder cancer, cancer of the urinary tract, constant (Kd) of s1 LM, s100 nM, s10 nM, s1 nM, or s(0.1 hepatoma, breast cancer, colon cancer, rectal cancer, colorec nM. In certain embodiments, an antibody specifically binds to tal cancer, endometrial or uterine carcinoma, salivary gland an epitope on a protein that is conserved among the protein carcinoma, kidney or renal cancer, prostate cancer, Vulval from different species. In another embodiment, specific bind cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, ing can include, but does not require exclusive binding. penile carcinoma, melanoma, Superficial spreading mela 0111. The term “antibody' herein is used in the broadest noma, lentigo maligna melanoma, acral lentiginous melano sense and encompasses various antibody structures, includ mas, nodular melanomas, multiple myeloma and B-cell lym ing but not limited to monoclonal antibodies, polyclonal anti phoma; chronic lymphocytic leukemia (CLL); acute bodies, multispecific antibodies (e.g., bispecific antibodies), lymphoblastic leukemia (ALL); hairy cell leukemia; chronic and antibody fragments so long as they exhibit the desired myeloblastic leukemia; and post-transplant lymphoprolifera antigen-binding activity. tive disorder (PTLD), as well as abnormal vascular prolifera 0112 An “antibody fragment” refers to a molecule other tion associated with phakomatoses, edema (such as that asso than an intact antibody that comprises a portion of an intact ciated with brain tumors), Meigs' syndrome, brain, as well as antibody that binds the antigen to which the intact antibody head and neck cancer, and associated metastases. In certain binds. Examples of antibody fragments include but are not embodiments, cancers that are amenable to treatment by the limited to Fv, Fab, Fab', Fab'-SH, F(ab'): diabodies; linear antibodies of the invention include breast cancer, colorectal antibodies; single-chain antibody molecules (e.g. ScFV); and cancer, rectal cancer, non-small cell lung cancer, glioblas multispecific antibodies formed from antibody fragments. toma, non-Hodgkins lymphoma (NHL), renal cell cancer, prostate cancer, liver cancer, pancreatic cancer, soft-tissue 0113. An “antibody that binds to the same epitope' as a sarcoma, kaposi's sarcoma, carcinoid carcinoma, head and reference antibody refers to an antibody that blocks binding neck cancer, ovarian cancer, mesothelioma, and multiple of the reference antibody to its antigen in a competition assay myeloma. In some embodiments, the cancer is selected from: by 50% or more, and conversely, the reference antibody non-Small cell lung cancer, glioblastoma, neuroblastoma, blocks binding of the antibody to its antigen in a competition melanoma, breast carcinoma (e.g. triple-negative breast can assay by 50% or more. An exemplary competition assay is cer), gastric cancer, colorectal cancer (CRC), and hepatocel provided herein. lular carcinoma. Yet, in Some embodiments, the cancer is 0114. The term “binding domain refers to the region of a selected from: non-Small cell lung cancer, colorectal cancer, polypeptide that binds to another molecule. In the case of an glioblastoma and breast carcinoma (e.g. triple-negative breast FcR, the binding domain can comprise a portion of a polypep cancer), including metastatic forms of those cancers. tide chain thereof (e.g. the alpha chain thereof) which is 0119) The terms “cell proliferative disorder” and “prolif responsible for binding an Fc region. One useful binding erative disorder” refer to disorders that are associated with domain is the extracellular domain of an FcRalpha chain. some degree of abnormal cell proliferation. In one embodi 0115. A polypeptide with a variant IgGFc with “altered ment, the cell proliferative disorder is cancer. FcR, ADCC or phagocytosis activity is one which has either 0.120. The term "chimeric' antibody refers to an antibody enhanced or diminished FcR binding activity (e.g., FcyR) in which a portion of the heavy and/or light chain is derived and/or ADCC activity and/or phagocytosis activity compared from a particular source or species, while the remainder of the to a parent polypeptide or to a polypeptide comprising a heavy and/or light chain is derived from a different source or native sequence Fc region. species. 0116. The term “OX40, as used herein, refers to any I0121 The “class” of an antibody refers to the type of native OX40 from any vertebrate source, including mammals constant domain or constant region possessed by its heavy Such as primates (e.g. humans) and rodents (e.g., mice and chain. There are five major classes of antibodies: IgA, Ig|D. rats), unless otherwise indicated. The term encompasses IgE. IgG, and IgM, and several of these may be further “full-length unprocessed OX40 as well as any form of OX40 divided into subclasses (isotypes), e.g., IgG, IgG, IgG that results from processing in the cell. The term also encom IgG, IgA, and IgA. The heavy chain constant domains that passes naturally occurring variants of OX40, e.g., splice Vari correspond to the different classes of immunoglobulins are ants or allelic variants. The amino acid sequence of an exem called C, Ö, e, Y, and L, respectively. plary human OX40 is shown in SEQID NO:1. (0.122 “Complement dependent cytotoxicity” or “CDC” 0117 “OX40 activation refers to activation, of the OX40 refers to the lysis of a target cell in the presence of comple receptor. Generally, OX40 activation results in signal trans ment. Activation of the classical complement pathway is ini duction. tiated by the binding of the first component of the comple US 2015/0307617 A1 Oct. 29, 2015 ment system (C1q) to antibodies (of the appropriate 0.126 “Effector functions' refer to those biological activi Subclass), which are bound to their cognate antigen. To assess ties attributable to the Fc region of an antibody, which vary complement activation, a CDC assay, e.g., as described in with the antibody isotype. Examples of antibody effector Gazzano-Santoro et al., J. Immunol. Methods 202:163 functions include: C1q binding and complement dependent (1996), may be performed. Polypeptide variants with altered cytotoxicity (CDC); Fc receptor binding; antibody-depen Fc region amino acid sequences (polypeptides with a variant dent cell-mediated cytotoxicity (ADCC); phagocytosis: Fc region) and increased or decreased C1q binding capability down regulation of cell Surface receptors (e.g. B cell recep are described, e.g., in U.S. Pat. No. 6,194.551 B1 and WO tor); and B cell activation. 1999/51642. See also, e.g., Idusogie et al. J. Immunol. 164: I0127. An "effective amount of an agent, e.g., a pharma 4178-4.184 (2000). ceutical formulation, refers to an amount effective, at dosages 0123. The term “cytostatic agent” refers to a compound or and for periods of time necessary, to achieve the desired composition which arrests growth of a cell either in vitro or in therapeutic or prophylactic result. vivo. Thus, a cytostatic agent may be one which significantly I0128 “Fc receptor” or “FCR” describes a receptor that reduces the percentage of cells in S phase. Further examples binds to the Fc region of an antibody. In some embodiments, of cytostatic agents include agents that block cell cycle pro an FcR is a native human FcR. In some embodiments, an FcR gression by inducing G0/G1 arrest or M-phase arrest. The is one which binds an IgG antibody (a gamma receptor) and humanized anti-Her2 antibody trastuzumab (HERCEP includes receptors of the FcyRI. FcyRII, and FcyRIII sub TINR) is an example of a cytostatic agent that induces G0/G1 classes, including allelic variants and alternatively spliced arrest. Classical M-phase blockers include the Vincas (vinc forms of those receptors. FeyRII receptors include FcyRIIA ristine and vinblastine), taxanes, and topoisomerase II inhibi (an “activating receptor) and FcyRIIB (an “inhibiting recep tors such as doxorubicin, epirubicin, daunorubicin, etopo tor”), which have similar amino acid sequences that differ side, and bleomycin. Certain agents that arrest G1 also spill primarily in the cytoplasmic domains thereof. Activating over into S-phase arrest, for example, DNA alkylating agents receptor FcyRIIA contains an immunoreceptor tyrosine Such as tamoxifen, prednisone, dacarbazine, mechlore based activation motif (ITAM) in its cytoplasmic domain. thamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Inhibiting receptor FcyRIIB contains an immunoreceptor Further information can be found in Mendelsohn and Israel, eds. The Molecular Basis of Cancer, Chapter 1, entitled tyrosine-based inhibition motif (ITIM) in its cytoplasmic “Cell cycle regulation, oncogenes, and antineoplastic drugs' domain. (see, e.g., Daéron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed, for example, in Ravetch and by Murakamietal. (W.B. Saunders, Philadelphia, 1995), e.g., Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., p. 13. The taxanes (paclitaxel and docetaxel) are anticancer Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. drugs both derived from the yew tree. Docetaxel (TAXO Clin. Med. 126:330-41 (1995). Other FcRs, including those to TERE(R), Rhone-Poulenc Rorer), derived from the European be identified in the future, are encompassed by the term yew, is a semisynthetic analogue of paclitaxel (TAXOL(R), “FcR” herein. The term “Fc receptor” or “FCR” also includes Bristol-Myers Squibb). Paclitaxel and docetaxel promote the the neonatal receptor, FcRn, which is responsible for the assembly of microtubules from tubulin dimers and stabilize transfer of maternal IgGs to the fetus (Guyer et al., J. Immu microtubules by preventing depolymerization, which results mol. 1 17:587 (1976) and Kim et al., J. Immunol. 24:249 in the inhibition of mitosis in cells. (1994)) and regulation of homeostasis of immunoglobulins. 0.124. The term “cytotoxic agent” as used herein refers to Methods of measuring binding to FcRn are known (see, e.g., a substance that inhibits or prevents a cellular function and/or Ghetie and Ward. Immunol. Today 18(12):592-598 (1997); causes cell death or destruction. Cytotoxic agents include, but Ghetie et al., Nature Biotechnology, 15(7):637-640 (1997); are not limited to, radioactive isotopes (e.g., At', I'', I'', Hinton et al., J. Biol. Chem. 279(8):6213-6216 (2004); WO Y', Re, Re, Sm's, Bil?, P, Pb?? and radioactive 2004/92219 (Hinton et al.). Binding to human FcRn in vivo isotopes of Lu); chemotherapeutic agents or drugs (e.g., and serum half life of human FcRn high affinity binding methotrexate, adriamicin, vinca alkaloids (Vincristine, Vin polypeptides can be assayed, e.g., in transgenic mice or trans blastine, etoposide), doxorubicin, melphalan, mitomycin C, fected human cell lines expressing human FcRn, or in pri chlorambucil, daunorubicin or other intercalating agents); mates to which the polypeptides with a variant Fc region are growth inhibitory agents; enzymes and fragments thereof administered. WO 2000/42072 (Presta) describes antibody Such as nucleolytic enzymes; antibiotics; toxins such as Small variants with improved or diminished binding to FcRs. See molecule toxins or enzymatically active toxins of bacterial, also, e.g., Shields et al. J. Biol. Chem.9(2):6591-6604 (2001). fungal, plant or animal origin, including fragments and/or I0129. The term “Fc region' herein is used to define a variants thereof, and the various antitumor or anticancer C-terminal region of an immunoglobulin heavy chain that agents disclosed below. contains at least a portion of the constant region. The term 0.125 A“depleting anti-OX40 antibody is an anti-OX40 includes native sequence Fc regions and variant Fc regions. In antibody that kills or depletes OX40-expressing cells. Deple one embodiment, a human IgG heavy chain Fc region extends tion of OX40 expressing cells can be achieved by various from Cys226, or from Pro230, to the carboxyl-terminus of the mechanisms, such as antibody-dependent cell-mediated heavy chain. However, the C-terminal lysine (Lys447) of the cytotoxicity and/or phagocytosis. Depletion of OX40-ex Fc region may or may not be present. Unless otherwise speci pressing cells may be assayed in vitro, and exemplary meth fied herein, numbering of amino acid residues in the Fc region ods for in vitro ADCC and phagocytosis assays are provided or constant region is according to the EU numbering system, herein. In some embodiments, the OX40-expressing cell is a also called the EU index, as described in Kabat et al., human CD4+ effector T cell. In some embodiments, the Sequences of Proteins of Immunological Interest, 5th Ed. OX40-expressing cell is a transgenic BT474 cell that Public Health Service, National Institutes of Health, expresses human OX40. Bethesda, Md., 1991. US 2015/0307617 A1 Oct. 29, 2015 0130. A “functional Fc region’ possesses an “effector those of a non-human antibody, and all or Substantially all of function of a native sequence Fc region. Exemplary “effec the FRs correspond to those of a human antibody. A human tor functions” include C1q binding; CDC; Fc receptor bind ized antibody optionally may comprise at least a portion of an ing; ADCC, phagocytosis; down regulation of cell Surface antibody constant region derived from a human antibody. A receptors (e.g. B cell receptor, BCR), etc. Such effector func "humanized form of an antibody, e.g., a non-human anti tions generally require the Fc region to be combined with a body, refers to an antibody that has undergone humanization. binding domain (e.g., an antibody variable domain) and can (0.138. The term “hypervariable region” or “HVR as used be assessed using various assays as disclosed, for example, in herein refers to each of the regions of an antibody variable definitions herein. domain which are hyperVariable in sequence ("complemen 0131 “Human effector cells' refer to leukocytes that tarity determining regions” or “CDRs) and/or form structur express one or more FcRs and perform effector functions. In ally defined loops (“hypervariable loops') and/or contain the certain embodiments, the cells express at least FcyRIII and antigen-contacting residues ("antigen contacts”). Generally, perform ADCC effector function(s). Examples of human leu antibodies comprise six HVRs: three in the VH(H1, H2,H3), kocytes which mediate ADCC include peripheral blood and three in the VL (L1, L2, L3). Exemplary HVRs herein mononuclear cells (PBMC), natural killer (NK) cells, mono include: cytes, cytotoxic T cells, and neutrophils. The effector cells (a) hyperVariable loops occurring at amino acid residues may be isolated from a native source, e.g., from blood. 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), (0132) “Framework” or “FR refers to variable domain and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901 residues other than hypervariable region (HVR) residues. The 917 (1987)); FR of a variable domain generally consists of four FR (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) and FR sequences generally appear in the following sequence (Kabat et al., Sequences of Proteins of Immunological Inter in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4. est, 5th Ed. Public Health Service, National Institutes of 0133. The terms “full length antibody,” “intact antibody.” Health, Bethesda, Md. (1991)); and “whole antibody' are used herein interchangeably to (c) antigen contacts occurring at amino acid residues 27c-36 refer to an antibody having a structure Substantially similar to (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and a native antibody structure or having heavy chains that con 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 tain an Fc region as defined herein. (1996)); and 0134. The terms “host cell,”“host cell line, and “host cell (d) combinations of (a), (b), and/or (c), including HVRamino culture' are used interchangeably and refer to cells into which acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), exogenous nucleic acid has been introduced, including the 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and progeny of such cells. Host cells include “transformants’ and 94-102 (H3). “transformed cells,” which include the primary transformed Unless otherwise indicated, HVR residues and other residues cell and progeny derived therefrom without regard to the in the variable domain (e.g., FR residues) are numbered number of passages. Progeny may not be completely identical herein according to Kabat et al., Supra. in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or In one embodiment, HVR residues comprise those identified biological activity as screened or selected for in the originally in FIGS. 11 A-I or elsewhere in the specification. transformed cell are included herein. 0.139. An “immunoconjugate' is an antibody conjugated 0135 A “human antibody' is one which possesses an to one or more heterologous molecule(s), including but not amino acid sequence which corresponds to that of an anti limited to a cytotoxic agent. body produced by a human or a human cell or derived from a 0140. An “individual' or “subject' is a mammal. Mam non-human Source that utilizes human antibody repertoires or mals include, but are not limited to, domesticated animals otherhuman antibody-encoding sequences. This definition of (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., a human antibody specifically excludes a humanized anti humans and non-human primates Such as monkeys), rabbits, body comprising non-human antigen-binding residues. and rodents (e.g., mice and rats). In certain embodiments, the 0136. A “human consensus framework” is a framework individual or Subject is a human. which represents the most commonly occurring amino acid 0141 “Promoting cell growth or proliferation” means residues in a selection of human immunoglobulin VL or VH increasing a cells growth or proliferation by at least 10%, framework sequences. Generally, the selection of human 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. immunoglobulin VL or VH sequences is from a Subgroup of 0142. An "isolated antibody is one which has been sepa variable domain sequences. Generally, the Subgroup of rated from a component of its natural environment. In some sequences is a Subgroup as in Kabat et al., Sequences of embodiments, an antibody is purified to greater than 95% or Proteins of Immunological Interest, Fifth Edition, NIH Pub 99% purity as determined by, for example, electrophoretic lication 91-3242, Bethesda Md. (1991), vols. 1-3. In one (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary elec embodiment, for the VL, the Subgroup is subgroup kappa I as trophoresis) or chromatographic (e.g., ion exchange or in Kabat et al., Supra. In one embodiment, for the VH, the reverse phase HPLC). For review of methods for assessment Subgroup is subgroup III as in Kabat et al., Supra. of antibody purity, see, e.g., Flatman et al., J. Chromatogr: B 0.137. A “humanized antibody refers to a chimeric anti 848:79-87 (2007). body comprising amino acid residues from non-human HVRS 0.143 An "isolated nucleic acid refers to a nucleic acid and amino acid residues from human FRS. In certain embodi molecule that has been separated from a component of its ments, a humanized antibody will comprise Substantially all natural environment. An isolated nucleic acid includes a of at least one, and typically two, variable domains, in which nucleic acid molecule contained in cells that ordinarily con all or substantially all of the HVRs (e.g., CDRs) correspond to tain the nucleic acid molecule, but the nucleic acid molecule US 2015/0307617 A1 Oct. 29, 2015 is present extrachromosomally or at a chromosomal location 0149 “Percent (%) amino acid sequence identity” with that is different from its natural chromosomal location. respect to a reference polypeptide sequence is defined as the 0144) “Isolated nucleic acid encoding an anti-OX40 anti percentage of amino acid residues in a candidate sequence body' refers to one or more nucleic acid molecules encoding that are identical with the amino acid residues in the reference antibody heavy and light chains (or fragments thereof), polypeptide sequence, after aligning the sequences and intro including Such nucleic acid molecule(s) in a single vector or ducing gaps, if necessary, to achieve the maximum percent separate vectors, and Such nucleic acid molecule(s) present at sequence identity, and not considering any conservative Sub one or more locations in a host cell. stitutions as part of the sequence identity. Alignment for pur 0145 The term “monoclonal antibody” as used herein poses of determining percent amino acid sequence identity refers to an antibody obtained from a population of Substan can be achieved in various ways that are within the skill in the tially homogeneous antibodies, i.e., the individual antibodies art, for instance, using publicly available computer Software comprising the population are identical and/or bind the same such as BLAST, BLAST-2, ALIGN or Megalign (DNAS epitope, except for possible variant antibodies, e.g., contain TAR) software. Those skilled in the art can determine appro ing naturally occurring mutations or arising during produc priate parameters for aligning sequences, including any algo tion of a monoclonal antibody preparation, Such variants gen rithms needed to achieve maximal alignment over the full erally being present in minor amounts. In contrast to length of the sequences being compared. For purposes herein, polyclonal antibody preparations, which typically include however, 96 amino acid sequence identity values are gener different antibodies directed against different determinants ated using the sequence comparison computer program (epitopes), each monoclonal antibody of a monoclonal anti ALIGN-2. The ALIGN-2 sequence comparison computer body preparation is directed against a single determinant on program was authored by Genentech, Inc., and the source an antigen. Thus, the modifier "monoclonal indicates the code has been filed with user documentation in the U.S. character of the antibody as being obtained from a Substan Copyright Office, Washington D.C., 20559, where it is regis tially homogeneous population of antibodies, and is not to be tered under U.S. Copyright Registration No. TXU510087. construed as requiring production of the antibody by any The ALIGN-2 program is publicly available from Genentech, particular method. For example, the monoclonal antibodies to Inc., South San Francisco, Calif., or may be compiled from be used inaccordance with the present invention may be made the source code. The ALIGN-2 program should be compiled by a variety of techniques, including but not limited to the for use on a UNIX operating system, including digital UNIX hybridoma method, recombinant DNA methods, phage-dis V4.0D. All sequence comparison parameters are set by the play methods, and methods utilizing transgenic animals con ALIGN-2 program and do not vary. taining all or part of the human immunoglobulin loci. Such 0150. In situations where ALIGN-2 is employed for amino methods and other exemplary methods for making mono acid sequence comparisons, the '% amino acid sequence iden clonal antibodies being described herein. tity of a given amino acid sequence A to, with, or against a 0146 A“naked antibody” refers to an antibody that is not given amino acid sequence B (which can alternatively be conjugated to a heterologous moiety (e.g., a cytotoxic moi phrased as a given amino acid sequence A that has or com ety) or radiolabel. The naked antibody may be present in a prises a certain 96 amino acid sequence identity to, with, or pharmaceutical formulation. against a given amino acid sequence B) is calculated as fol 0147 “Native antibodies’ refer to naturally occurring lows: immunoglobulin molecules with varying structures. For 100 times the fraction XY example, native IgG antibodies are heterotetrameric glyco proteins of about 150,000 daltons, composed of two identical where X is the number of amino acid residues scored as light chains and two identical heavy chains that are disulfide identical matches by the sequence alignment program bonded. From N- to C-terminus, each heavy chain has a ALIGN-2 in that programs alignment of A and B, and where variable region (VH), also called a variable heavy domain or Y is the total number of amino acid residues in B. It will be a heavy chain variable domain, followed by three constant appreciated that where the length of amino acid sequence A is domains (CH1, CH2, and CH3). Similarly, from N- to C-ter not equal to the length of amino acid sequence B, the 96 amino minus, each light chain has a variable region (VL), also called acid sequence identity of A to B will not equal the 96 amino a variable light domain or a light chain variable domain, acid sequence identity of B to A. Unless specifically stated followed by a constant light (CL) domain. The light chain of otherwise, all '% amino acid sequence identity values used an antibody may be assigned to one of two types, called kappa hereinare obtained as described in the immediately preceding (K) and lambda (W), based on the amino acid sequence of its paragraph using the ALIGN-2 computer program. constant domain. A "native sequence Fc region' comprises an 0151. The term “pharmaceutical formulation” refers to a amino acid sequence identical to the amino acid sequence of preparation which is in Such form as to permit the biological an Fc region found in nature. Native sequence human Fc activity of an active ingredient contained therein to be effec regions include a native sequence human IgG1 Fc region tive, and which contains no additional components which are (non-A and A allotypes); native sequence human IgG2 Fc unacceptably toxic to a subject to which the formulation region; native sequence human IgG3 Fc region; and native would be administered. sequence human IgG4 Fc region as well as naturally occur 0152 A“pharmaceutically acceptable carrier refers to an ring variants thereof. ingredient in a pharmaceutical formulation, other than an 0148. The term “package insert” is used to refer to instruc active ingredient, which is nontoxic to a Subject. A pharma tions customarily included in commercial packages of thera ceutically acceptable carrier includes, but is not limited to, a peutic products, that contain information about the indica buffer, excipient, stabilizer, or preservative. tions, usage, dosage, administration, combination therapy, 0153. As used herein, “treatment' (and grammatical varia contraindications and/or warnings concerning the use of such tions thereof such as “treat' or “treating) refers to clinical therapeutic products. intervention in an attempt to alter the natural course of the US 2015/0307617 A1 Oct. 29, 2015 individual being treated, and can be performed either for (SEQ ID NO:223)-H2-RFTISRDNSKNTLYLQMNSL prophylaxis or during the course of clinical pathology. Desir RAEDTAVYYC (SEQ ID NO:224)-H3-WGQGTLVTVSS able effects of treatment include, but are not limited to, pre (SEQ ID NO:225). venting occurrence or recurrence of disease, alleviation of 0159. A “VL subgroup I consensus framework' com symptoms, diminishment of any direct or indirect pathologi prises the consensus sequence obtained from the amino acid cal consequences of the disease, preventing metastasis, sequences in variable light kappa Subgroup I of Kabat etal. In decreasing the rate of disease progression, amelioration or one embodiment, the VH subgroup I consensus framework palliation of the disease state, and remission or improved amino acid sequence comprises at least a portion orall of each prognosis. In some embodiments, antibodies of the invention of the following sequences: are used to delay development of a disease or to slow the (0160 DIQMTQSPSSLSASVGDRVTITC (SEQ ID progression of a disease. NO:226)-L1-WYQQKPGKAPKLLIY (SEQ ID NO:227)- 0154 The term “tumor refers to all neoplastic cell growth L2-GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ and proliferation, whether malignant or benign, and all pre ID NO:228)-L3-FGQGTKVEIK (SEQID NO:229). cancerous and cancerous cells and tissues. The terms 'can 0.161 The term “cytotoxic agent” as used herein refers to cer.” “cancerous.” “cell proliferative disorder,” “proliferative a substance that inhibits or prevents a cellular function and/or disorder and “tumor are not mutually exclusive as referred causes cell death or destruction. Cytotoxic agents include, but to herein. are not limited to, radioactive isotopes (e.g., At211, I 131, (O155 The term “variable region” or “variable domain I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and refers to the domain of an antibody heavy or light chain that is radioactive isotopes of Lu); chemotherapeutic agents; growth involved in binding the antibody to antigen. The variable inhibitory agents; enzymes and fragments thereof Such as domains of the heavy chain and light chain (VH and VL, nucleolytic enzymes; and toxins such as Small molecule tox respectively) of a native antibody generally have similar ins or enzymatically active toxins of bacterial, fungal, plant or structures, with each domain comprising four conserved animal origin, including fragments and/or variants thereof. framework regions (FRs) and three hypervariable regions Exemplary cytotoxic agents can be selected from anti-micro (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6" ed., tubule agents, platinum coordination complexes, alkylating W.H. Freeman and Co., page 91 (2007).) A single VH or VL agents, antibiotic agents, topoisomerase II inhibitors, antime domain may be sufficient to confer antigen-binding specific tabolites, topoisomerase I inhibitors, hormones and hormonal ity. Furthermore, antibodies that bind a particular antigen analogues, signal transduction pathway inhibitors, non-re may be isolated using a VH or VL domain from an antibody ceptor tyrosine kinase angiogenesis inhibitors, immunothera that binds the antigen to screen a library of complementary peutic agents, proapoptotic agents, inhibitors of LDH-A. VL or VH domains, respectively. See, e.g., Portolano et al., J. inhibitors of fatty acid biosynthesis; cell cycle signalling Immunol. 150:880-887 (1993); Clarkson et al., Nature 352: inhibitors: HDAC inhibitors, proteasome inhibitors; and 624-628 (1991). inhibitors of cancer metabolism. 0156. A “variant Fc region' comprises an amino acid 0162. In one embodiment the cytotoxic agent is selected sequence which differs from that of a native sequence Fc from anti-microtubule agents, platinum coordination com region by virtue of at least one amino acid modification, plexes, alkylating agents, antibiotic agents, topoisomerase II preferably one or more amino acid substitution(s). Preferably, inhibitors, antimetabolites, topoisomerase I inhibitors, hor the variant Fc region has at least one amino acid Substitution mones and hormonal analogues, signal transduction pathway compared to a native sequence Fc region or to the Fc region of inhibitors, non-receptor tyrosine kinase angiogenesis inhibi a parent polypeptide, e.g. from about one to about ten amino tors, immunotherapeutic agents, proapoptotic agents, inhibi acid substitutions, and preferably from about one to about five tors of LDH-A, inhibitors offatty acid biosynthesis, cell cycle amino acid substitutions in a native sequence Fc region or in signalling inhibitors, HDAC inhibitors, proteasome inhibi the Fc region of the parent polypeptide. The variant Fc region tors, and inhibitors of cancer metabolism. In one embodiment herein will preferably possess at least about 80% homology the cytotoxic agent is a taxane. In one embodiment the taxane with a native sequence Fc region and/or with an Fc region of is paclitaxel or docetaxel. In one embodiment the cytotoxic a parent polypeptide, and most preferably at least about 90% agent is a platinum agent. In one embodiment the cytotoxic homology therewith, more preferably at least about 95% agent is an antagonist of EGFR. In one embodiment the homology therewith. antagonist of EGFR is N-(3-ethynylphenyl)-6,7-bis(2-meth O157. The term “vector” as used herein, refers to a nucleic oxyethoxy)guinazolin-4-amine (e.g., erlotinib). In one acid molecule capable of propagating another nucleic acid to embodiment the cytotoxic agent is a RAF inhibitor. In one which it is linked. The term includes the vector as a self embodiment, the RAF inhibitor is a BRAF and/or CRAF replicating nucleic acid structure as well as the vector incor inhibitor. In one embodiment the RAF inhibitor is vemu porated into the genome of a host cell into which it has been rafenib. In one embodiment the cytotoxic agent is a PI3K introduced. Certain vectors are capable of directing the inhibitor. expression of nucleic acids to which they are operatively 0163 “Chemotherapeutic agent' includes chemical com linked Such vectors are referred to herein as “expression pounds useful in the treatment of cancer. Examples of che vectors. motherapeutic agents include erlotinib (TARCEVAR), 0158. A “VH subgroup III consensus framework' com Genentech/OSI Pharm.), bortezomib (VELCADE(R), Millen prises the consensus sequence obtained from the amino acid nium Pharm.), disulfiram, epigallocatechin gallate, salino sequences in variable heavy Subgroup III of Kabat etal. In one sporamide A, carfilzomib. 17-AAG (geldanamycin), radici embodiment, the VH subgroup III consensus framework col, lactate dehydrogenase A (LDH-A), fulvestrant amino acid sequence comprises at least a portion orall of each (FASLODEX(R), AstraZeneca), Sunitib (SUTENTR, Pfizer/ of the following sequences: EVOLVESGGGLVOPGGSL Sugen), letrozole (FEMARAR), Novartis), imatinib mesylate RLSCAAS (SEQ ID NO:222)-H1-WVRQAPGKGLEWV (GLEEVECR), Novartis), finasunate (VATALANIB(R), US 2015/0307617 A1 Oct. 29, 2015 Novartis), oxaliplatin (ELOXATINR), Sanofi), 5-FU (5-fluo charide complex (JHS Natural Products, Eugene, Oreg.); rouracil), leucovorin, Rapamycin (Sirolimus, RAPAM razoxane; rhizoxin; sizofuran; Spirogermanium; tenuaZonic UNER, Wyeth), Lapatinib (TYKERB(R, GSK572016, Glaxo acid; triaziquone; 2.2.2"-trichlorotriethylamine; trichoth Smith Kline), Lonafamib (SCH 66336), Sorafenib (NEXA ecenes (especially T-2 toxin, Verracurin A, roridin A and VARR), Bayer Labs), gefitinib (IRESSAR), AstraZeneca), anguidine); urethan; vindesine; dacarbazine; mannomustine; AG1478, alkylating agents such as thiotepa and mitobronitol; mitolactol; pipobroman, gacytosine; arabino CYTOXANR) cyclosphosphamide: alkyl sulfonates such as side (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., buSulfan, improSulfan and piposulfan; aziridines Such as ben TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princ Zodopa, carboquone, meturedopa, and uredopa; ethylen eton, N.J.), ABRAXANER) (Cremophor-free), albumin-en imines and methylamelamines including altretamine, trieth gineered nanoparticle formulations of paclitaxel (American ylenemelamine, triethylenephosphoramide, Pharmaceutical Partners, Schaumberg, Ill.), and TAXO TERE(R) (docetaxel, doxetaxel; Sanofi-Aventis); chloranm triethylenethiophosphoramide and trimethylomelamine; bucil; GEMZARR) (gemcitabine); 6-thioguanine; mercap acetogenins (especially bullatacin and bullatacinone); a topurine; methotrexate; platinum analogs such as cisplatin camptothecin (including topotecan and irinotecan); bryosta and carboplatin: vinblastine: etoposide (VP-16); ifosfamide: tin: cally statin: CC-1065 (including its adozelesin, carzelesin mitoxantrone; vincristine; NAVELBINE(R) (vinorelbine): and bizelesin synthetic analogs); cryptophycins (particularly novantrone; teniposide; ediatrexate, daunomycin; aminop cryptophycin 1 and cryptophycin 8); adrenocorticosteroids terin; capecitabine (XELODAR); ibandronate; CPT-11; (including prednisone and prednisolone); cyproterone topoisomerase inhibitor RFS 2000; difluoromethylornithine acetate; 5C.-reductases including finasteride and dutasteride); (DMFO); retinoids such as retinoic acid; and pharmaceuti Vorinostat, romidepsin, panobinostat, valproic acid, moceti cally acceptable salts, acids and derivatives of any of the nostat dolastatin; aldesleukin, talc duocarmycin (including above. the synthetic analogs, KW-2189 and CB1-TM1); eleuther obin: pancratistatin; a sarcodictyin; spongistatin: nitrogen 0164 Chemotherapeutic agent also includes (i) anti-hor mustards such as chlorambucil, chlomaphazine, chlorophos monal agents that act to regulate or inhibit hormone action on phamide, estramustine, ifosfamide, mechlorethamine, tumors such as anti-estrogens and selective estrogen receptor mechlorethamine oxide hydrochloride, melphalan, novem modulators (SERMs), including, for example, tamoxifen (in bichin, phenesterine, prednimustine, trofosfamide, uracil cluding NOLVADEXOR); tamoxifen citrate), raloxifene, mustard; nitrosoureas such as carmustine, chlorozotocin, droloxifene, iodoxy fene, 4-hydroxytamoxifen, trioxifene, fotemustine, lomustine, nimustine, and ranimnustine; antibi keoxifene, LY 1 17018, onapristone, and FARESTONR) otics Such as the enediyne antibiotics (e.g., calicheamicin, (toremifine citrate); (ii) aromatase inhibitors that inhibit the especially calicheamicin Y1I and calicheamicin (ol I (Angew enzyme aromatase, which regulates estrogen production in Chem. Intl. Ed. Engl. 1994.33:183-186); dynemicin, includ the adrenal glands, such as, for example, 4(5)-imidazoles, ing dynemicin A; bisphosphonates, such as clodronate; an aminoglutethimide, MEGASE(R) (megestrol acetate), ARO esperamicin; as well as neocarzinostatin chromophore and MASINR) (exemestane: Pfizer), formestanie, fadrozole, related chromoprotein enediyne antibiotic chromophores), RIVISOR(R) (vorozole), FEMARAR) (letrozole; Novartis), aclacinomysins, actinomycin, authramycin, aZaserine, bleo and ARIMIDEXOR (anastrozole; AstraZeneca); (iii) anti-an mycins, cactinomycin, carabicin, caminomycin, carZinophi drogens Such as flutamide, nilutamide, bicalutamide, leupro lin, chromomycinis, dactinomycin, daunorubicin, detorubi lide and goserelin; buserelin, tripterelin, medroxyprogester cin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCINCR) one acetate, diethylstilbestrol, premarin, fluoxymesterone, all (doxorubicin), morpholino-doxorubicin, cyanomorpholino transretionic acid, fenretinide, as well as troxacitabine (a doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubi 1,3-dioxolane nucleoside cytosine analog); (iv) protein cin), epirubicin, esorubicin, idarubicin, marcellomycin, mito kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense mycins such as mitomycin C, mycophenolic acid, oligonucleotides, particularly those which inhibit expression nogalamycin, olivomycins, peplomycin, porfiromycin, puro of genes in signaling pathways implicated in aberrant cell mycin, quelamycin, rodorubicin, streptonigrin, Streptozocin, proliferation, such as, for example, PKC-alpha, Ralf and tubercidin, ubenimex, Zinostatin, Zorubicin; anti-metabolites H-Ras; (vii) ribozymes such as VEGF expression inhibitors such as methotrexate and 5-fluorouracil (5-FU); folic acid (e.g., ANGIOZYME(R) and HER2 expression inhibitors: analogs such as denopterin, methotrexate, pteropterin, trime (viii) vaccines such as gene therapy Vaccines, for example, trexate; purine analogs such as fludarabine, 6-mercaptopu ALLOVECTINR, LEUVECTINR, and VAXIDR, PRO rine, thiamiprine, thioguanine; pyrimidine analogs such as LEUKINR), rIL-2; a topoisomerase 1 inhibitor such as LUR ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, TOTECANR); ABARELIX(R) rmRH; and (ix) pharmaceuti dideoxyuridine, doxifluridine, enocitabine, floxuridine: cally acceptable salts, acids and derivatives of any of the androgens Such as calusterone, dromoStanolone propionate, above. epitioStanol, mepitioStane, testolactone; anti-adrenals such as 0.165 Chemotherapeutic agent also includes antibodies aminoglutethimide, mitotane, triloStane; folic acid replen such as alemtuzumab (Campath), bevacizumab (AVAS isher Such as frolinic acid; aceglatone; aldophosphamide gly TINR), Genentech); cetuximab (ERBITUX(R), Imclone): coside; aminolevulinic acid; eniluracil; amsacrine; panitumumab (VECTIBIX(R), Amgen), rituximab (RIT bestrabucil; bisantrene; ediatraxate; defofamine; demecol UXANR), Genentech/Biogen Idec), pertuzumab (OMNI cine; diaziquone; elfomithine; elliptinium acetate; an TARG(R), 2C4, Genentech), trastuzumab (HERCEPTINR, epothilone; etoglucid, gallium nitrate; hydroxyurea; lentinan; Genentech), to situmomab (BeXXar, Corixia), and the anti lonidainine; maytansinoids such as maytansine and ansami body drug conjugate, gemtuzumab ozogamicin (MYLO tocins; mitoguaZone; mitoxantrone; mopidamnol; nitraerine; TARG(R), Wyeth). Additional humanized monoclonal anti pentostatin: phenamet, pirarubicin; losoxantrone; podophyl bodies with therapeutic potential as agents in combination linic acid; 2-ethylhydrazide; procarbazine; PSKR polysac with the compounds of the invention include: apolizumab, US 2015/0307617 A1 Oct. 29, 2015 aselizumab, atlizumab, bapineuZumab, bivatuZumab mer 4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX tansine, cantuzumab mertansine, cedelizumab, certolizumab 1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl pegol, cidfusituzumab, cidtuZumab, daclizumab, eculi piperidin-4-yl)-pyrimido5,4-dipyrimidine-2,8-diamine, Zumab, efalizumab, epratuZumab, erlizumab, felvizumab, Boehringer Ingelheim); PKI-166 ((R)-4-4-(1-phenylethyl) fontolizumab, gemtuzumab ozogamicin, inotuZumab ozo amino)-1H-pyrrolo2,3-dipyrimidin-6-yl-phenol); (R)-6- gamicin, ipilimumab, labetuZumab, lintuZumab, matuZumab, (4-hydroxyphenyl)-4-(1-phenylethyl)amino-7H-pyrrolo2, mepolizumab, motavizumab, motovizumab, natalizumab, 3-dipyrimidine); CL-387785 (N-4-(3-bromophenyl) nimotuZumab, nolovizumab, numavizumab, ocrelizumab, amino-6-quinazolinyl-2-butynamide); EKB-569 (N-4-(3- omalizumab, palivizumab, pascolizumab, pectfusituzumab, chloro-4-fluorophenyl)amino-3-cyano-7-ethoxy-6- pectuZumab, pexelizumab, ralivizumab, ranibizumab, quinolinyl-4-(dimethylamino)-2-butenamide) (Wyeth): reslivizumab, reslizumab, resy Vizumab, rovelizumab, rupli AG1478 (Pfizer): AG1571 (SU 5271; Pfizer); dual EGFR/ Zumab, SibrotuZumab, SipliZumab, Sontuzumab, tacatuZumab HER2 tyrosine kinase inhibitors such as lapatinib (TYK tetraxetan, tadocizumab, talizumab, tefibazumab, tocili ERB(R), GSK572016 or N-3-chloro-4-(3 fluorophenyl) Zumab, toralizumab, tucotuZumab celmoleukin, tucusitu methoxyphenyl]-652methylsulfonyl)ethylamino Zumab, umavizumab, urtoxazumab, ustekinumab, visili methyl-2-furanyl-4-quinazolinamine). Zumab, and the anti-interleukin-12 (ABT-874/J695, Wyeth 0.167 Chemotherapeutic agents also include “tyrosine Research and Abbott Laboratories) which is a recombinant kinase inhibitors' including the EGFR-targeted drugs noted exclusively human-sequence, full-length IgG1 antibody in the preceding paragraph; Small molecule HER2 tyrosine genetically modified to recognize interleukin-12p40 protein. kinase inhibitor such as TAK165 available from Takeda; 0166 Chemotherapeutic agent also includes “EGFR CP-724,714, an oral selective inhibitor of the ErbB2 receptor inhibitors, which refers to compounds that bind to or other tyrosine kinase (Pfizer and OSI): dual-HER inhibitors such as wise interact directly with EGFR and prevent or reduce its EKB-569 (available from Wyeth) which preferentially binds signaling activity, and is alternatively referred to as an “EGFR EGFR but inhibits both HER2 and EGFR-overexpressing antagonist.” Examples of Such agents include antibodies and cells; lapatinib (GSK572016; available from Glaxo-Smith small molecules that bind to EGFR. Examples of antibodies Kline), an oral HER2 and EGFR tyrosine kinase inhibitor; which bind to EGFR include MAb 579 (ATCC CRL HB PKI-166 (available from Novartis); pan-HER inhibitors such 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as CRL 8508), MAb 528 (ATCCCRL 8509) (see, U.S. Pat. No. antisense agent ISIS-5132 available from ISIS Pharmaceuti 4,943,533, Mendelsohn et al.) and variants thereof, such as cals which inhibit Raf-1 signaling; non-HER targeted TK chimerized 225 (C225 or Cetuximab; ERBUTIX(R) and inhibitors such as imatinib mesylate (GLEEVECR), available reshaped human 225 (H225) (see, WO 96/40210, Imclone from Glaxo SmithKline); multi-targeted tyrosine kinase Systems Inc.); IMC-11F8, a fully human, EGFR-targeted inhibitors such as Sunitinib (SUTENTR), available from antibody (Imclone); antibodies that bind type II mutant Pfizer); VEGF receptor tyrosine kinase inhibitors such as EGFR (U.S. Pat. No. 5.212,290); humanized and chimeric vatalanib (PTK787/ZK222584, available from Novartis/ antibodies that bind EGFR as described in U.S. Pat. No. Schering AG); MAPK extracellular regulated kinase I inhibi 5,891,996; and human antibodies that bind EGFR, such as tor CI-1040 (available from Pharmacia); quinazolines, such ABX-EGF or Panitumumab (see WO98/50433, Abgenix/ as PD 153035, 4-(3-chloroanilino) quinazoline: pyridopyri Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A: midines; pyrimidopyrimidines; pyrrolopyrimidines, such as 636-640 (1996)); EMD7200 (matuzumab) a humanized CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrim EGFR antibody directed against EGFR that competes with idines, 4-(phenylamino)-7H-pyrrolo2,3-dipyrimidines; cur both EGF and TGF-alpha for EGFR binding (EMD/Merck); cumin (diferuloyl methane, 4,5-bis(4-fluoroanilino)phthal human EGFR antibody, HuMax-EGFR (GenMab); fully imide); tyrphostines containing nitrothiophene moieties; human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, PD-0183805 (Warner-Lamber); antisense molecules (e.g. E2.11, E6.3 and E7.6.3 and described in U.S. Pat. No. 6,235, those that bind to HER-encoding nucleic acid); quinoxalines 883; MDX-447 (Medarex Inc); and mAb 806 or humanized (U.S. Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804, mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 396); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering (2004)). The anti-EGFR antibody may be conjugated with a AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac cytotoxic agent, thus generating an immunoconjugate (see, (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVEC(R): e.g., EP659,439A2, Merck Patent GmbH). EGFRantagonists PKI 166 (Novartis); GW2016 (GlaxoSmithKline): CI-1033 include Small molecules such as compounds described in (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, (AstraZeneca); PTK-787 (Novartis/Schering AG); INC 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE(R); or 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, as described in any of the following patent publications: U.S. 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, Pat. No. 5,804.396; WO 1999/09016 (American Cyanamid); 5,760,041, 6,002,008, and 5,747,498, as well as the following WO 1998/43960 (American Cyanamid); WO 1997/38983 PCT publications: WO98/14451, WO98/50038, WO99/ (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 09016, and WO99/24037. Particular small molecule EGFR 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, antagonists include OSI-774 (CP-358.774, erlotinib, Inc): WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) TARCEVAR) Genentech/OSI Pharmaceuticals); PD 183805 and WO 1996/33980 (Zeneca). (CI 1033, 2-propenamide, N-4-(3-chloro-4-fluorophenyl) 0168 Chemotherapeutic agents also include dexametha amino-7-3-(4-morpholinyl)propoxy-6-quinazolinyl-, Sone, interferons, colchicine, metoprine, cyclosporine, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSAR) amphotericin, metronidazole, alemtuzumab, alitretinoin, 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholino allopurinol, amifostine, arsenic trioxide, asparaginase, BCG propoxy)guinazoline, AstraZeneca); ZM 105180 ((6-amino live, bevacuzimab, bexarotene, cladribine, clofarabine, dar US 2015/0307617 A1 Oct. 29, 2015 bepoetin alfa, denileukin, dexraZOxane, epoetin alfa, elotinib, above; as well as combinations of two or more of the above filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, such as CHOP, an abbreviation for a combined therapy of interferon alfa-2b, lenalidomide, levamisole, mesna, methox cyclophosphamide, doxorubicin, Vincristine, and predniso salen, nandrolone, nelarabine, nofetumomab, oprelvekin, lone; and FOLFOX, an abbreviation for a treatment regimen palifermin, pamidronate, pegademase, pegaspargase, peg with oxaliplatin (ELOXATINTM) combined with 5-FU and filgrastim, pemetrexed disodium, plicamycin, porfimer leucovorin. Sodium, quinacrine, rasburicase, SargramoStim, temozolo 0170 Chemotherapeutic agents also include non-steroidal mide, VM-26, 6-TG, toremifene, tretinoin, ATRA, walrubi anti-inflammatory drugs with analgesic, antipyretic and anti cin, Zoledronate, and Zoledronic acid, and pharmaceutically inflammatory effects. NSAIDs include non-selective inhibi acceptable salts thereof. tors of the enzyme cyclooxygenase. Specific examples of 0169 Chemotherapeutic agents also include hydrocorti NSAIDs include aspirin, propionic acid derivatives such as Sone, hydrocortisone acetate, cortisone acetate, tiXocortol ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin pivalate, triamcinolone acetonide, triamcinolone alcohol, and naproxen, acetic acid derivatives Such as indomethacin, mometasone, amcinonide, budesonide, desonide, fluocinon Sulindac, etodolac, diclofenac, enolic acid derivatives such as ide, fluocinolone acetonide, betamethasone, betamethasone piroXicam, meloxicam, tenoxicam, droxicam, lornoxicam Sodium phosphate, dexamethasone, dexamethasone sodium and isoxicam, fenamic acid derivatives such as mefenamic phosphate, fluocortolone, hydrocortisone-17-butyrate, acid, meclofenamic acid, flufenamic acid, tolfenamic acid, hydrocortisone-17-Valerate, aclometasone dipropionate, and COX-2 inhibitors such as celecoxib, etoricoxib, lumira betamethasone Valerate, betamethasone dipropionate, pred coxib, parecoxib, rofecoxib, rofecoxib, and Valdecoxib. nicarbate, clobetasone-17-butyrate, clobetasol-17-propi NSAIDs can be indicated for the symptomatic relief of con onate, fluocortolone caproate, fluocortolone pivalate and flu ditions such as rheumatoid arthritis, osteoarthritis, inflamma prednidene acetate; immune selective anti-inflammatory tory arthropathies, ankylosing spondylitis, psoriatic arthritis, peptides (ImSAIDs) such as phenylalanine-glutamine-gly Reiter's syndrome, acute gout, dysmenorrhoea, metastatic cine (FEG) and its D-isomeric form (fed) (IMULAN Bio bone pain, headache and migraine, postoperative pain, mild Therapeutics, LLC); anti-rheumatic drugs such as azathio to-moderate pain due to inflammation and tissue injury, pyr prine, ciclosporin (cyclosporine A), D-penicillamine, gold exia, ileus, and renal colic. salts, hydroxychloroquine, leflunomideminocycline, Sul 0171 The term “cytokine' is a generic term for proteins fasalazine, tumor necrosis factor alpha (TNFO.) blockers such released by one cell population that act on another cell as as etanercept (Enbrel), infliximab (Remicade), adalimumab intercellular mediators. Examples of such cytokines are lym (Humira), certolizumab pegol (Cimzia), golimumab (Sim phokines, monokines; interleukins (ILS) Such as IL-1, IL-la, poni), Interleukin 1 (IL-1) blockers such as anakinra (Ki IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, neret), T cell costimulation blockers such as abatacept (Oren IL-15; a tumor necrosis factor such as TNF-C. or TNF-B; and cia), Interleukin 6 (IL-6) blockers such as tocilizumab other polypeptide factors including LIF and kit ligand (KL) (ACTEMERAR); Interleukin 13 (IL-13) blockers such as and gamma interferon. As used herein, the term cytokine lebrikizumab: Interferon alpha (IFN) blockers such as Ron includes proteins from natural Sources or from recombinant talizumab. Beta 7 integrin blockers such as rhuMAb Beta7; cell culture and biologically active equivalents of the native IgE pathway blockers such as Anti-M1 prime: Secreted sequence cytokines, including synthetically produced Small homotrimeric LTa3 and membrane bound heterotrimer LTalf molecule entities and pharmaceutically acceptable deriva B2 blockers such as Anti-lymphotoxin alpha (LTa); radioac tives and salts thereof. tive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, 0172. The term “PD-1 axis binding antagonist' is a mol Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu); ecule that inhibits the interaction of a PD-1 axis binding miscellaneous investigational agents such as thioplatin, partner with either one or more of its binding partner, so as to PS-341, phenylbutyrate, ET-18-OCH3, or farnesyl trans remove T-cell dysfunction resulting from signaling on the ferase inhibitors (L-739749, L-744832); polyphenols such as PD-1 signaling axis—with a result being to restore or quercetin, resveratrol, piceatannol, epigallocatechine gallate, enhance T-cell function (e.g., proliferation, cytokine produc theaflavins, flavanols, procyanidins, betulinic acid and tion, target cell killing) As used herein, a PD-1 axis binding derivatives thereof, autophagy inhibitors such as chloro antagonist includes a PD-1 binding antagonist, a PD-L1 bind quine; delta-9-tetrahydrocannabinol (dronabinol, ing antagonist and a PD-L2 binding antagonist. MARINOL(R); beta-lapachone; lapachol; colchicines; betu 0173 The term “PD-1 binding antagonists’ is a molecule linic acid; acetylcamptothecin, Scopolectin, and 9-ami that decreases, blocks, inhibits, abrogates or interferes with nocamptothecin); podophyllotoxin; tegafur (UFTORAL(R): signal transduction resulting from the interaction of PD-1 bexarotene (TARGRETINR); bisphosphonates such as clo with one or more of its binding partners, such as PD-L1, dronate (for example, BONEFOS(R) or OSTAC(R), etidronate PD-L2. In some embodiments, the PD-1 binding antagonist is (DIDROCAL(R), NE-58095, Zoledronic acid/zoledronate a molecule that inhibits the binding of PD-1 to its binding (ZOMETAR), alendronate (FOSAMAX(R), pamidronate partners. In a specific aspect, the PD-1 binding antagonist (AREDIAR), tiludronate (SKELID(R), or risedronate (AC inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For TONELR); and epidermal growth factor receptor (EGF-R): example, PD-1 binding antagonists include anti-PD-1 anti vaccines such as THERATOPER vaccine; perifosine, COX-2 bodies, antigen binding fragments thereof, immunoadhesins, inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor fusion proteins, oligopeptides and other molecules that (e.g. PS341); CCI-779; tipifarnib (R11577); orafenib, decrease, block, inhibit, abrogate or interfere with signal ABT510; Bcl-2 inhibitor such as oblimersen sodium (GE transduction resulting from the interaction of PD-1 with PD NASENSE(R); pixantrone; farnesyltransferase inhibitors L1 and/or PD-L2. In one embodiment, a PD-1 binding such as lonafarnib (SCH 6636, SARASARTM); and pharma antagonist reduces the negative co-stimulatory signal medi ceutically acceptable salts, acids or derivatives of any of the ated by or through cell Surface proteins expressed on T lym US 2015/0307617 A1 Oct. 29, 2015 phocytes mediated signaling through PD-1 So as render a ing presence of a detectably labeled cell within another cell dysfunctional T-cell less dysfunctional (e.g., enhancing (which may be detectably labeled, e.g., with a different label effector responses to antigen recognition). In some embodi than the first cell). ments, the PD-1 binding antagonist is an anti-PD-1 antibody. 0177. The phrase “does not possess substantial activity” or In a specific aspect, a PD-1 binding antagonist is MDX-1 106 “substantially no activity” with respect to an antibody, as used described herein. In another specific aspect, a PD-1 binding herein, means the antibody does not exhibit an activity that is antagonist is Merck 3745 described herein. In another spe above background level (in some embodiments, that is above cific aspect, a PD-1 binding antagonist is CT-011 described background level that is statistically significant). The phrase herein. “little to no activity” with respect to an antibody, as used 0.174. The term “PD-L1 binding antagonists’ is a mol herein, means the antibody does not display a biologically ecule that decreases, blocks, inhibits, abrogates or interferes meaningful amount of a function. The function can be mea with signal transduction resulting from the interaction of Sured or detected according to any assay or technique known PD-L1 with either one or more of its binding partners, such as in the art, including, e.g., those described herein. In some PD-1, B7-1. In some embodiments, a PD-L1 binding antago embodiments, antibody function is stimulation of effector T nist is a molecule that inhibits the binding of PD-L1 to its cell proliferation and/or cytokine secretion. binding partners. In a specific aspect, the PD-L1 binding 0.178 The term “biomarker' or “marker as used herein antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1. In refers generally to a molecule, including a gene, mRNA, Some embodiments, the PD-L1 binding antagonists include protein, carbohydrate structure, or glycolipid, the expression anti-PD-L1 antibodies, antigen binding fragments thereof, of which in or on a tissue or cell or secreted can be detected by immunoadhesins, fusion proteins, oligopeptides and other known methods (or methods disclosed herein) and is predic molecules that decrease, block, inhibit, abrogate or interfere tive or can be used to predict (or aid prediction) for a cell, with signal transduction resulting from the interaction of tissue, or patients responsiveness to treatment regimes. PD-L1 with one or more of its binding partners, such as PD-1, 0179. By “patient sample' is meant a collection of cells or B7-1. In one embodiment, a PD-L1 binding antagonist fluids obtained from a cancer patient. The source of the tissue reduces the negative co-stimulatory signal mediated by or or cell sample may be solid tissue as from a fresh, frozen through cell Surface proteins expressed on T lymphocytes and/or preserved organ or tissue sample or biopsy or aspirate; mediated signaling through PD-L1 so as to render a dysfunc blood or any blood constituents: bodily fluids such as cere tional T-cell less dysfunctional (e.g., enhancing effector brospinal fluid, amniotic fluid, peritoneal fluid, or interstitial responses to antigen recognition). In some embodiments, a fluid; cells from any time in gestation or development of the PD-L1 binding antagonist is an anti-PD-L1 antibody. In a Subject. The tissue sample may contain compounds which are specific aspect, an anti-PD-L1 antibody is YW243.55.S70 not naturally intermixed with the tissue in nature such as described herein. In another specific aspect, an anti-PD-L1 preservatives, anticoagulants, buffers, fixatives, nutrients, antibody is MDX-1 105 described herein. In still another antibiotics, or the like. Examples of tumor samples herein specific aspect, an anti-PD-L1 antibody is MPDL3280A include, but are not limited to, tumor biopsy, fine needle described herein. aspirate, bronchiolar lavage, pleural fluid, sputum, urine, a 0.175. The term “PD-L2 binding antagonists’ is a mol Surgical specimen, circulating tumor cells, serum, plasma, ecule that decreases, blocks, inhibits, abrogates or interferes circulating plasma proteins, ascitic fluid, primary cell cul with signal transduction resulting from the interaction of tures or cell lines derived from tumors or exhibiting tumor PD-L2 with either one or more of its binding partners, such as like properties, as well as preserved tumor samples, such as PD-1. In some embodiments, a PD-L2 binding antagonist is a formalin-fixed, paraffin-embedded tumor samples or frozen molecule that inhibits the binding of PD-L2 to its binding tumor samples. partners. In a specific aspect, the PD-L2 binding antagonist 0180. The phrase “based on expression of when used inhibits binding of PD-L2 to PD-1. In some embodiments, the herein means that information about expression level or pres PD-L2 antagonists include anti-PD-L2 antibodies, antigen ence or absence of expression (e.g., presence or absence or binding fragments thereof, immunoadhesins, fusion proteins, prevalence of (e.g., percentage of cells displaying) of the one oligopeptides and other molecules that decrease, block, or more biomarkers herein (e.g., presence or absence of or inhibit, abrogate or interfere with signal transduction result amount or prevelance of FcR-expressing cells, or e.g., pres ing from the interaction of PD-L2 with either one or more of ence or absence or amount or prevelance of human effector its binding partners. Such as PD-1. In one embodiment, a cells) is used to inform a treatment decision, information PD-L2 binding antagonist reduces the negative co-stimula provided on a package insert, or marketing/promotional guid tory signal mediated by or through cell Surface proteins ance etc. expressed on T lymphocytes mediated signaling through PD 0181. A cancer or biological sample which “has human L2 so as rendera dysfunctional T-cell less dysfunctional (e.g., effector cells' is one which, in a diagnostic test, has human enhancing effector responses to antigen recognition). In some effector cells present in the sample (e.g., infiltrating human embodiments, a PD-L2 binding antagonist is an immunoad effector cells). hesin. 0182. A cancer or biological sample which “has FcR 0176 The term “phagocytosis” means the internalization expressing cells' is one which, in a diagnostic test, has FcR of cells or particulate matter by cells. In some embodiments, expressing present in the sample (e.g., infiltrating FcR-ex the phagocytic cells or phagocytes are macrophages or neu pressing cells). In some embodiments, FcR is FcyR. In some trophils. In some embodiments, the cells are cells that express embodiments, FcR is an activating Fcy.R. human OX40. Methods for assaying phagocytosis are known 0183 The phrase “recommending a treatment as used in the art and include use of microscopy to detect the presence herein refers to using the information or data generated relat of cells internalized within another cells. In other embodi ing to the level or presence ofc-met in a sample of a patient to ments, phagocytosis is detected using FACS, e.g., by detect identify the patient as suitably treated or not suitably treated US 2015/0307617 A1 Oct. 29, 2015 with a therapy. In some embodiments the therapy may com EC50 of about 1.5 ug/ml. In some embodiments, binding to prise c-met antibody (e.g., onartuzumab). In some embodi cynomolgus OX40 has an EC50 of about 1.4 ug/ml. ments, the therapy may comprise VEGF antagonist (e.g., 0188 In some embodiments, the anti-human OX40 ago bevacizumab). In some embodiments, the therapy may com nist antibody does not bind to rat OX40 or mouse OX40. prise anti-human OX40 agonistantibody. The information or 0189 In some embodiments, the anti-human OX40 ago data may be in any form, written, oral or electronic. In some nistantibody is a depleting anti-human OX40 antibody (e.g., embodiments, using the information or data generated depletes cells that express human OX40). In some embodi includes communicating, presenting, reporting, storing, ments, the OX40 agonistantibody depletes cells that express sending, transferring, Supplying, transmitting, delivering, human OX40 in vitro. In some embodiments, the human dispensing, or combinations thereof. In some embodiments, OX40 expressing cells are CD4+ effector T cells. In some communicating, presenting, reporting, storing, sending. embodiments, the human OX40 expressing cells are Treg transferring, Supplying, transmitting, delivering, dispensing, cells. In some embodiments, depleting is by ADCC and/or or combinations thereof are performed by a computing phagocytosis. In some embodiments, the antibody mediates device, analyzer unit or combination thereof. In some further ADCC by binding FcyR expressed by a human effector cell embodiments, communicating, presenting, reporting, Stor and activating the human effector cell function. In some ing, sending, transferring, Supplying, transmitting, dispens embodiments, the antibody mediates phagocytosis by bind ing, or combinations thereof are performed by an individual ing FcyR expressed by a human effector cell and activating (e.g., a laboratory or medical professional). In some embodi the human effector cell function. Exemplary human effector ments, the information or data includes a comparison of the cells include, e.g., macrophage, natural killer (NK) cells, amount or prevelance of FcR expressing cells to a reference monocytes, neutrophils. In some embodiments, the human level. In some embodiments, the information or data includes effector cell is macrophage. In some embodiments, the a comparison of the amount or prevelance of human effector human effector cell is NK cells. In some embodiments, deple cells to a reference level. In some embodiments, the informa tion is not by apoptosis. tion or data includes an indication that human effector cells or 0190. In some embodiments, the anti-human OX40 ago FcR-expressing cells are present or absent in the sample. In nist antibody has a functional Fc region. In some embodi Some embodiments, the information or data includes an indi ments, effector function of a functional Fc region is ADCC. In cation that FcR-expressing cells and/or human effector cells some embodiments, effector function of a functional Fc are present in a particular percentage of cells (e.g., high region is phagocytosis. In some embodiments, effector func prevelance). In some embodiments, the information or data tion of a functional Fc region is ADCC and phagocytosis. In includes an indication that the patient is Suitably treated or not Some embodiments, the Fc region is human IgG1. In some suitably treated with a therapy comprising anti-human OX40 embodiments, the Fc region is human IgG4. agonist antibody. 0191 In some embodiments, the anti-human OX40 ago nistantibody does not induce apoptosis in OX40-expressing II. COMPOSITIONS AND METHODS cells (e.g., Treg). In some embodiments, apoptosis is assayed using an antibody concentration of 30 ug/ml, e.g., by deter 0184. In one aspect, the invention is based, in part, on mining whether apoptosis has occurred using annexin V and identification of a variety of OX40 binding agents. In certain proprodium iodide stained Treg. embodiments, antibodies (e.g., agonist antibodies) that bind 0.192 In some embodiments, the anti-human OX40 ago to human OX40 are provided. Antibodies of the invention are nist antibody enhances CD4+ effector T cell function, for useful, e.g., for the diagnosis or treatment of cancer and other example, by increasing CD4+ effector T cell proliferation disorders associated with OX40 expression and/or activity. and/or increasing gamma interferon production by the CD4+ effector T cell (for example, as compared to proliferation A. Exemplary Anti-OX40 Antibodies and/or cytokine production prior to treatment with anti-hu man OX40 agonist antibody). In some embodiments, the 0185. In one aspect, the invention provides isolated anti cytokine is gamma interferon. In some embodiments, the bodies that bind to human OX40. anti-human OX40 agonist antibody increases number of 0186. In some embodiments, the anti-human OX40 ago intratumoral (infiltrating) CD4+ effector T cells (e.g., total nistantibody binds human OX40 with an affinity of less than number of CD4+ effector T cells, or e.g., percentage of CD4+ or equal to about 0.45 nM. In some embodiments, the OX40 cells in CD45+ cells), e.g., as compared to number of intra agonist antibody binds human OX40 with an affinity of less tumoral (infiltrating) CD4+ T cells prior to treatment with than or equal to about 1 nM. In some embodiments, the anti-human OX40 agonist antibody. In some embodiments, anti-human OX40 antibody binds human OX40 with an affin the anti-human OX40 agonist antibody increases number of ity of less than or equal to about 0.4 nM. In some embodi intratumoral (infiltrating) CD4+ effector T cells that express ments, the anti-human OX40 antibody binds human OX40 gamma interferon (e.g., total gamma interferon expressing with an affinity of less than or equal to about 0.5 nM. In some CD4+ cells, or e.g., percentage of gamma interferon express embodiments, the binding affinity is determined using radio ing CD4+ cells in total CD4+ cells), e.g., as compared to immunoassay. number of intratumoral (infiltrating) CD4+ T cells that 0187. In some embodiments, the anti-human OX40 ago express gamma interferon prior to treatment with anti-human nist antibody binds human OX40 and cynomolgus OX40. In OX40 agonistantibody. Some embodiments, binding is determined using a FACS 0193 In some embodiments, the anti-human OX40 ago assay. In some embodiments, binding to human OX40 has an nist antibody increases number of intratumoral (infiltrating) EC50 of about 0.2 ug/ml. In some embodiments, binding to CD8+ effector T cells (e.g., total number of CD8+ effector T human OX40 has an EC50 of about 0.3 ug/ml or lower. In cells, or e.g., percentage of CD8+ in CD45+ cells), e.g., as Some embodiments, binding to cynomolgus OX40 has an compared to number of intratumoral (infiltrating) CD8+ T US 2015/0307617 A1 Oct. 29, 2015 20 effector cells prior to treatment with anti-human OX40 ago 0201 In some embodiments, antibody cross-linking is nist antibody. In some embodiments, the anti-human OX40 required for anti-human OX40 agonist antibody function. In agonist antibody increases number of intratumoral (infiltrat some embodiments, function is stimulation of CD4+ effector ing) CD8+ effector T cells that express gamma interferon T cell proliferation. In some embodiments, antibody cross (e.g., percentage of CD8+ cells that express gamma inter linking is determined by providing anti-human OX40 agonist feron in total CD8+ cells), e.g., compared to number of intra antibody adhered on a solid Surface (e.g., a cell culture plate). tumoral (infiltrating) CD8+ T cells that express gamma inter In some embodiments, antibody cross-linking is determined feron prior to treatment with anti-human OX40 agonist by introducing a mutation in the antibody's IgG1 Fc portion antibody. (e.g., a DANA mutation) and testing function of the mutant 0194 In some embodiments, the anti-human OX40 ago antibody. nistantibody enhances memory T cell function, for example by increasing memory T cell proliferation and/or increasing 0202 In some embodiments, the anti-human OX40 ago cytokine production by the memory cell. In some embodi nist antibody competes for binding to human OX40 with ments, the cytokine is gamma interferon. OX40L. In some embodiments, addition of OX40L does not 0.195. In some embodiments, the anti-human OX40 ago enhance anti-human OX40 antibody function in an in vitro nistantibody inhibits Tregfunction, for example, by decreas assay. ing Treg Suppression of effector T cell function (e.g., effector T cell proliferation and/or effector T cell cytokine secretion). 0203. According to another embodiment, the anti-human In some embodiments, the effector T cell is a CD4+ effector OX40 agonist antibodies include any one, any combination, T cell. In some embodiments, the anti-human OX40 agonist or all of the following properties: (1) binds human OX40 with antibody reduces the number of intratumoral (infiltrating) an affinity of less than or equal to about 0.45 nM, in some Treg (e.g., total number of Tregor e.g., percentage of Fox3p-- embodiments, binds human OX40 with an affinity of less than cells in CD4+ cells). or equal to about 0.4 nM, in some embodiments, binds human 0196. In some embodiments, the anti-human OX40 ago OX40 with an affinity of less than or equal to about 0.5 nM, in nistantibody is engineered to increase effector function (e.g., Some embodiments, the binding affinity is determined using compared to effector function in a wild-type IgG1). In some radioimmunoassay; (2) binds human OX40 and cynomolgus embodiments, the antibody has increased binding to a Fcy OX40, in some embodiments, binding is determined using a receptor. In some embodiments, the antibody lacks fucose FACS assay, (3) binds human OX40 with an EC50 of about attached (directly or indirectly) to the Fc region. For example, 0.2 ug/ml, in some embodiments, binds to human OX40 has the amount of fucose in such antibody may be from 1% to an EC50 of about 0.3 ug/ml or lower, in some embodiments, 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. binds to cynomolgus OX40 with an EC50 of about 1.5ug/ml, In some embodiments, the Fc region comprises bisected oli in some embodiments, binds to cynomolgus OX40 has an gosaccharides, e.g., in which a biantennary oligosaccharide EC50 of about 1.4 ug/ml, (4) does not substantially bind to rat attached to the Fc region of the antibody is bisected by OX40 or mouse OX40, (6) is a depleting anti-human OX40 GlcNAc. In some embodiments, the antibody comprises an antibody (e.g., depletes cells that express human OX40), in Fc region with one or more amino acid substitutions which some embodiments, the cells are CD4+ effector T cells and/or improve ADCC, e.g., substitutions at positions 298, 333, Treg cells, (7) enhances CD4+ effector T cell function, for and/or 334 of the Fc region (EU numbering of residues). example, by increasing CD4+ effector T cell proliferation 0197) In some embodiments, the anti-human OX40 ago and/or increasing gamma interferon production by the CD4+ nist antibody increases OX40 signal transduction in a target effector T cell (for example, as compared to proliferation cell that expresses OX40. In some embodiments, OX40 signal and/or cytokine production prior to treatment with anti-hu transduction is detected by monitoring NFkB downstream man OX40 agonist antibody), (8) enhances memory T cell signaling. function, for example by increasing memory T cell prolifera 0198 In some embodiments, the anti-human OX40 ago tion and/or increasing cytokine production by the memory nistantibody is stable after treatment at 40°C. for two weeks. cell, (9) inhibits Treg function, for example, by decreasing 0199. In some embodiments, the anti-human OX40 ago Treg suppression of effector T cell function (e.g., effector T nist antibody binds human effector cells, e.g., binds FcyR cell proliferation and/or effector T cell cytokine secretion). In (e.g., an activating FcyR) expressed by human effector cells. some embodiments, the effector T cell is a CD4+ effector T In some embodiments, the human effector cell performs (is cell, (10) increases OX40 signal transduction in a target cell capable of performing) ADCC effector function. In some that expresses OX40 (in some embodiments, OX40 signal embodiments, the human effector cell performs (is capable of transduction is detected by monitoring NFkB downstream performing) phagocytosis effector function. signaling), (11) is stable after treatment at 40° C. for two 0200. In some embodiments, the anti-human OX40 ago weeks, (12) binds human effector cells, e.g., binds FcyR nistantibody comprising a variant IgG1 Fc polypeptide com expressed by human effector cells, (13) anti-human OX40 prising a mutation that eliminates binding to human effector agonist antibody comprising a variant IgG1 Fc polypeptide cells (e.g., a DANA mutation) has diminished activity (e.g., comprising a mutation that eliminates binding to human CD4+ effector T cell function, e.g., proliferation), relative to effector cells (e.g., N297G) has diminished activity (e.g., anti-human OX40 agonist antibody comprising native CD4+ effector T cell function, e.g., proliferation), relative to sequence IgG1 Fc portion. In some embodiment, the anti anti-human OX40 agonist antibody comprising native human OX40 agonistantibody comprising a variant IgG1 Fc sequence IgG1 Fc portion, in Some embodiment, the anti polypeptide comprising a mutation that eliminates binding to human OX40 agonistantibody comprising a variant IgG1 Fc human effector cells (e.g., a DANA mutation) does not pos polypeptide comprising a mutation that eliminates binding to sess substantial activity (e.g., CD4+ effector T cell function, human effector cells (e.g., N297G) does not possess substan e.g., proliferation). tial activity (e.g., CD4+ effector T cell function, e.g., prolif US 2015/0307617 A1 Oct. 29, 2015 eration), (14) antibody cross-linking (e.g., by Fc receptor sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an binding) is required for anti-human OX40 agonist antibody amino acid sequence selected from SEQID NO:7. function. 0209. In one aspect, the invention provides an anti-human 0204. In one aspect, the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQID NO:6; and (f) HVR-L3 comprising the sequence of SEQID NO:6; and (f) HVR-L3 comprising the amino acid sequence of SEQID NO:26. amino acid sequence of SEQID NO:7. 0210. In another embodiment, the antibody comprises 0205. In one aspect, the invention provides an anti-human HVR-H3 comprising the amino acid sequence of SEQ ID OX40 agonistantibody comprising at least one, at least two, NO:4 and HVR-L3 comprising the amino acid sequence of or all three VH HVR sequences selected from (a) HVR-H1 SEQID NO:26. In a further embodiment, the antibody com comprising the amino acid sequence of SEQ ID NO:2; (b) prises HVR-H3 comprising the amino acid sequence of SEQ HVR-H2 comprising the amino acid sequence of SEQ ID ID NO:4, HVR-L3 comprising the amino acid sequence of NO:3; and (c) HVR-H3 comprising the amino acid sequence SEQ ID NO:26, and HVR-H2 comprising the amino acid of SEQID NO:4. In one embodiment, the antibody comprises sequence of SEQID NO:3. HVR-H3 comprising the amino acid sequence of SEQ ID 0211. In another aspect, an antibody of the invention com NO:4. In another embodiment, the antibody comprises HVR prises (a) a VH domain comprising at least one, at least two, H3 comprising the amino acid sequence of SEQID NO.4 and or all three VH HVR sequences selected from (i) HVR-H1 HVR-L3 comprising the amino acid sequence of SEQ ID comprising the amino acid sequence of SEQ ID NO:2, (ii) NO:7. In a further embodiment, the antibody comprises HVR-H2 comprising the amino acid sequence of SEQ ID HVR-H3 comprising the amino acid sequence of SEQ ID NO:3, and (iii) HVR-H3 comprising an amino acid sequence NO:4, HVR-L3 comprising the amino acid sequence of SEQ selected from SEQID NO:4; and (b) a VL domain comprising ID NO:7, and HVR-H2 comprising the amino acid sequence at least one, at least two, or all three VL HVR sequences of SEQ ID NO:3. In a further embodiment, the antibody selected from (i) HVR-L1 comprising the amino acid comprises (a) HVR-H1 comprising the amino acid sequence sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid amino acid sequence of SEQ ID NO:6, and (c) HVR-L3 sequence of SEQID NO:3; and (c) HVR-H3 comprising the comprising the amino acid sequence of SEQID NO:26. amino acid sequence of SEQID NO:4. 0212. In another aspect, the invention provides an anti 0206. In another aspect, the invention provides an anti body comprising (a) HVR-H1 comprising the amino acid human OX40 agonist antibody comprising at least one, at sequence of SEQ ID NO:2; (b) HVR-H2 comprising the least two, or all three VL HVR sequences selected from (a) amino acid sequence of SEQID NO:3; (c) HVR-H3 compris HVR-L1 comprising the amino acid sequence of SEQ ID ing the amino acid sequence of SEQID NO:4; (d) HVR-L1 NO:5; (b) HVR-L2 comprising the amino acid sequence of comprising the amino acid sequence of SEQ ID NO:5; (e) SEQID NO:6; and (c) HVR-L3 comprising the amino acid HVR-L2 comprising the amino acid sequence of SEQ ID sequence of SEQID NO:7. In one embodiment, the antibody NO:6; and (f) HVR-L3 comprising an amino acid sequence comprises (a) HVR-L1 comprising the amino acid sequence selected from SEQID NO:26. of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid 0213. In one aspect, the invention provides an anti-human sequence of SEQID NO:6; and (c) HVR-L3 comprising the OX40 agonist antibody comprising at least one, two, three, amino acid sequence of SEQID NO:7. four, five, or six HVRs selected from (a) HVR-H1 comprising 0207. In another aspect, an anti-human OX40agonistanti the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 body of the invention comprises (a) a VH domain comprising comprising the amino acid sequence of SEQ ID NO:3; (c) at least one, at least two, or all three VH HVR sequences HVR-H3 comprising the amino acid sequence of SEQ ID selected from (i) HVR-H1 comprising the amino acid NO:4; (d) HVR-L1 comprising the amino acid sequence of sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the SEQ ID NO:5; (e) HVR-L2 comprising the amino acid amino acid sequence of SEQ ID NO:3, and (iii) HVR-H3 sequence of SEQID NO:6; and (f) HVR-L3 comprising the comprising an amino acid sequence selected from SEQ ID amino acid sequence of SEQID NO:27. NO:4; and (b) a VL domain comprising at least one, at least 0214. In another embodiment, the antibody comprises two, or all three VL HVR sequences selected from (i) HVR HVR-H3 comprising the amino acid sequence of SEQ ID L1 comprising the amino acid sequence of SEQID NO:5, (ii) NO:4 and HVR-L3 comprising the amino acid sequence of HVR-L2 comprising the amino acid sequence of SEQ ID SEQID NO:27. In a further embodiment, the antibody com NO:6, and (c) HVR-L3 comprising the amino acid sequence prises HVR-H3 comprising the amino acid sequence of SEQ of SEQ ID NO:7. ID NO:4, HVR-L3 comprising the amino acid sequence of 0208. In another aspect, the invention provides an anti SEQ ID NO:27, and HVR-H2 comprising the amino acid human OX40 agonistantibody comprising (a) HVR-H1 com sequence of SEQID NO:3. prising the amino acid sequence of SEQID NO:2; (b) HVR 0215. In another aspect, an antibody of the invention com H2 comprising the amino acid sequence of SEQID NO:3; (c) prises (a) a VH domain comprising at least one, at least two, HVR-H3 comprising the amino acid sequence of SEQ ID or all three VH HVR sequences selected from (i) HVR-H1 NO:4; (d) HVR-L1 comprising the amino acid sequence of comprising the amino acid sequence of SEQ ID NO:2, (ii) SEQ ID NO:5; (e) HVR-L2 comprising the amino acid HVR-H2 comprising the amino acid sequence of SEQ ID US 2015/0307617 A1 Oct. 29, 2015 22 NO:3, and (iii) HVR-H3 comprising an amino acid sequence or all three VH HVR sequences selected from (i) HVR-H1 selected from SEQID NO:4; and (b) a VL domain comprising comprising the amino acid sequence of SEQID NO: 2, 8 or 9. at least one, at least two, or all three VL HVR sequences (ii) HVR-H2 comprising the amino acid sequence of SEQID selected from (i) HVR-L1 comprising the amino acid NO: 3, 10, 11, 12, 13 or 14, and (iii) HVR-H3 comprising an sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence selected from SEQID NO: 4, 15, or 19: amino acid sequence of SEQ ID NO:6, and (c) HVR-L3 and (b) a VL domain comprising at least one, at least two, or comprising the amino acid sequence of SEQID NO:27. all three VL HVR sequences selected from (i) HVR-L1 com 0216. In another aspect, the invention provides an anti prising the amino acid sequence of SEQID NO:5, (ii) HVR body comprising (a) HVR-H1 comprising the amino acid L2 comprising the amino acid sequence of SEQID NO:6, and sequence of SEQ ID NO:2; (b) HVR-H2 comprising the (c) HVR-L3 comprising the amino acid sequence of SEQID amino acid sequence of SEQID NO:3; (c) HVR-H3 compris NO: 7, 22, 23, 24, 25, 26, 27, or 28. ing the amino acid sequence of SEQID NO:4; (d) HVR-L1 0221. In another aspect, the invention provides an anti comprising the amino acid sequence of SEQ ID NO:5; (e) body comprising (a) HVR-H1 comprising the amino acid HVR-L2 comprising the amino acid sequence of SEQ ID sequence of SEQID NO: 2, 8 or 9; (b) HVR-H2 comprising NO:6; and (f) HVR-L3 comprising an amino acid sequence the amino acid sequence of SEQID NO: 3, 10, 11, 12, 13 or selected from SEQID NO:27. 14; (c) HVR-H3 comprising the amino acid sequence of SEQ 0217. In one aspect, the invention provides an anti-human ID NO: 4, 15, or 19; (d) HVR-L1 comprising the amino acid OX40 agonist antibody comprising at least one, two, three, sequence of SEQ ID NO:5; (e) HVR-L2 comprising the four, five, or six HVRs selected from (a) HVR-H1 comprising amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 the amino acid sequence of SEQID NO:2, 8 or 9; (b) HVR comprising an amino acid sequence selected from SEQ ID H2 comprising the amino acid sequence of SEQID NO:3, 10. NO: 7, 22, 23, 24, 25, 26, 27, or 28. 11, 12, 13 or 14; (c) HVR-H3 comprising the amino acid sequence of SEQID NO:4, 15, or 19; (d) HVR-L1 comprising 0222. In one aspect, the invention provides an anti-human the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 OX40 agonist antibody comprising at least one, two, three, comprising the amino acid sequence of SEQID NO:6; and (f) four, five, or six HVRs selected from (a) HVR-H1 comprising HVR-L3 comprising the amino acid sequence of SEQ ID the amino acid sequence of SEQ ID NO:172; (b) HVR-H2 NO:7, 22, 23, 24, 25, 26, 27, or 28. comprising the amino acid sequence of SEQID NO:173; (c) 0218. In one aspect, the invention provides an antibody HVR-H3 comprising the amino acid sequence of SEQ ID comprising at least one, at least two, or all three VH HVR NO:174; (d) HVR-L1 comprising the amino acid sequence of sequences selected from (a) HVR-H1 comprising the amino SEQ ID NO:5; (e) HVR-L2 comprising the amino acid acid sequence of SEQ ID NO: 2, 8 or 9; (b) HVR-H2 com sequence of SEQID NO:6; and (f) HVR-L3 comprising the prising the amino acid sequence of SEQID NO: 3, 10, 11, 12, amino acid sequence of SEQ ID NO: 175. In some embodi 13 or 14; and (c) HVR-H3 comprising the amino acid ment, HVR-H2 is not DMYPDAAAASYNOKFRE (SEQID sequence of SEQID NO: 4, 15, or 19. In one embodiment, the NO:230). In some embodiments, HVR-H3 is not antibody comprises HVR-H3 comprising the amino acid APRWAAAA (SEQ ID NO:231). In some embodiments, sequence of SEQID NO: 4, 15, or 19. In another embodiment, HVR-L3 is not QAAAAAAAT (SEQID NO:232). the antibody comprises HVR-H3 comprising the amino acid 0223) In one aspect, the invention provides an antibody sequence of SEQID NO:4, 15, or 19 and HVR-L3 comprising comprising at least one, at least two, or all three VH HVR the amino acid sequence of SEQID NO: 7, 22, 23, 24, 25, 26, sequences selected from (a) HVR-H1 comprising the amino 27, or 28. In a further embodiment, the antibody comprises acid sequence of SEQID NO:172; (b) HVR-H2 comprising HVR-H3 comprising the amino acid sequence of SEQ ID the amino acid sequence of SEQID NO:173; and (c) HVR NO: 4, 15, or 19, HVR-L3 comprising the amino acid H3 comprising the amino acid sequence of SEQID NO:174. sequence of SEQID NO: 7, 22, 23, 24, 25, 26, 27, or 28, and In one embodiment, the antibody comprises HVR-H3 com HVR-H2 comprising the amino acid sequence of SEQ ID prising the amino acid sequence of SEQ ID NO:174. In NO: 3, 10, 11, 12, 13 or 14. In a further embodiment, the another embodiment, the antibody comprises HVR-H3 com antibody comprises (a) HVR-H1 comprising the amino acid prising the amino acid sequence of SEQ ID NO:174 and sequence of SEQID NO: 2, 8 or 9; (b) HVR-H2 comprising HVR-L3 comprising the amino acid sequence of SEQ ID the amino acid sequence of SEQID NO: 3, 10, 11, 12, 13 or NO:175. In a further embodiment, the antibody comprises 14; and (c) HVR-H3 comprising the amino acid sequence of HVR-H3 comprising the amino acid sequence of SEQ ID SEQID NO: 4, 15, or 19. NO:174, HVR-L3 comprising the amino acid sequence of 0219. In another aspect, the invention provides an anti SEQ ID NO:175, and HVR-H2 comprising the amino acid body comprising at least one, at least two, or all three VL sequence of SEQ ID NO:173. In a further embodiment, the HVR sequences selected from (a) HVR-L1 comprising the antibody comprises (a) HVR-H1 comprising the amino acid amino acid sequence of SEQ ID NO: 5; (b) HVR-L2 com sequence of SEQ ID NO:172; (b) HVR-H2 comprising the prising the amino acid sequence of SEQ ID NO:6; and (c) amino acid sequence of SEQ ID NO:173; and (c) HVR-H3 HVR-L3 comprising the amino acid sequence of SEQID NO: comprising the amino acid sequence of SEQID NO:174. In 7, 22, 23, 24, 25, 26, 27, or 28. In one embodiment, the some embodiment, HVR-H2 is not DMYPDAAAASYNOK antibody comprises (a) HVR-L1 comprising the amino acid FRE (SEQID NO:230). In some embodiments, HVR-H3 is sequence of SEQ ID NO:5; (b) HVR-L2 comprising the not APRWAAAA (SEQID NO:231). In some embodiments, amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 HVR-L3 is not QAAAAAAAT (SEQID NO:232). comprising the amino acid sequence of SEQID NO: 7, 22, 23, 0224. In another aspect, the invention provides an anti 24, 25, 26, 27, or 28. body comprising (a) HVR-L1 comprising the amino acid 0220. In another aspect, an antibody of the invention com sequence of SEQ ID NO:5; (b) HVR-L2 comprising the prises (a) a VH domain comprising at least one, at least two, amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 US 2015/0307617 A1 Oct. 29, 2015 comprising the amino acid sequence of SEQID NO: 175. In amino acid sequence of SEQ ID NO:37; (b) HVR-L2 com some embodiments, HVR-L3 is not QAAAAAAAT (SEQID prising the amino acid sequence of SEQ ID NO:39; and (c) NO:232). HVR-L3 comprising the amino acid sequence of SEQ ID 0225. In another aspect, an antibody of the invention com NO:42. In one embodiment, the antibody comprises (a) prises (a) a VH domain comprising at least one, at least two, HVR-L1 comprising the amino acid sequence of SEQ ID or all three VH HVR sequences selected from (i) HVR-H1 NO:37; (b) HVR-L2 comprising the amino acid sequence of comprising the amino acid sequence of SEQID NO: 172, (ii) SEQID NO:39; and (c) HVR-L3 comprising the amino acid HVR-H2 comprising the amino acid sequence of SEQ ID sequence of SEQID NO:42. NO:173, and (iii) HVR-H3 comprising an amino acid 0231. In another aspect, an antibody of the invention com sequence selected from SEQ ID NO:174; and (b) a VL prises (a) a VH domain comprising at least one, at least two, domain comprising at least one, at least two, or all three VL or all three VH HVR sequences selected from (i) HVR-H1 HVR sequences selected from (i) HVR-L1 comprising the comprising the amino acid sequence of SEQID NO:29, (ii) amino acid sequence of SEQID NO:5, (ii) HVR-L2 compris HVR-H2 comprising the amino acid sequence of SEQ ID ing the amino acid sequence of SEQID NO:6, and (c) HVR NO:30, and (iii) HVR-H3 comprising an amino acid L3 comprising the amino acid sequence of SEQID NO: 175. sequence selected from SEQID NO:33; and (b) a VL domain 0226. In another aspect, the invention provides an anti comprising at least one, at least two, or all three VL HVR body comprising (a) HVR-H1 comprising the amino acid sequences selected from (i) HVR-L1 comprising the amino sequence of SEQ ID NO:172; (b) HVR-H2 comprising the acid sequence of SEQID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQID NO:173; (c) HVR-H3 com amino acid sequence of SEQ ID NO:39, and (c) HVR-L3 prising the amino acid sequence of SEQ ID NO: 174; (d) comprising the amino acid sequence of SEQID NO:42. HVR-L1 comprising the amino acid sequence of SEQ ID 0232. In another aspect, the invention provides an anti NO:5; (e) HVR-L2 comprising the amino acid sequence of body comprising (a) HVR-H1 comprising the amino acid SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the sequence selected from SEQ ID NO:175. In some embodi amino acid sequence of SEQ ID NO:30; (c) HVR-H3 com ment, HVR-H2 is not DMYPDAAAASYNOKFRE (SEQID prising the amino acid sequence of SEQID NO:33; (d) HVR NO:230). In some embodiments, HVR-H3 is not L1 comprising the amino acid sequence of SEQID NO:37; APRWAAAA (SEQ ID NO:231). In some embodiments, (e) HVR-L2 comprising the amino acid sequence of SEQID HVR-L3 is not QAAAAAAAT (SEQ ID NO:232). NO:39; and (f) HVR-L3 comprising an amino acid sequence 0227 All possible combinations of the above substitutions selected from SEQID NO:42. are encompassed by the consensus sequences of SEQ ID 0233. In one aspect, the invention provides an anti-human NO: 172,173, 174 and 175. OX40 agonist antibody comprising at least one, two, three, 0228. In one aspect, the invention provides an anti-human four, five, or six HVRs selected from (a) HVR-H1 comprising OX40 agonist antibody comprising at least one, two, three, the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 four, five, or six HVRs selected from (a) HVR-H1 comprising comprising the amino acid sequence of SEQ ID NO:30; (c) the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 HVR-H3 comprising the amino acid sequence of SEQ ID comprising the amino acid sequence of SEQ ID NO:30; (c) NO:33; (d) HVR-L1 comprising the amino acid sequence of HVR-H3 comprising the amino acid sequence of SEQ ID SEQ ID NO:37; (e) HVR-L2 comprising the amino acid NO:33; (d) HVR-L1 comprising the amino acid sequence of sequence of SEQID NO:40; and (f) HVR-L3 comprising the SEQ ID NO:37; (e) HVR-L2 comprising the amino acid amino acid sequence of SEQID NO:42. sequence of SEQID NO:39; and (f) HVR-L3 comprising the 0234. In another aspect, the invention provides an anti amino acid sequence of SEQID NO:42. body comprising at least one, at least two, or all three VL 0229. In one aspect, the invention provides an antibody HVR sequences selected from (a) HVR-L1 comprising the comprising at least one, at least two, or all three VH HVR amino acid sequence of SEQ ID NO:37; (b) HVR-L2 com sequences selected from (a) HVR-H1 comprising the amino prising the amino acid sequence of SEQ ID NO:40; and (c) acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising HVR-L3 comprising the amino acid sequence of SEQ ID the amino acid sequence of SEQID NO:30; and (c) HVR-H3 NO:42. In one embodiment, the antibody comprises (a) comprising the amino acid sequence of SEQ ID NO:33. In HVR-L1 comprising the amino acid sequence of SEQ ID one embodiment, the antibody comprises HVR-H3 compris NO:37; (b) HVR-L2 comprising the amino acid sequence of ing the amino acid sequence of SEQ ID NO:33. In another SEQID NO:40; and (c) HVR-L3 comprising the amino acid embodiment, the antibody comprises HVR-H3 comprising sequence of SEQID NO:42. the amino acid sequence of SEQ ID NO:33 and HVR-L3 0235. In another aspect, an antibody of the invention com comprising the amino acid sequence of SEQID NO:42. In a prises (a) a VH domain comprising at least one, at least two, further embodiment, the antibody comprises HVR-H3 com or all three VH HVR sequences selected from (i) HVR-H1 prising the amino acid sequence of SEQID NO:33, HVR-L3 comprising the amino acid sequence of SEQID NO:29, (ii) comprising the amino acid sequence of SEQID NO:42, and HVR-H2 comprising the amino acid sequence of SEQ ID HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising an amino acid NO:30. In a further embodiment, the antibody comprises (a) sequence selected from SEQID NO:33; and (b) a VL domain HVR-H1 comprising the amino acid sequence of SEQ ID comprising at least one, at least two, or all three VL HVR NO:29; (b) HVR-H2 comprising the amino acid sequence of sequences selected from (i) HVR-L1 comprising the amino SEQID NO:30; and (c) HVR-H3 comprising the amino acid acid sequence of SEQID NO:37, (ii) HVR-L2 comprising the sequence of SEQID NO:33. amino acid sequence of SEQ ID NO:40, and (c) HVR-L3 0230. In another aspect, the invention provides an anti comprising the amino acid sequence of SEQID NO:42. body comprising at least one, at least two, or all three VL 0236. In another aspect, the invention provides an anti HVR sequences selected from (a) HVR-L1 comprising the body comprising (a) HVR-H1 comprising the amino acid US 2015/0307617 A1 Oct. 29, 2015 24 sequence of SEQ ID NO:29; (b) HVR-H2 comprising the sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQID NO:30; (c) HVR-H3 com amino acid sequence of SEQID NO:30, 31, or 32; (c) HVR prising the amino acid sequence of SEQID NO:33; (d) HVR H3 comprising the amino acid sequence of SEQID NO:33; L1 comprising the amino acid sequence of SEQID NO:37; (d) HVR-L1 comprising the amino acid sequence of SEQID (e) HVR-L2 comprising the amino acid sequence of SEQID NO:37; (e) HVR-L2 comprising the amino acid sequence of NO:40; and (f) HVR-L3 comprising an amino acid sequence SEQ ID NO: 39, 40 or 41; and (f) HVR-L3 comprising an selected from SEQID NO:42. amino acid sequence selected from SEQID NO: 42,43, or 44. 0237. In one aspect, the invention provides an anti-human 0242. In one aspect, the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQID NO:30, 31, or comprising the amino acid sequence of SEQID NO: 175; (c) 32; (c) HVR-H3 comprising the amino acid sequence of SEQ HVR-H3 comprising the amino acid sequence of SEQ ID ID NO:33; (d) HVR-L1 comprising the amino acid sequence NO:33; (d) HVR-L1 comprising the amino acid sequence of of SEQ ID NO:37: (e) HVR-L2 comprising the amino acid SEQ ID NO:37; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, 40 or 41; and (f) HVR-L3 sequence of SEQ ID NO:177; and (f) HVR-L3 comprising comprising the amino acid sequence of SEQID NO:42, 43, or the amino acid sequence of SEQID NO:178. 44. 0243 In one aspect, the invention provides an antibody 0238. In one aspect, the invention provides an antibody comprising at least one, at least two, or all three VH HVR comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQID NO:175; and (c) HVR the amino acid sequence of SEQID NO:30, 31, or 32; and (c) H3 comprising the amino acid sequence of SEQID NO:33. In HVR-H3 comprising the amino acid sequence of SEQ ID another embodiment, the antibody comprises HVR-H3 com NO:33. In another embodiment, the antibody comprises prising the amino acid sequence of SEQID NO:33 and HVR HVR-H3 comprising the amino acid sequence of SEQ ID L3 comprising the amino acid sequence of SEQID NO:177. NO:33 and HVR-L3 comprising the amino acid sequence of In a further embodiment, the antibody comprises HVR-H3 SEQ ID NO: 42, 43, or 44. In a further embodiment, the comprising the amino acid sequence of SEQ ID NO:33, antibody comprises HVR-H3 comprising the amino acid HVR-L3 comprising the amino acid sequence of SEQ ID sequence of SEQID NO:33, HVR-L3 comprising the amino NO:178, and HVR-H2 comprising the amino acid sequence acid sequence of SEQ ID NO: 42, 43, or 44, and HVR-H2 of SEQ ID NO:176. In a further embodiment, the antibody comprising the amino acid sequence of SEQID NO:39, 40 or comprises (a) HVR-H1 comprising the amino acid sequence 41. In a further embodiment, the antibody comprises (a) of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid HVR-H1 comprising the amino acid sequence of SEQ ID sequence of SEQ ID NO: 176; and (c) HVR-H3 comprising NO:29; (b) HVR-H2 comprising the amino acid sequence of the amino acid sequence of SEQID NO:33. SEQ ID NO:30, 31, or 32; and (c) HVR-H3 comprising the 0244. In another aspect, the invention provides an anti amino acid sequence of SEQID NO:33. body comprising at least one, at least two, or all three VL 0239. In another aspect, the invention provides an anti HVR sequences selected from (a) HVR-L1 comprising the body comprising at least one, at least two, or all three VL amino acid sequence of SEQ ID NO:37; (b) HVR-L2 com HVR sequences selected from (a) HVR-L1 comprising the prising the amino acid sequence of SEQID NO:177; and (c) amino acid sequence of SEQID NO:37; (b) HVR-L2 com HVR-L3 comprising the amino acid sequence of SEQ ID prising the amino acid sequence of SEQID NO:39, 40 or 41; NO:177. In one embodiment, the antibody comprises (a) and (c) HVR-L3 comprising the amino acid sequence of SEQ HVR-L1 comprising the amino acid sequence of SEQ ID ID NO: 42, 43, or 44. In one embodiment, the antibody NO:37; (b) HVR-L2 comprising the amino acid sequence of comprises (a) HVR-L1 comprising the amino acid sequence SEQID NO:177; and (c) HVR-L3 comprising the amino acid of SEQ ID NO:37; (b) HVR-L2 comprising the amino acid sequence of SEQID NO:178. sequence of SEQ ID NO: 39, 40 or 41; and (c) HVR-L3 0245. In another aspect, an antibody of the invention com comprising the amino acid sequence of SEQID NO: 42, 43, prises (a) a VH domain comprising at least one, at least two, or 44. or all three VH HVR sequences selected from (i) HVR-H1 0240. In another aspect, an antibody of the invention com comprising the amino acid sequence of SEQID NO:29, (ii) prises (a) a VH domain comprising at least one, at least two, HVR-H2 comprising the amino acid sequence of SEQ ID or all three VH HVR sequences selected from (i) HVR-H1 NO:176, and (iii) HVR-H3 comprising an amino acid comprising the amino acid sequence of SEQID NO:29, (ii) sequence selected from SEQID NO:33; and (b) a VL domain HVR-H2 comprising the amino acid sequence of SEQ ID comprising at least one, at least two, or all three VL HVR NO:30, 31, or 32, and (iii) HVR-H3 comprising an amino sequences selected from (i) HVR-L1 comprising the amino acid sequence selected from SEQ ID NO:33; and (b) a VL acid sequence of SEQID NO:37, (ii) HVR-L2 comprising the domain comprising at least one, at least two, or all three VL amino acid sequence of SEQ ID NO:177, and (c) HVR-L3 HVR sequences selected from (i) HVR-L1 comprising the comprising the amino acid sequence of SEQID NO:178. amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 com 0246. In another aspect, the invention provides an anti prising the amino acid sequence of SEQID NO:39, 40 or 41, body comprising (a) HVR-H1 comprising the amino acid and (c) HVR-L3 comprising the amino acid sequence of SEQ sequence of SEQ ID NO:29; (b) HVR-H2 comprising the ID NO: 42, 43, or 44. amino acid sequence of SEQID NO:176; (c) HVR-H3 com 0241. In another aspect, the invention provides an anti prising the amino acid sequence of SEQID NO:33; (d) HVR body comprising (a) HVR-H1 comprising the amino acid L1 comprising the amino acid sequence of SEQID NO:37; US 2015/0307617 A1 Oct. 29, 2015 (e) HVR-L2 comprising the amino acid sequence of SEQID two or three HVRs selected from (a) HVR-L1 comprising the NO:177; and (f) HVR-L3 comprising an amino acid sequence amino acid sequence of SEQID NO:5; (b) HVR-L2 compris selected from SEQID NO:178. ing the amino acid sequence of SEQID NO:6; and (c) HVR 0247. In any of the above embodiments, an anti-OX40 L3 comprising the amino acid sequence of SEQID NO:7. agonist antibody is humanized. In one embodiment, an anti 0250 In another aspect, an anti-human OX40 agonistanti OX40 antibody comprises HVRs as in any of the above body comprises a heavy chain variable domain (VH) embodiments or for any of the embodiments in FIGS. 11 A-I. sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, and further comprises an acceptor human framework, e.g. a 96%, 97%, 98%, 99%, or 100% sequence identity to the human immunoglobulin framework or a human consensus amino acid sequence of SEQ ID NO:56. In certain embodi framework. In another embodiment, an anti-OX40 antibody ments, a VH sequence having at least 90%, 91%, 92%, 93%, comprises HVRs as in any of the above embodiments, and 94%. 95%, 96%, 97%, 98%, or 99% identity contains substi further comprises a VH and/or VL comprising an FR tutions (e.g., conservative Substitutions), insertions, or dele sequence shown in FIGS. 11 A-I. tions relative to the reference sequence, but an anti-human 0248. In another aspect, an anti-human OX40agonistanti OX40 agonist antibody comprising that sequence retains the body comprises a heavy chain variable domain (VH) ability to bind to OX40. In certain embodiments, a total of 1 sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, to 10 amino acids have been substituted, inserted and/or 96%, 97%, 98%, 99%, or 100% sequence identity to the deleted in SEQID NO:56. In certain embodiments, substitu amino acid sequence of SEQIDNO:56, 58,60,62, 64, 66,68, tions, insertions, or deletions occur in regions outside the 70, 72, 74,76, 78,80, 82,84, 86, 88,90, 92,94, 96, 98, 100, HVRs (i.e., in the FRs). Optionally, the anti-human OX40 108, 114, 116, 233, or 234. In certain embodiments, a VH agonist antibody comprises the VH sequence in SEQ ID sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, NO:56, including post-translational modifications of that 96%, 97%, 98%, or 99% identity contains substitutions (e.g., sequence. In a particular embodiment, the VH comprises one, conservative Substitutions), insertions, or deletions relative to two or three HVRs selected from: (a) HVR-H1 comprising the reference sequence, but an anti-human OX40 agonist the amino acid sequence of SEQ ID NO:2, (b) HVR-H2 antibody comprising that sequence retains the ability to bind comprising the amino acid sequence of SEQID NO:3, and (c) to OX40. In certain embodiments, a total of 1 to 10 amino HVR-H3 comprising the amino acid sequence of SEQ ID acids have been substituted, inserted and/or deleted in SEQ NO:4. ID NO:56,58, 60, 62, 64, 66, 68, 70, 72, 74,76, 78,80, 82,84, 0251. In another aspect, an anti-human OX40 agonistanti 86, 88,90, 92,94, 96, 98, 100, 108, 114, 116, 233, or 234. In body is provided, wherein the antibody comprises a light certain embodiments, Substitutions, insertions, or deletions chain variable domain (VL) having at least 90%, 91%, 92%, occur in regions outside the HVRs (i.e., in the FRs). Option 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence ally, the anti-human OX40 agonist antibody comprises the identity to the amino acid sequence of SEQ ID NO:57. In VH sequence in SEQID NO: SEQID NO:56, 58,60, 62, 64, certain embodiments, a VL sequence having at least 90%, 66, 68,70, 72, 74,76, 78,80, 82,84, 86, 88,90, 92,94, 96, 98, 91%, 92%.93%, 94%, 95%,96%.97%, 98%, or 99% identity 100, 108, 114, 116, 233, or 234, including post-translational contains Substitutions (e.g., conservative substitutions), modifications of that sequence. In a particular embodiment, insertions, or deletions relative to the reference sequence, but the VH comprises one, two or three HVRs selected from: (a) an anti-human OX40 agonist antibody comprising that HVR-H1 comprising the amino acid sequence of SEQ ID sequence retains the ability to bind to OX40. In certain NO:2, (b) HVR-H2 comprising the amino acid sequence of embodiments, a total of 1 to 10 amino acids have been sub SEQID NO:3, and (c) HVR-H3 comprising the amino acid stituted, inserted and/or deleted in SEQID NO: 57. In certain sequence of SEQID NO:4. embodiments, the Substitutions, insertions, or deletions occur 0249. In another aspect, an anti-human OX40agonistanti in regions outside the HVRs (i.e., in the FRs). Optionally, the body is provided, wherein the antibody comprises a light anti-human OX40 agonist antibody comprises the VL chain variable domain (VL) having at least 90%, 91%, 92%, sequence in SEQ ID NO: 57, including post-translational 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence modifications of that sequence. In a particular embodiment, identity to the amino acid sequence of SEQID NO:57, 59, 61. the VL comprises one, two or three HVRs selected from (a) 63, 65,67, 69,71, 73,75, 77, 79,81, 83, 85, 87, 89,91, 93, 95, HVR-L1 comprising the amino acid sequence of SEQ ID 97, 99, 101, 109, 115 or 117. In certain embodiments, a VL NO:5; (b) HVR-L2 comprising the amino acid sequence of sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, SEQID NO:6; and (c) HVR-L3 comprising the amino acid 96%, 97%, 98%, or 99% identity contains substitutions (e.g., sequence of SEQID NO:7. conservative Substitutions), insertions, or deletions relative to 0252. In another aspect, an anti-human OX40 agonistanti the reference sequence, but an anti-human OX40 agonist body comprises a heavy chain variable domain (VH) antibody comprising that sequence retains the ability to bind sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, to OX40. In certain embodiments, a total of 1 to 10 amino 96%, 97%, 98%, 99%, or 100% sequence identity to the acids have been substituted, inserted and/or deleted in SEQ amino acid sequence of SEQID NO: 180. In certain embodi ID NO:57, 59, 61,63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, ments, a VH sequence having at least 90%, 91%, 92%, 93%, 85, 87, 89,91, 93, 95, 97,99, 101, 109, 115 or 117. In certain 94%. 95%, 96%, 97%, 98%, or 99% identity contains substi embodiments, the Substitutions, insertions, or deletions occur tutions (e.g., conservative Substitutions), insertions, or dele in regions outside the HVRs (i.e., in the FRs). Optionally, the tions relative to the reference sequence, but an anti-human anti-human OX40 agonist antibody comprises the VL OX40 agonist antibody comprising that sequence retains the sequence in SEQID NO:57, 59, 61,63, 65, 67, 69,71, 73,75, ability to bind to OX40. In certain embodiments, a total of 1 77,79, 81, 83, 85, 87, 89,91, 93, 95, 97,99, 101, 109,115 or to 10 amino acids have been substituted, inserted and/or 117, including post-translational modifications of that deleted in SEQID NO:180. In certain embodiments, substi sequence. In a particular embodiment, the VL comprises one, tutions, insertions, or deletions occur in regions outside the US 2015/0307617 A1 Oct. 29, 2015 26 HVRs (i.e., in the FRs). Optionally, the anti-human OX40 an anti-human OX40 agonist antibody comprising that agonist antibody comprises the VH sequence in SEQ ID sequence retains the ability to bind to OX40. In certain NO: 180, including post-translational modifications of that embodiments, a total of 1 to 10 amino acids have been sub sequence. In a particular embodiment, the VH comprises one, stituted, inserted and/or deleted in SEQID NO:95. In certain two or three HVRs selected from: (a) HVR-H1 comprising embodiments, the Substitutions, insertions, or deletions occur the amino acid sequence of SEQ ID NO:2, (b) HVR-H2 in regions outside the HVRs (i.e., in the FRs). Optionally, the comprising the amino acid sequence of SEQID NO:3, and (c) anti-human OX40 agonist antibody comprises the VL HVR-H3 comprising the amino acid sequence of SEQ ID sequence in SEQ ID NO:95, including post-translational NO:4. modifications of that sequence. In a particular embodiment, 0253) In another aspect, an anti-human OX40agonistanti the VL comprises one, two or three HVRs selected from (a) body is provided, wherein the antibody comprises a light HVR-L1 comprising the amino acid sequence of SEQ ID chain variable domain (VL) having at least 90%, 91%, 92%, NO:5; (b) HVR-L2 comprising the amino acid sequence of 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence SEQID NO:6; and (c) HVR-L3 comprising the amino acid identity to the amino acid sequence of SEQID NO:179. In sequence of SEQID NO:26. certain embodiments, a VL sequence having at least 90%, 0256 Inanother aspect, an anti-human OX40 agonistanti 91%, 92%.93%, 94%. 95%,96%.97%.98%, or 99% identity body comprises a heavy chain variable domain (VH) contains Substitutions (e.g., conservative substitutions), sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, insertions, or deletions relative to the reference sequence, but 96%, 97%, 98%, 99%, or 100% sequence identity to the an anti-human OX40 agonist antibody comprising that amino acid sequence of SEQ ID NO:96. In certain embodi sequence retains the ability to bind to OX40. In certain ments, a VH sequence having at least 90%, 91%, 92%, 93%, embodiments, a total of 1 to 10 amino acids have been sub 94%. 95%, 96%, 97%, 98%, or 99% identity contains substi stituted, inserted and/or deleted in SEQID NO: 179. In cer tutions (e.g., conservative Substitutions), insertions, or dele tain embodiments, the Substitutions, insertions, or deletions tions relative to the reference sequence, but an anti-human occur in regions outside the HVRs (i.e., in the FRs). Option OX40 agonist antibody comprising that sequence retains the ally, the anti-human OX40 agonist antibody comprises the ability to bind to OX40. In certain embodiments, a total of 1 VL sequence in SEQ ID NO: 179, including post-transla to 10 amino acids have been substituted, inserted and/or tional modifications of that sequence. In a particular embodi deleted in SEQID NO:96. In certain embodiments, substitu ment, the VL comprises one, two or three HVRs selected from tions, insertions, or deletions occur in regions outside the (a) HVR-L1 comprising the amino acid sequence of SEQID HVRs (i.e., in the FRs). Optionally, the anti-human OX40 NO:5; (b) HVR-L2 comprising the amino acid sequence of agonist antibody comprises the VH sequence in SEQ ID SEQID NO:6; and (c) HVR-L3 comprising the amino acid NO:96, including post-translational modifications of that sequence of SEQID NO:7. sequence. In a particular embodiment, the VH comprises one, 0254. In another aspect, an anti-human OX40agonistanti two or three HVRs selected from: (a) HVR-H1 comprising body comprises a heavy chain variable domain (VH) the amino acid sequence of SEQ ID NO:2, (b) HVR-H2 sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, comprising the amino acid sequence of SEQID NO:3, and (c) 96%, 97%, 98%, 99%, or 100% sequence identity to the HVR-H3 comprising the amino acid sequence of SEQ ID amino acid sequence of SEQ ID NO:94. In certain embodi NO:4. ments, a VH sequence having at least 90%, 91%, 92%, 93%, 0257. In another aspect, an anti-human OX40 agonistanti 94%. 95%, 96%, 97%, 98%, or 99% identity contains substi body is provided, wherein the antibody comprises a light tutions (e.g., conservative Substitutions), insertions, or dele chain variable domain (VL) having at least 90%, 91%, 92%, tions relative to the reference sequence, but an anti-human 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence OX40 agonistantibody comprising that sequence retains the identity to the amino acid sequence of SEQ ID NO:97. In ability to bind to OX40. In certain embodiments, a total of 1 certain embodiments, a VL sequence having at least 90%, to 10 amino acids have been substituted, inserted and/or 91%, 92%.93%, 94%, 95%,96%.97%, 98%, or 99% identity deleted in SEQID NO:94. In certain embodiments, substitu contains Substitutions (e.g., conservative substitutions), tions, insertions, or deletions occur in regions outside the insertions, or deletions relative to the reference sequence, but HVRs (i.e., in the FRs). Optionally, the anti-human OX40 an anti-human OX40 agonist antibody comprising that agonist antibody comprises the VH sequence in SEQ ID sequence retains the ability to bind to OX40. In certain NO:94, including post-translational modifications of that embodiments, a total of 1 to 10 amino acids have been sub sequence. In a particular embodiment, the VH comprises one, stituted, inserted and/or deleted in SEQID NO:97. In certain two or three HVRs selected from: (a) HVR-H1 comprising embodiments, the Substitutions, insertions, or deletions occur the amino acid sequence of SEQ ID NO:2, (b) HVR-H2 in regions outside the HVRs (i.e., in the FRs). Optionally, the comprising the amino acid sequence of SEQID NO:3, and (c) anti-human OX40 agonist antibody comprises the VL HVR-H3 comprising the amino acid sequence of SEQ ID sequence in SEQ ID NO:97, including post-translational NO:4. modifications of that sequence. In a particular embodiment, 0255 Inanother aspect, an anti-human OX40agonistanti the VL comprises one, two or three HVRs selected from (a) body is provided, wherein the antibody comprises a light HVR-L1 comprising the amino acid sequence of SEQ ID chain variable domain (VL) having at least 90%, 91%, 92%, NO:5; (b) HVR-L2 comprising the amino acid sequence of 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence SEQID NO:6; and (c) HVR-L3 comprising the amino acid identity to the amino acid sequence of SEQ ID NO:95. In sequence of SEQID NO:27. certain embodiments, a VL sequence having at least 90%, 0258. In another aspect, an anti-human OX40 agonistanti 91%, 92%.93%, 94%. 95%,96%.97%.98%, or 99% identity body comprises a heavy chain variable domain (VH) contains Substitutions (e.g., conservative substitutions), sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, insertions, or deletions relative to the reference sequence, but 96%, 97%, 98%, 99%, or 100% sequence identity to the US 2015/0307617 A1 Oct. 29, 2015 27 amino acid sequence of SEQID NO: 118, 120, 122, 124, 126, sequences in SEQ ID NO:64 and SEQ ID NO:65, respec 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148. In tively, including post-translational modifications of those certain embodiments, a VH sequence having at least 90%, sequences. In one embodiment, the antibody comprises the 91%, 92%.93%, 94%. 95%,96%.97%.98%, or 99% identity VHandVL sequences in SEQID NO:66 and SEQID NO:67, contains Substitutions (e.g., conservative substitutions), respectively, including post-translational modifications of insertions, or deletions relative to the reference sequence, but those sequences. In one embodiment, the antibody comprises an anti-human OX40 agonist antibody comprising that the VH and VL sequences in SEQ ID NO:68 and SEQ ID sequence retains the ability to bind to OX40. In certain NO:69, respectively, including post-translational modifica embodiments, a total of 1 to 10 amino acids have been sub tions of those sequences. In one embodiment, the antibody stituted, inserted and/or deleted in SEQIDNO: 118, 120, 122, comprises the VH and VL sequences in SEQID NO:70 and 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, SEQ ID NO:71, respectively, including post-translational 148. In certain embodiments, Substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). modifications of those sequences. In one embodiment, the Optionally, the anti-human OX40agonistantibody comprises antibody comprises the VH and VL sequences in SEQ ID the VH sequence in SEQID NO: SEQID NO: 118, 120, 122, NO:72 and SEQ ID NO:73, respectively, including post 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, translational modifications of those sequences. In one 148, including post-translational modifications of that embodiment, the antibody comprises the VH and VL sequence. In a particular embodiment, the VH comprises one, sequences in SEQ ID NO:74 and SEQ ID NO:75, respec two or three HVRs selected from: (a) HVR-H1 comprising tively, including post-translational modifications of those the amino acid sequence of SEQ ID NO: 29, (b) HVR-H2 sequences. In one embodiment, the antibody comprises the comprising the amino acid sequence of SEQID NO:30, and VHandVL sequences in SEQID NO:76 and SEQID NO:77, (c) HVR-H3 comprising the amino acid sequence of SEQID respectively, including post-translational modifications of NO:33. those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:78 and SEQ ID 0259. In another aspect, an anti-human OX40agonistanti NO:79, respectively, including post-translational modifica body is provided, wherein the antibody comprises a light tions of those sequences. In one embodiment, the antibody chain variable domain (VL) having at least 90%, 91%, 92%, comprises the VH and VL sequences in SEQID NO:80 and 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence SEQ ID NO:81, respectively, including post-translational identity to the amino acid sequence of SEQID NO: 119, 121, modifications of those sequences. In one embodiment, the 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, antibody comprises the VH and VL sequences in SEQ ID 147, 149. In certain embodiments, a VL sequence having at NO:82 and SEQ ID NO:83, respectively, including post least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or translational modifications of those sequences. In one 99% identity contains substitutions (e.g., conservative substi embodiment, the antibody comprises the VH and VL tutions), insertions, or deletions relative to the reference sequences in SEQ ID NO:84 and SEQ ID NO:85, respec sequence, but an anti-human OX40 agonist antibody com tively, including post-translational modifications of those prising that sequence retains the ability to bind to OX40. In sequences. In one embodiment, the antibody comprises the certain embodiments, a total of 1 to 10amino acids have been VHandVL sequences in SEQID NO:86 and SEQID NO:87, substituted, inserted and/or deleted in SEQID NO: 119, 121, respectively, including post-translational modifications of 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, those sequences. In one embodiment, the antibody comprises 147, 149. In certain embodiments, the substitutions, inser the VH and VL sequences in SEQ ID NO:88 and SEQ ID tions, or deletions occur in regions outside the HVRS (i.e., in NO:89, respectively, including post-translational modifica the FRs). Optionally, the anti-human OX40 agonistantibody tions of those sequences. In one embodiment, the antibody comprises the VL sequence in SEQ ID NO: 119, 121, 123, comprises the VH and VL sequences in SEQID NO:90 and 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, SEQ ID NO:91, respectively, including post-translational 149, including post-translational modifications of that modifications of those sequences. In one embodiment, the sequence. In a particular embodiment, the VL comprises one, antibody comprises the VH and VL sequences in SEQ ID two or three HVRs selected from (a) HVR-L1 comprising the NO:92 and SEQ ID NO:93, respectively, including post amino acid sequence of SEQID NO:37; (b) HVR-L2 com translational modifications of those sequences. In one prising the amino acid sequence of SEQ ID NO:39; and (c) embodiment, the antibody comprises the VH and VL HVR-L3 comprising the amino acid sequence of SEQ ID sequences in SEQ ID NO:94 and SEQ ID NO:95, respec NO:42. tively, including post-translational modifications of those 0260. In one embodiment, the antibody comprises the VH sequences. In one embodiment, the antibody comprises the and VL sequences in SEQ ID NO:56 and SEQ ID NO:57, VHandVL sequences in SEQID NO:96 and SEQID NO:97, respectively, including post-translational modifications of respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:58 and SEQ ID the VH and VL sequences in SEQ ID NO:98 and SEQ ID NO:59, respectively, including post-translational modifica NO:99, respectively, including post-translational modifica tions of those sequences. In one embodiment, the antibody tions of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQID NO:60 and comprises the VHand VL sequences in SEQID NO:100 and SEQ ID NO:61, respectively, including post-translational SEQ ID NO: 101, respectively, including post-translational modifications of those sequences. In one embodiment, the modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID antibody comprises the VH and VL sequences in SEQ ID NO:62 and SEQ ID NO:63, respectively, including post NO:108 and SEQ ID NO:109, respectively, including post translational modifications of those sequences. In one translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL embodiment, the antibody comprises the VH and VL US 2015/0307617 A1 Oct. 29, 2015 28 sequences in SEQID NO:114 and SEQID NO:115, respec antibodies shown in FIGS. 11A-I, and a VL as in any of the tively, including post-translational modifications of those embodiments provided above or as in any of the antibodies sequences. In one embodiment, the antibody comprises the shown in FIGS. 11 A-I. VH and VL sequences in SEQ ID NO:116 and SEQ ID 0263. In a further aspect, the invention provides an anti NO: 117, respectively, including post-translational modifica body that binds to the same epitope as an anti-human OX40 tions of those sequences. In one embodiment, the antibody antibody provided herein. In some embodiments, the anti comprises the VHand VL sequences in SEQID NO:233 and body is an anti-human OX40 agonist antibody. SEQ ID NO:65, respectively, including post-translational 0264. In a further aspect of the invention, an anti-OX40 modifications of those sequences. In one embodiment, the antibody according to any of the above embodiments is a antibody comprises the VH and VL sequences in SEQ ID monoclonal antibody, including a chimeric, humanized or NO:234 and SEQ ID NO:69, respectively, including post human antibody. In one embodiment, an anti-OX40 antibody translational modifications of those sequences. is an antibody fragment, e.g., a Fv, Fab., Fab', scFv, diabody, or 0261. In one embodiment, the antibody comprises the VH F(ab')2 fragment. In another embodiment, the antibody is a and VL sequences in SEQID NO: 118 and SEQID NO:119, full length antibody, e.g., an intact IgG1 antibody or other respectively, including post-translational modifications of antibody class or isotype as defined herein. In some embodi those sequences. In one embodiment, the antibody comprises ments, the antibody is a full length intact IgG4 antibody. the VH and VL sequences in SEQ ID NO:120 and SEQ ID 0265. In a further aspect, an anti-OX40 antibody accord NO:121, respectively, including post-translational modifica ing to any of the above embodiments may incorporate any of tions of those sequences. In one embodiment, the antibody the features, singly or in combination, as described in Sec comprises the VHand VL sequences in SEQID NO:122 and tions 1-7 below: SEQ ID NO:123, respectively, including post-translational 0266 1. Antibody Affinity modifications of those sequences. In one embodiment, the 0267 In certain embodiments, an antibody provided antibody comprises the VH and VL sequences in SEQ ID herein has a dissociation constant (Kd) of s1 uM, s100 nM, NO.124 and SEQID NO:125, respectively, including post s10 nM, s1 nM. s.0.1 nM. s.0.01 nM, or s().001 nM (e.g. translational modifications of those sequences. In one 10M or less, e.g. from 10M to 10'M, e.g., from 10M embodiment, the antibody comprises the VH and VL to 10' M). sequences in SEQID NO:126 and SEQID NO.127, respec 0268. In one embodiment, Kd is measured by a radiola tively, including post-translational modifications of those beled antigen binding assay (RIA). In one embodiment, an sequences. In one embodiment, the antibody comprises the RIA is performed with the Fab version of an antibody of VH and VL sequences in SEQ ID NO:128 and SEQ ID interestand its antigen. For example, Solution binding affinity NO: 129, respectively, including post-translational modifica of Fabs for antigen is measured by equilibrating Fab with a tions of those sequences. In one embodiment, the antibody minimal concentration of ('I)-labeled antigen in the pres comprises the VHand VL sequences in SEQID NO: 130 and ence of a titration series of unlabeled antigen, then capturing SEQ ID NO:131, respectively, including post-translational bound antigen with an anti-Fab antibody-coated plate (see, modifications of those sequences. In one embodiment, the e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999)). To estab antibody comprises the VH and VL sequences in SEQ ID lish conditions for the assay, MICROTITER(R) multi-well NO:132 and SEQ ID NO:133, respectively, including post plates (Thermo Scientific) are coated overnight with 5ug/ml translational modifications of those sequences. In one of a capturing anti-Fab antibody (Cappel Labs) in 50 mM embodiment, the antibody comprises the VH and VL sodium carbonate (pH 9.6), and subsequently blocked with sequences in SEQID NO:134 and SEQID NO:135, respec 2% (w/v) bovine serum albumin in PBS for two to five hours tively, including post-translational modifications of those at room temperature (approximately 23°C.). In a non-adsor sequences. In one embodiment, the antibody comprises the bent plate (Nunc #269620), 100 pM or 26 pM'I-antigen VH and VL sequences in SEQ ID NO:136 and SEQ ID are mixed with serial dilutions of a Fab of interest (e.g., NO:137, respectively, including post-translational modifica consistent with assessment of the anti-VEGF antibody, Fab tions of those sequences. In one embodiment, the antibody 12, in Presta et al., Cancer Res. 57:4593-4599 (1997)). The comprises the VHand VL sequences in SEQID NO: 138 and Fab of interest is then incubated overnight; however, the SEQ ID NO:139, respectively, including post-translational incubation may continue for a longer period (e.g., about 65 modifications of those sequences. In one embodiment, the hours) to ensure that equilibrium is reached. Thereafter, the antibody comprises the VH and VL sequences in SEQ ID mixtures are transferred to the capture plate for incubation at NO:140 and SEQID NO:141, respectively, including post room temperature (e.g., for one hour). The Solution is then translational modifications of those sequences. In one removed and the plate washed eight times with 0.1% polysor embodiment, the antibody comprises the VH and VL bate 20 (TWEEN-20R) in PBS. When the plates have dried, sequences in SEQID NO:142 and SEQID NO:143, respec 150 ul/well of scintillant (MICROSCINT-20TM; Packard) is tively, including post-translational modifications of those added, and the plates are counted on a TOPCOUNTTM sequences. In one embodiment, the antibody comprises the gamma counter (Packard) for ten minutes. Concentrations of VH and VL sequences in SEQ ID NO:144 and SEQ ID each Fab that give less than or equal to 20% of maximal NO:145, respectively, including post-translational modifica binding are chosen for use in competitive binding assays. tions of those sequences. In one embodiment, the antibody 0269. According to another embodiment, Kd is measured comprises the VHand VL sequences in SEQID NO:146 and using a BIACORE(R) surface plasmon resonance assay. For SEQ ID NO:147, respectively, including post-translational example, an assay using a BIACORE(R)-2000 or a BIA modifications of those sequences. CORE(R)-3000 (BIAcore, Inc., Piscataway, N.J.) is performed 0262. In another aspect, an anti-human OX40 agonistanti at 25° C. with immobilized antigen CM5 chips at ~10 body is provided, wherein the antibody comprises aVH as in response units (RU). In one embodiment, carboxymethylated any of the embodiments provided above or as in any of the dextranbiosensor chips (CM5, BIACORE, Inc.) are activated US 2015/0307617 A1 Oct. 29, 2015 29 with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide example, a chimeric antibody comprises a non-human vari hydrochloride (EDC) and N-hydroxysuccinimide (NHS) able region (e.g., a variable region derived from a mouse, rat, according to the Supplier's instructions. Antigen is diluted hamster, rabbit, or non-human primate, Such as a monkey) with 10 mM sodium acetate, pH 4.8, to 5 g/ml (-0.2 uM) and a human constant region. In a further example, a chimeric before injection at a flow rate of 5 ul/minute to achieve antibody is a “class switched antibody in which the class or approximately 10 response units (RU) of coupled protein. Subclass has been changed from that of the parent antibody. Following the injection of antigen, 1 M ethanolamine is Chimeric antibodies include antigen-binding fragments injected to block unreacted groups. For kinetics measure thereof. ments, two-fold serial dilutions of Fab (0.78 nM to 500 nM) 0277. In certain embodiments, a chimeric antibody is a are injected in PBS with 0.05% polysorbate 20 (TWEEN humanized antibody. Typically, a non-human antibody is 20TM) surfactant (PBST) at 25° C. at a flow rate of approxi humanized to reduce immunogenicity to humans, while mately 25 Jul/min. Association rates (k) and dissociation retaining the specificity and affinity of the parental non-hu rates (k) are calculated using a simple one-to-one Langmuir man antibody. Generally, a humanized antibody comprises binding model (BIACORE(R) Evaluation Software version one or more variable domains in which HVRs, e.g., CDRs, (or 3.2) by simultaneously fitting the association and dissociation portions thereof) are derived from a non-human antibody, and sensorgrams. The equilibrium dissociation constant (Kd) is FRS (or portions thereof) are derived from human antibody calculated as the ratio k/k, See, e.g., Chen et al., J. Mol. sequences. A humanized antibody optionally will also com Biol. 293:865-881 (1999). If the on-rate exceeds 106 M-1 prise at least a portion of a human constant region. In some S-1 by the Surface plasmon resonance assay above, then the embodiments. Some FR residues in a humanized antibody are on-rate can be determined by using a fluorescent quenching Substituted with corresponding residues from a non-human technique that measures the increase or decrease in fluores antibody (e.g., the antibody from which the HVR residues are cence emission intensity (excitation=295 mm; emission=340 derived), e.g., to restore or improve antibody specificity or nm, 16 nm band-pass) at 25° C. of a 20 nM anti-antigen affinity. antibody (Fab form) in PBS, pH 7.2, in the presence of 0278 Humanized antibodies and methods of making them increasing concentrations of antigen as measured in a spec are reviewed, e.g., in Almagro and Fransson, Front. Biosci. trometer, Such as a stop-flow equipped spectrophometer 13:1619-1633 (2008), and are further described, e.g., in (Aviv Instruments) or a 8000-series SLM-AMINCOTM spec Riechmann et al., Nature 332:323-329 (1988); Queen et al., trophotometer (ThermoSpectronic) with a stirred cuvette. Proc. Nat I Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. 0270 2. Antibody Fragments Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409: Kash 0271 In certain embodiments, an antibody provided miri et al., Methods 36:25-34 (2005) (describing specificity herein is an antibody fragment. Antibody fragments include, determining region (SDR) grafting); Padlan, Mol. Immunol. but are not limited to, Fab, Fab', Fab'-SH, F(ab'). Fv, and scFv 28:489-498 (1991) (describing “resurfacing); Dall’Acqua et fragments, and other fragments described below. For a review al., Methods 36:43-60 (2005) (describing “FR shuffling): of certain antibody fragments, see Hudson et al. Nat. Med. and Osbournet al., Methods 36:61-68 (2005) and Klimka et 9:129-134 (2003). For a review of schv fragments, see, e.g., al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided Pluckthin, in The Pharmacology of Monoclonal Antibodies, selection' approach to FR shuffling). vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New 0279 Human framework regions that may be used for York), pp. 269-315 (1994); see also WO 93/16185; and U.S. humanization include but are not limited to: framework Pat. Nos. 5,571,894 and 5,587,458. For discussion of Fab and regions selected using the “best-fit’ method (see, e.g., Sims et F(ab')2 fragments comprising salvage receptor binding al. J. Immunol. 151:2296 (1993)); framework regions derived epitope residues and having increased in vivo half-life, see from the consensus sequence of human antibodies of a par U.S. Pat. No. 5,869,046. ticular subgroup of light or heavy chain variable regions (see, 0272 Diabodies are antibody fragments with two antigen e.g., Carteret al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); binding sites that may be bivalent or bispecific. See, for and Presta et al. J. Immunol., 151:2623 (1993)); human example, EP 404,097; WO 1993/01161; Hudson et al., Nat. mature (somatically mutated) framework regions or human Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. germline framework regions (see, e.g., Almagro and Frans Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetra son, Front. Biosci. 13:1619-1633 (2008)); and framework bodies are also described in Hudson et al., Nat. Med. 9:129 regions derived from Screening FR libraries (see, e.g., Baca et 134 (2003). al., J. Biol. Chem. 272:10678-10684 (1997) and Rosoket al., 0273 Single-domain antibodies are antibody fragments J. Biol. Chem. 271:22611-22618 (1996)). comprising all or a portion of the heavy chain variable domain 0280. 4. Human Antibodies or all or a portion of the light chain variable domain of an 0281. In certain embodiments, an antibody provided antibody. In certain embodiments, a single-domain antibody herein is a human antibody. Human antibodies can be pro is a human single-domain antibody (Domantis, Inc., duced using various techniques known in the art. Human Waltham, Mass.: see, e.g., U.S. Pat. No. 6,248,516 B1). antibodies are described generally in Van Dijk and Van de 0274 Antibody fragments can be made by various tech Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lon niques, including but not limited to proteolytic digestion of an berg, Curr. Opin. Immunol. 20:450-459 (2008). intact antibody as well as production by recombinant host 0282 Human antibodies may be prepared by administer cells (e.g. E. coli or phage), as described herein. ing an immunogen to a transgenic animal that has been modi 0275 3. Chimeric and Humanized Antibodies fied to produce intact human antibodies or intact antibodies 0276. In certain embodiments, an antibody provided with human variable regions in response to antigenic chal herein is a chimericantibody. Certain chimericantibodies are lenge. Such animals typically contain all or a portion of the described, e.g., in U.S. Pat. No. 4,816,567; and Morrison et human immunoglobulin loci, which replace the endogenous al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). In one immunoglobulin loci, or which are present extrachromo US 2015/0307617 A1 Oct. 29, 2015 30 Somally or integrated randomly into the animal’s chromo single-chain FV (ScPV) fragments or as Fab fragments. Librar Somes. In such transgenic mice, the endogenous immunoglo ies from immunized sources provide high-affinity antibodies bulin loci have generally been inactivated. For review of to the immunogen without the requirement of constructing methods for obtaining human antibodies from transgenic ani hybridomas. Alternatively, the naive repertoire can be cloned mals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See (e.g., from human) to provide a single source of antibodies to also, e.g., U.S. Pat. Nos. 6,075,181 and 6,150.584 describing a wide range of non-self and also self antigens without any XENOMOUSETM technology; U.S. Pat. No. 5,770,429 immunization as described by Griffiths et al., EMBOJ, 12: describing HUMAB(R) technology; U.S. Pat. No. 7,041,870 725-734 (1993). Finally, naive libraries can also be made describing K-M MOUSER) technology, and U.S. Patent synthetically by cloning unrearranged V-gene segments from Application Publication No. US 2007/0061900, describing stem cells, and using PCR primers containing random VELOCIMOUSE(R) technology). Human variable regions from sequence to encode the highly variable CDR3 regions and to intact antibodies generated by Such animals may be further accomplish rearrangement in vitro, as described by Hoogen modified, e.g., by combining with a different human constant boom and Winter, J. Mol. Biol., 227:381-388 (1992). Patent region. publications describing human antibody phage libraries 0283 Human antibodies can also be made by hybridoma include, for example: U.S. Pat. No. 5,750,373, and US Patent based methods. Human myeloma and mouse-human hetero Publication Nos. 2005/0079574, 2005/01 19455, 2005/ myeloma cell lines for the production of human monoclonal 0266000, 2007/0117126, 2007/0160598, 2007/0237764, antibodies have been described. (See, e.g., Kozbor J. Immu 2007/0292936, and 2009/0002360. mol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody 0288 Antibodies or antibody fragments isolated from Production Techniques and Applications, pp. 51-63 (Marcel human antibody libraries are considered human antibodies or Dekker, Inc., New York, 1987); and Boerner et al., J. Immu human antibody fragments herein. mol., 147: 86 (1991).) Human antibodies generated via human (0289. 6. Multispecific Antibodies B-cell hybridoma technology are also described in Li et al., 0290. In certain embodiments, an antibody provided Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Addi herein is a multispecific antibody, e.g. a bispecific antibody. tional methods include those described, for example, in U.S. Multispecific antibodies are monoclonal antibodies that have Pat. No. 7, 189,826 (describing production of monoclonal binding specificities for at least two different sites. In certain human IgM antibodies from hybridoma cell lines) and Ni, embodiments, one of the binding specificities is for OX40 and Xiandai Mianyixue, 26(4):265-268 (2006) (describing the other is for any other antigen. In certain embodiments, human-human hybridomas). Human hybridoma technology bispecific antibodies may bind to two different epitopes of (Trioma technology) is also described in Vollmers and OX40. Bispecific antibodies may also be used to localize Brandlein, Histology and Histopathology, 2003): 927-937 cytotoxic agents to cells which express OX40. Bispecific (2005) and Vollmers and Brandlein, Methods and Findings in antibodies can be prepared as full length antibodies or anti Experimental and Clinical Pharmacology, 27(3):185-91 body fragments. (2005). 0291 Techniques for making multispecific antibodies 0284 Human antibodies may also be generated by isolat include, but are not limited to, recombinant co-expression of ing Fv clone variable domain sequences selected from two immunoglobulin heavy chain-light chain pairs having human-derived phage display libraries. Such variable domain different specificities (see Milstein and Cuello, Nature 305: sequences may then be combined with a desired human con 537 (1983)), WO 93/08829, and Traunecker et al., EMBO.J. stant domain. Techniques for selecting human antibodies 10: 3655 (1991)), and “knob-in-hole' engineering (see, e.g., from antibody libraries are described below. U.S. Pat. No. 5,731,168). Multi-specific antibodies may also 0285) 5. Library-Derived Antibodies be made by engineering electrostatic steering effects for mak 0286 Antibodies of the invention may be isolated by ing antibody Fc-heterodimeric molecules (WO 2009/ screening combinatorial libraries for antibodies with the 089004A1); cross-linking two or more antibodies or frag desired activity or activities. For example, a variety of meth ments (see, e.g., U.S. Pat. No. 4,676.980, and Brennan et al., ods are known in the art for generating phage display libraries Science, 229: 81 (1985)); using leucine Zippers to produce and screening Such libraries for antibodies possessing the bi-specific antibodies (see, e.g., Kostelny et al., J. Immunol., desired binding characteristics. Such methods are reviewed, 148(5):1547-1553 (1992)); using “diabody” technology for e.g., in Hoogenboom et al. in Methods in Molecular Biology making bispecific antibody fragments (see, e.g., Hollinger et 178:1-37 (O'Brien et al., ed., Human Press, Totowa, N.J., al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and 2001) and further described, e.g., in the McCafferty et al., using single-chain FV (SFV) dimers (see,e.g. Gruber et al., J. Nature 348:552-554; Clackson et al., Nature 352: 624–628 Immunol., 152:5368 (1994)); and preparing trispecific anti (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Marks bodies as described, e.g., in Tutt et al. J. Immunol. 147: 60 and Bradbury, in Methods in Molecular Biology 248:161-175 (1991). (Lo, ed., Human Press, Totowa, N.J., 2003); Sidhu et al., J. 0292 Engineered antibodies with three or more functional Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. antigen binding sites, including "Octopus antibodies are 340(5): 1073-1093 (2004): Fellouse, Proc. Natl. Acad. Sci. also included herein (see, e.g. US 2006/0025576A1). USA 101 (34): 12467-12472 (2004); and Lee et al., J. Immu 0293. The antibody or fragment herein also includes a mol. Methods 284(1-2): 119-132(2004). “Dual Acting FAb’ or “DAF comprising an antigen binding 0287. In certain phage display methods, repertoires of VH site that binds to OX40 as well as another, different antigen and VL genes are separately cloned by polymerase chain (see, US 2008/0069820, for example). reaction (PCR) and recombined randomly in phage libraries, 0294 7. Antibody Variants which can then be screened for antigen-binding phage as 0295. In certain embodiments, amino acid sequence vari described in Winter et al., Ann. Rev. Immunol., 12: 433-455 ants of the antibodies provided herein are contemplated. For (1994). Phage typically display antibody fragments, either as example, it may be desirable to improve the binding affinity US 2015/0307617 A1 Oct. 29, 2015 and/or other biological properties of the antibody. Amino acid retained certain biological properties of the parent antibody. sequence variants of an antibody may be prepared by intro An exemplary Substitutional variant is an affinity matured ducing appropriate modifications into the nucleotide antibody, which may be conveniently generated, e.g., using sequence encoding the antibody, or by peptide synthesis. phage display-based affinity maturation techniques such as Such modifications include, for example, deletions from, and/ those described herein. Briefly, one or more HVR residues are or insertions into and/or substitutions of residues within the mutated and the variant antibodies displayed on phage and amino acid sequences of the antibody. Any combination of screened for a particular biological activity (e.g. binding deletion, insertion, and Substitution can be made to arrive at affinity). the final construct, provided that the final construct possesses 0307 Alterations (e.g., substitutions) may be made in the desired characteristics, e.g., antigen-binding. HVRs, e.g., to improve antibody affinity. Such alterations 0296 a) Substitution, Insertion, and Deletion Variants may be made in HVR “hotspots, i.e., residues encoded by 0297. In certain embodiments, antibody variants having codons that undergo mutation at high frequency during the one or more amino acid substitutions are provided. Sites of Somatic maturation process (see, e.g., Chowdhury, Methods interest for substitutional mutagenesis include the HVRs and Mol. Biol. 207:179-196 (2008)), and/or residues that contact FRs. Conservative substitutions are shown in Table A under antigen, with the resulting variant VH or VL being tested for the heading of “preferred substitutions.” More substantial binding affinity. Affinity maturation by constructing and rese changes are provided in Table A under the heading of “exem lecting from secondary libraries has been described, e.g., in plary substitutions.” and as further described below in refer Hoogenboom et al. in Methods in Molecular Biology 178:1- ence to amino acid side chain classes. Amino acid substitu 37 (O'Brienet al.,ed., Human Press, Totowa, N.J., (2001).) In tions may be introduced into an antibody of interest and the Some embodiments of affinity maturation, diversity is intro products screened for a desired activity, e.g., retained/im duced into the variable genes chosen for maturation by any of proved antigen binding, decreased immunogenicity, or a variety of methods (e.g., error-prone PCR, chain shuffling, improved ADCC or CDC. or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify TABLE A any antibody variants with the desired affinity. Another Original Exemplary Preferred method to introduce diversity involves HVR-directed Residue Substitutions Substitutions approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen Ala (A) Val; Leu: Ile Wal binding may be specifically identified, e.g., using alanine Arg (R) Lys; Glin; ASn Lys ASn (N) Gln; His; Asp, Lys; Arg Gln scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in Asp (D) Glu: Asn Glu particular are often targeted. Cys (C) Ser: Ala Ser 0308. In certain embodiments, substitutions, insertions, or Gln (Q) ASn: Glu ASn Glu (E) Asp: Gln Asp deletions may occur within one or more HVRS So long as Such Gly (G) Ala Ala alterations do not substantially reduce the ability of the anti His (H) ASn; Glin; Lys; Arg Arg body to bind antigen. For example, conservative alterations Ile (I) Leu; Val: Met: Ala: Phe: Norleucine Leu (e.g., conservative Substitutions as provided herein) that do Leu (L) Norleucine: Ile: Val: Met: Ala: Phe Ile Lys (K) Arg: Gln; ASn Arg not substantially reduce binding affinity may be made in Met (M) Leu: Phe: Ile Leu HVRs. Such alterations may, for example, be outside of anti Phe (F) Trp; Leu; Val: Ile: Ala: Tyr Tyr gen contacting residues in the HVRS. In certain embodiments Pro (P) Ala Ala of the variant VH and VL sequences provided above, each Ser (S) Thr Thr Thr (T) Val; Ser Ser HVReither is unaltered, or contains no more than one, two or Trp (W) Tyr; Phe Tyr three amino acid Substitutions. Tyr (Y) Trp; Phe: Thr; Ser Phe 0309. A useful method for identification of residues or Val (V) Ile: Leu: Met; Phe: Ala: Norleucine Leu regions of an antibody that may be targeted for mutagenesis is called 'alanine Scanning mutagenesis' as described by Cun 0298 Amino acids may be grouped according to common ningham and Wells (1989) Science, 244:1081-1085. In this side-chain properties: method, a residue or group of target residues (e.g., charged 0299 (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, residues such as arg, asp. his, lys, and glu) are identified and Ile: replaced by a neutral or negatively charged amino acid (e.g., 0300 (2) neutral hydrophilic: Cys, Ser. Thr, Asn., Gln; alanine or polyalanine) to determine whether the interaction 0301 (3) acidic: Asp, Glu: of the antibody with antigen is affected. Further substitutions 0302 (4) basic: His, Lys, Arg; may be introduced at the amino acid locations demonstrating 0303 (5) residues that influence chain orientation: Gly, functional sensitivity to the initial substitutions. Alterna Pro; tively, or additionally, a crystal structure of an antigen-anti 0304 (6) aromatic: Trp, Tyr, Phe. body complex to identify contact points between the antibody 0305 Non-conservative substitutions will entail exchang and antigen. Such contact residues and neighboring residues ing a member of one of these classes for another class. may be targeted or eliminated as candidates for Substitution. 0306 One type of substitutional variant involves substi Variants may be screened to determine whether they contain tuting one or more hyperVariable region residues of a parent the desired properties. antibody (e.g. a humanized or human antibody). Generally, 0310 Amino acid sequence insertions include amino the resulting variant(s) selected for further study will have and/or carboxyl-terminal fusions ranging in length from one modifications (e.g., improvements) in certain biological residue to polypeptides containing a hundred or more resi properties (e.g., increased affinity, reduced immunogenicity) dues, as well as intrasequence insertions of single or multiple relative to the parent antibody and/or will have substantially amino acid residues. Examples of terminal insertions include US 2015/0307617 A1 Oct. 29, 2015 32 an antibody with an N-terminal methionyl residue. Other gosaccharide attached to the Fc region of the antibody is insertional variants of the antibody molecule include the bisected by GlcNAc. Such antibody variants may have fusion to the N- or C-terminus of the antibody to an enzyme reduced fucosylation and/or improved ADCC function. (e.g. for ADEPT) or a polypeptide which increases the serum Examples of such antibody variants are described, e.g., in WO half-life of the antibody. 2003/01 1878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 0311 b) Glycosylation Variants (Umana et al.); and US 2005/0123546 (Umana et al.). Anti 0312. In certain embodiments, an antibody provided body variants with at least one galactose residue in the oli herein is altered to increase or decrease the extent to which the gosaccharide attached to the Fc region are also provided. antibody is glycosylated. Addition or deletion of glycosyla Such antibody variants may have improved CDC function. tion sites to an antibody may be conveniently accomplished Such antibody variants are described, e.g., in WO 1997/ by altering the amino acid sequence such that one or more 30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO glycosylation sites is created or removed. 1999/22764 (Raju, S.). 0313 Where the antibody comprises an Fc region, the 0316 c) Fc Region Variants carbohydrate attached thereto may be altered. Native antibod ies produced by mammalian cells typically comprise a 0317. In certain embodiments, one or more amino acid branched, biantennary oligosaccharide that is generally modifications may be introduced into the Fc region of an attached by an N-linkage to Asn297 of the CH2 domain of the antibody provided herein, thereby generating an Fc region Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). variant. The Fc region variant may comprise a human Fc The oligosaccharide may include various carbohydrates, e.g., region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc mannose, N-acetyl glucosamine (GlcNAc), galactose, and region) comprising an amino acid modification (e.g. a substi sialic acid, as well as a fucose attached to a GlcNAc in the tution) at one or more amino acid positions. 'stem” of the biantennary oligosaccharide structure. In some 0318. In certain embodiments, the invention contemplates embodiments, modifications of the oligosaccharide in an an antibody variant that possesses some but not all effector antibody of the invention may be made in order to create functions, which make it a desirable candidate for applica antibody variants with certain improved properties. tions in which the halflife of the antibody in vivo is important 0314. In one embodiment, antibody variants are provided yet certain effector functions (such as complement and having a carbohydrate structure that lacks fucose attached ADCC) are unnecessary or deleterious. In vitro and/or in vivo (directly or indirectly) to an Fc region. For example, the cytotoxicity assays can be conducted to confirm the reduc amount of fucose in such antibody may be from 1% to 80%, tion/depletion of CDC and/or ADCC activities. For example, from 1% to 65%, from 5% to 65% or from 20% to 40%. The Fc receptor (FcR) binding assays can be conducted to ensure amount of fucose is determined by calculating the average that the antibody lacks FcyR binding (hence likely lacking amount of fucose within the sugar chain at Asn297, relative to ADCC activity), but retains FcRn binding ability. The pri the sum of all glycostructures attached to ASn 297 (e.g. com mary cells for mediating ADCC, NK cells, express Fc(RIII plex, hybrid and high mannose structures) as measured by only, whereas monocytes express Fc(RI, Fc(RII and Fc(RIII. MALDI-TOF mass spectrometry, as described in WO 2008/ FcR expression on hematopoietic cells is Summarized in 077546, for example. Asn297 refers to the asparagine residue Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immu located at about position 297 in the Fc region (Eu numbering mol. 9:457-492 (1991). Non-limiting examples of in vitro of Fc region residues); however, Asn297 may also be located assays to assess ADCC activity of a molecule of interest is about t3 amino acids upstream or downstream of position described in U.S. Pat. No. 5,500,362 (see, e.g. Hellstrom, I. et 297, i.e., between positions 294 and 300, due to minor al. Proc. Nat I Acad. Sci. USA 83:7059–7063 (1986)) and sequence variations in antibodies. Such fucosylation variants Hellstrom, I et al., Proc. Nat 'l Acad. Sci. USA 82:1499-1502 may have improved ADCC function. See, e.g., US Patent (1985); U.S. Pat. No. 5,821,337 (see Bruggemann, M. et al., Publication Nos. US 2003/0157108 (Presta, L.); US 2004/ J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-ra 0093.621 (Kyowa Hakko Kogyo Co., Ltd). Examples of pub dioactive assays methods may be employed (see, for lications related to “defucosylated' or “fucose-deficient’ example, ACTITM non-radioactive cytotoxicity assay for flow antibody variants include: US 2003/0157108; WO 2000/ cytometry (CellTechnology, Inc. Mountain View, Calif.; and 61739; WO 2001/29246; US 2003/0115614; US 2002/ CytoTox 96(R) non-radioactive cytotoxicity assay (Promega, 0164328; US 2004/0093621; US 2004/0132140; US 2004/ Madison, Wis.). Useful effector cells for such assays include 0110704; US 2004/0110282: US 2004/0109865; WO 2003/ peripheral blood mononuclear cells (PBMC) and Natural 085119, WO 2003/084.570; WO 2005/035586: WO 2005/ Killer (NK) cells. Alternatively, or additionally, ADCC activ 035778; WO2005/053742: WO2002/031140; Okazaki et al. ity of the molecule of interest may be assessed in Vivo, e.g., in J. Mol. Biol. 336:1239-1249 (2004): Yamane-Ohnuki et al. a animal model Such as that disclosed in Clynes et al. Proc. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines Natl Acad. Sci. USA95:652-656 (1998). C1q binding assays capable of producing defucosylated antibodies include Lec13 may also be carried out to confirm that the antibody is unable CHO cells deficient in protein fucosylation (Ripka et al. Arch. to bind C1q and hence lacks CDC activity. See, e.g., C1q and Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US C3c binding ELISA in WO 2006/029879 and WO 2005/ 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, 100402. To assess complement activation, a CDC assay may Adams et al., especially at Example 11), and knockout cell be performed (see, for example, GaZZano-Santoro et al., J. lines, such as alpha-1,6-fucosyltransferase gene, FUT8, Immunol. Methods 202:163 (1996); Cragg, M.S. et al., Blood knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. 101:1045-1052 (2003); and Cragg, M. S. and M. J. Glennie, Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., Blood 103:2738-2743 (2004)). FcRn binding and in vivo 94(4):680-688 (2006); and WO2003/085107). clearance/half life determinations can also be performed 0315 Antibodies variants are further provided with using methods known in the art (see, e.g., Petkova, S.B. et al., bisected oligosaccharides, e.g., in which a biantennary oli Int'l, Immunol. 18(12): 1759-1769 (2006)). US 2015/0307617 A1 Oct. 29, 2015 0319 Antibodies with reduced effector function include lose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly those with substitution of one or more of Fc region residues 1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhy 238,265, 269, 270, 297, 327 and 329 (U.S. Pat. No. 6,737, dride copolymer, polyaminoacids (either homopolymers or 056). Such Fc mutants include Fc mutants with substitutions random copolymers), and dextran or poly(n-vinyl pyrroli at two or more of amino acid positions 265,269,270,297 and done)polyethylene glycol, propropylene glycol homopoly 327, including the so-called “DANA' Fc mutant with substi mers, prolypropylene oxide/ethylene oxide co-polymers, tution of residues 265 and 297 to alanine (U.S. Pat. No. polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, 7.332.581). and mixtures thereof. Polyethylene glycol propionaldehyde 0320 Certain antibody variants with improved or dimin may have advantages in manufacturing due to its stability in ished binding to FcRs are described. (See, e.g., U.S. Pat. No. water. The polymer may be of any molecular weight, and may 6,737,056; WO 2004/056312, and Shields et al., J. Biol. be branched or unbranched. The number of polymers Chem. 9(2): 6591-6604 (2001).) attached to the antibody may vary, and if more than one 0321. In certain embodiments, an antibody variant com polymer are attached, they can be the same or different mol prises an Fc region with one or more amino acid substitutions ecules. In general, the number and/or type of polymers used which improve ADCC, e.g., substitutions at positions 298, for derivatization can be determined based on considerations 333, and/or 334 of the Fc region (EU numbering of residues). including, but not limited to, the particular properties or func 0322. In some embodiments, alterations are made in the Fc tions of the antibody to be improved, whether the antibody region that result in altered (i.e., either improved or dimin derivative will be used in a therapy under defined conditions, ished) C1q binding and/or Complement Dependent Cytotox etc. icity (CDC), e.g., as described in U.S. Pat. No. 6,194.551, 0329. In another embodiment, conjugates of an antibody WO99/51642, and Idusogie et al. J. Immunol. 164: 4178 and nonproteinaceous moiety that may be selectively heated 4.184 (2000). by exposure to radiation are provided. In one embodiment, 0323 Antibodies with increased half lives and improved the nonproteinaceous moiety is a carbon nanotube (Kam et binding to the neonatal Fc receptor (FcRn), which is respon al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). sible for the transfer of maternal IgGs to the fetus (Guyer et The radiation may be of any wavelength, and includes, but is al., J. Immunol. 1 17:587 (1976) and Kim et al., J. Immunol. not limited to, wavelengths that do not harm ordinary cells, 24:249 (1994)), are described in US2005/0014934A1 (Hin but which heat the nonproteinaceous moiety to a temperature ton et al.). Those antibodies comprise an Fc region with one or at which cells proximal to the antibody-nonproteinaceous more substitutions therein which improve binding of the Fc moiety are killed. region to FcRn. Such Fc variants include those with substi tutions at one or more of Fc region residues: 238, 256, 265, B. Recombinant Methods and Compositions 272, 286,303, 305, 307, 311, 312,317, 340,356, 360, 362, 0330 Antibodies may be produced using recombinant 376, 378,380,382, 413, 424 or 434, e.g., substitution of Fc methods and compositions, e.g., as described in U.S. Pat. No. region residue 434 (U.S. Pat. No. 7,371,826). 4,816,567. In one embodiment, isolated nucleic acid encod 0324 See also Duncan & Winter, Nature 322:738-40 ing an anti-OX40 antibody described herein is provided. Such (1988): U.S. Pat. No. 5,648,260; U.S. Pat. No. 5,624,821; and nucleic acid may encode an amino acid sequence comprising WO 94/29351 concerning other examples of Fc region vari the VL and/or an amino acid sequence comprising the VH of antS. the antibody (e.g., the light and/or heavy chains of the anti 0325 d) Cysteine Engineered Antibody Variants body). In a further embodiment, one or more vectors (e.g., 0326 In certain embodiments, it may be desirable to cre expression vectors) comprising Such nucleic acid are pro ate cysteine engineered antibodies, e.g., “thioMAbs in vided. In a further embodiment, a host cell comprising Such which one or more residues of an antibody are substituted nucleic acid is provided. In one such embodiment, a host cell with cysteine residues. In particular embodiments, the Sub comprises (e.g., has been transformed with): (1) a vector stituted residues occur at accessible sites of the antibody. By comprising a nucleic acid that encodes an amino acid Substituting those residues with cysteine, reactive thiol sequence comprising the VL of the antibody and an amino groups are thereby positioned at accessible sites of the anti acid sequence comprising the VH of the antibody, or (2) a first body and may be used to conjugate the antibody to other vector comprising a nucleic acid that encodes an amino acid moieties, such as drug moieties or linker-drug moieties, to sequence comprising the VL of the antibody and a second create an immunoconjugate, as described further herein. In vector comprising a nucleic acid that encodes an amino acid certain embodiments, any one or more of the following resi sequence comprising the VH of the antibody. In one embodi dues may be substituted with cysteine: V205 (Kabat number ment, the host cell is eukaryotic, e.g. a Chinese Hamster ing) of the light chain; A118 (EU numbering) of the heavy Ovary (CHO) cellor lymphoid cell (e.g., Y0, NS0, Sp20 cell). chain; and 5400 (EU numbering) of the heavy chain Fc In one embodiment, a method of making an anti-OX40 anti region. Cysteine engineered antibodies may be generated as body is provided, wherein the method comprises culturing a described, e.g., in U.S. Pat. No. 7,521,541. host cell comprising a nucleic acid encoding the antibody, as 0327 e) Antibody Derivatives provided above, under conditions suitable for expression of 0328. In certain embodiments, an antibody provided the antibody, and optionally recovering the antibody from the herein may be further modified to contain additional nonpro host cell (or host cell culture medium). teinaceous moieties that are known in the art and readily 0331. For recombinant production of an anti-OX40 anti available. The moieties suitable for derivatization of the anti body, nucleic acid encoding an antibody, e.g., as described body include but are not limited to water soluble polymers. above, is isolated and inserted into one or more vectors for Non-limiting examples of water soluble polymers include, further cloning and/or expression in a host cell. Such nucleic but are not limited to, polyethylene glycol (PEG), copolymers acid may be readily isolated and sequenced using conven of ethylene glycol/propylene glycol, carboxymethylcellu tional procedures (e.g., by using oligonucleotide probes that US 2015/0307617 A1 Oct. 29, 2015 34 are capable of binding specifically to genes encoding the 0338 1. Binding Assays and Other Assays heavy and light chains of the antibody). 0339. In one aspect, an antibody of the invention is tested 0332 Suitable host cells for cloning or expression of anti for its antigen binding activity, e.g., by known methods such body-encoding vectors include prokaryotic or eukaryotic as ELISA, Western blot, etc. OX40 binding may be deter cells described herein. For example, antibodies may be pro mined using methods known in the art and exemplary meth duced in bacteria, in particular when glycosylation and Fc ods are disclosed herein. In one embodiment, binding is mea effector function are not needed. For expression of antibody Sured using radioimmunoassay. An exemplary fragments and polypeptides in bacteria, see, e.g., U.S. Pat. radioimmunassay is exemplified in the Examples. OX40 anti Nos. 5,648.237, 5,789,199, and 5,840,523. (See also Charl body is iodinated, and competition reaction mixtures are pre ton, Methods in Molecular Biology, Vol. 248 (B.K. C. Lo, ed., pared containing a fixed concentration of iodinated antibody Humana Press, Totowa, N.J., 2003), pp. 245-254, describing and decreasing concentrations of serially diluted, unlabeled expression of antibody fragments in E. coli.) After expres OZX40 antibody. Cells expressing OX40 (e.g., BT474 cells sion, the antibody may be isolated from the bacterial cell stably transfected with human OX40) are added to the reac paste in a soluble fraction and can be further purified. tion mixture. Following an incubation, cells are washed to separate the free iodinated OX40 antibody from the OX40 0333. In addition to prokaryotes, eukaryotic microbes antibody bound to the cells. Level of bound iodinated OX40 Such as filamentous fungi or yeast are suitable cloning or antibody is determined, e.g., by counting radioactivity asso expression hosts for antibody-encoding vectors, including ciated with cells, and binding affinity determined using stan fungi and yeast strains whose glycosylation pathways have dard methods. In another embodiment, ability of OX40 anti been “humanized, resulting in the production of an antibody body to bind to surface-expressed OX40 (e.g., on T cell with a partially or fully human glycosylation pattern. See subsets) is assessed using flow cytometry. Peripheral white Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., blood cells are obtained (e.g., from human, cynomolgus mon Nat. Biotech. 24:210-215 (2006). key, rat or mouse) and cells are blocked with serum. Labeled 0334 Suitable host cells for the expression of glycosy OX40 antibody is added in serial dilutions, and T cells are also lated antibody are also derived from multicellular organisms stained to identify T cell subsets (using methods known in the (invertebrates and vertebrates). Examples of invertebrate art). Following incubation of the samples and washing, the cells include plant and insect cells. Numerous baculoviral cells are sorted using flow cytometer, and data analyzed using strains have been identified which may be used in conjunction methods well known in theart. In another embodiment, OX40 with insect cells, particularly for transfection of Spodoptera binding may be analyzed using surface plasmon resonance. frugiperda cells. An exemplary Surface plasmon resonance method is exem 0335 Plant cell cultures can also be utilized as hosts. See, plified in the Examples. e.g., U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125, 0340. In another aspect, competition assays may be used 978, and 6,417,429 (describing PLANTIBODIESTM technol to identify an antibody that competes with any of the anti ogy for producing antibodies in transgenic plants). OX40 antibodies disclosed herein for binding to OX40. In 0336 Vertebrate cells may also be used as hosts. For certain embodiments, such a competing antibody binds to the example, mammalian cell lines that are adapted to grow in same epitope (e.g., a linear or a conformational epitope) that Suspension may be useful. Other examples of useful mam is bound by any of the anti-OX40 antibodies disclosed herein. malian host cell lines are monkey kidney CV1 line trans Detailed exemplary methods for mapping an epitope to which formed by SV40 (COS-7); human embryonic kidney line an antibody binds are provided in Morris (1996) “Epitope (293 or 293 cells as described, e.g., in Graham et al., J. Gen Mapping Protocols.” in Methods in Molecular Biology vol. 66 Virol. 36:59 (1977)); baby hamster kidney cells (BHK); (Humana Press, Totowa, N.J.). A competition assay is exem mouse sertoli cells (TM4 cells as described, e.g., in Mather, plified in the Examples. Biol. Reprod. 23:243-251 (1980)); monkey kidney cells 0341. In an exemplary competition assay, immobilized (CV1); African green monkey kidney cells (VERO-76): OX40 is incubated in a solution comprising a first labeled human cervical carcinoma cells (HELA); canine kidney cells antibody that binds to OX40 (e.g., mab 1A7.gr.1, mab 3C8. (MDCK; buffalo rat liver cells (BRL 3A); human lung cells grS) and a second unlabeled antibody that is being tested for (W138); human liver cells (Hep G2); mouse mammary tumor its ability to compete with the first antibody for binding to (MMT 060562); TRIcells, as described, e.g., in Matheret al., OX40. The second antibody may be present in a hybridoma Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and supernatant. As a control, immobilized OX40 is incubated in FS4 cells. Other useful mammalian host cell lines include a solution comprising the first labeled antibody but not the Chinese hamster ovary (CHO) cells, including DHFR CHO second unlabeled antibody. After incubation underconditions cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 permissive for binding of the first antibody to OX40, excess (1980)); and myeloma cell lines such as Y0, NSO and Sp2/0. unbound antibody is removed, and the amount of label asso For a review of certain mammalian host cell lines suitable for ciated with immobilized OX40 is measured. If the amount of antibody production, see, e.g., Yazaki and Wu, Methods in label associated with immobilized OX40 is substantially Molecular Biology, Vol. 248 (B.K. C. Lo, ed., Humana Press, reduced in the test sample relative to the control sample, then Totowa, N.J.), pp. 255-268 (2003). that indicates that the second antibody is competing with the first antibody for binding to OX40. See Harlow and Lane (1988) Antibodies. A Laboratory Manual ch.14 (Cold Spring C. Assays Harbor Laboratory, Cold Spring Harbor, N.Y.). 0337 Anti-OX40 antibodies provided herein may be iden 0342. 2. Activity Assays tified, screened for, or characterized for their physical/chemi 0343. In one aspect, assays are provided for identifying cal properties and/or biological activities by various assays anti-OX40 antibodies thereofhaving biological activity. Bio known in the art. logical activity may include, e.g., binding OX40 (e.g., bind US 2015/0307617 A1 Oct. 29, 2015 ing human and/or cynomolgus OX40), increasing OX40-me results in increased NFkB transcription, which is detected diated signal transduction (e.g., increasing NFkB-mediated using an assay for the reporter gene. transcription), depleting cells that express human OX40 (e.g., 0348 Phagocytosis may be assayed, e.g., by using mono T cells), depleting cells that express human OX40 by ADCC cyte-derived macrophages, or U937 cells (a human histio and/or phagocytosis, enhancing Teffector cell function (e.g., cytic lymphoma cells line with the morphology and charac CD4+ effector T cell), e.g., by increasing effector T cell teristics of mature macrophages). OX40 expressing cells are proliferation and/or increasing cytokine production (e.g., added to the monocyte-derived macrophages or U937 cells in gamma interferon) by effector T cells, enhancing memory T the presence or absence of anti-OX40 agonist antibody. Fol cell function (e.g., CD4+ memory T cell), e.g., by increasing lowing culturing of the cells for a suitable period of time, the memory T cell proliferation and/or increasing cytokine pro percentage of phagocytosis is determined by examining per duction by memory T cells (e.g., gamma interferon), inhibit centage of cells that double stain for markers of 1) the mac ing regulatory T cell function (e.g., by decreasing Treg Sup rophage or U937 cell and 2) the OX40 expressing cell, and pression of effector T cell function (e.g., CD4+ effector T cell dividing this by the total number of cells that show markers of function), binding human effector cells. Antibodies having the OX40 expressing cell (e.g., GFP). Analysis may be done Such biological activity in vivo and/or in vitro are also pro by flow cytometry. In another embodiment, analysis may be vided. done by fluorescent microscopy analysis. 0344. In certain embodiments, an antibody of the inven 0349 ADCC may be assayed, e.g., using methods well tion is tested for Such biological activity. known in the art. Exemplary methods are described in the 0345 T cell costimulation may be assayed using methods definition section and an exemplary assay is disclosed in the known in the art and exemplary methods are disclosed herein. Examples. In some embodiments, level of OX40 is charac For example, T cells (e.g., memory or effector T cells) may be terized on an OX40 expressing cell that is used for testing in obtained from peripheral white blood cells (e.g., isolated an ADCC assay. The cell may be stained with a detectably from human whole blood using Ficoll gradient centrifuga labeled anti-OX40 antibody (e.g., PE labeled), then level of tion). Memory T cells (e.g., CD4+ memory T cells) or effector fluorescence determined using flow cytometry, and results T cells (e.g. CD4+ Teff cells) may be isolated from PBMC presented as median fluorescence intensity (MFI). In another using methods known in the art. For example, the Miltenyi embodiment, ADCC may be analyzed by CellTiter Glo assay CD4+ memory T cell isolation kit or Miltenyi naive CD4+ T kit and cell viability/cytotoxicity may be determined by che cell isolation kit may be used. Isolated T cells are cultured in mioluminescence. the presence of antigen presenting cells (e.g., irradiated L 0350. The binding affinities of various antibodies to cells that express CD32 and CD80), and activated by addition FcyRIA, FcyRIIA, FcyRIIB, and two allotypes of FcyRIIIA of anti-CD3 antibody in the presence or absence of OX40 (F158 and V158) may be measured in ELISA-based ligand agonistantibody. Effect of agonist OX40 antibody of T cell binding assays using the respective recombinant Fcy recep proliferation may be measured using methods well known in tors. Purified human Fcy receptors are expressed as fusion the art. For example, the CelTiter Glo kit (Promega) may be proteins containing the extracellular domain of the receptory used, and results read on a Multilabel Reader (PerkinElmer). chain linked to a Gly/6xHis/glutathione S-transferase (GST) Effect of agonist OX40 antibody on T cell function may also polypeptide tag at the C-terminus. The binding affinities of be determined by analysis of cytokines produced by the T antibodies to those human Fcy receptors are assayed as fol cell. In one embodiment, production of interferon gamma by lows. For the low-affinity receptors, i.e. FcyRIIA (CD32A), CD4+ T cells is determined, e.g., by measurement of inter FcyRIIB (CD32B), and the two allotypes of FcyRIIIA feron gamma in cell culture Supernatant. Methods for mea (CD16), F-158 and V-158, antibodies may be tested as mul Suring interferon gamma are well-known in the art. timers by cross-linking with a F(ab')2 fragment of goat anti human kappa chain (ICN Biomedical; Irvine, Calif.) at an 0346 Treg cell function may be assayed using methods approximate molar ratio of 1:3 antibody:cross-linking F(ab') known in the art and exemplary methods are disclosed herein. Plates are coated with an anti-GST antibody (Genentech) In one example, the ability of Treg to suppress effector T cell and blocked with bovine serum albumin (BSA). After wash proliferation is assayed. T cells are isolated from human ing with phosphate-buffered saline (PBS) containing 0.05% whole blood using methods known in the art (e.g., isolating Tween-20 with an ELX405TM plate washer (Biotek Instru memory T cells or naive T cells). Purified CD4+ naive T cells ments; Winooski, Vt.), Fcy receptors are added to the plate at are labeled (e.g., with CFSE) and purified Treg cells are 25 ng/well and incubated at room temperature for 1 hour. labeled with a different reagent. Irradiated antigen presenting After the plates are washed, serial dilutions of testantibodies cells (e.g., L cells expressing CD32 and CD80) are co-cul are added as multimeric complexes and the plates were incu tured with the labeled purified naive CD4+ T cells and puri bated at room temperature for 2 hours. Following plate wash fied Tregs. The co-cultures are activated using anti-CD3 anti ing to remove unbound antibodies, the antibodies bound to body and tested in the presence or absence of agonist OX40 the Fcy receptor are detected with horseradish peroxidase antibody. Following a Suitable time (e.g., 6 days of coculture), (HRP)-conjugated F(ab')2 fragment of goat anti-human level of CD4+ naive T cell proliferation is tracked by dye F(ab') (Jackson ImmunoResearch Laboratories; West Grove, dilution in reduced label staining (e.g., reduced CFSE label Pa.) followed by the addition of substrate, tetramethylbenzi staining) using FACS analysis. dine (TMB) (Kirkegaard & Perry Laboratories; Gaithersburg, 0347 OX40 signaling may be assayed using methods well Md.). The plates are incubated at room temperature for 5-20 known in the art and exemplary methods are disclosed herein. minutes, depending on the Fcy receptors tested, to allow color In one embodiment, transgenic cells are generated that development. The reaction is terminated with 1 MHPO and express human OX40 and a reporter gene comprising the absorbance at 450 nm was measured with a microplate reader NFkB promoter fused to a reporter gene (e.g., beta (SpectraMax(R) 190, Molecular Devices; Sunnyvale, Calif.). luciferase). Addition of OX40 agonist antibody to the cells Dose-response binding curves are generated by plotting the US 2015/0307617 A1 Oct. 29, 2015 36 mean absorbance values from the duplicates of antibody dilu Chem. 45:4336-4343 (2002); and U.S. Pat. No. 6,630.579); tions against the concentrations of the antibody. Values for the methotrexate; Vindesine; a taxane Such as docetaxel, pacli effective concentration of the antibody at which 50% of the taxel, larotaxel, tesetaxel, and ortataxel; a trichothecene; and maximum response from binding to the Fcy receptor is CC1065. detected (EGO were determined after fitting the binding 0357. In another embodiment, an immunoconjugate com curve with a four-parameter equation using SoftMax Pro prises an antibody as described herein conjugated to an enzy (Molecular Devices). matically active toxin or fragment thereof, including but not 0351. To select for antibodies which induce cell death, loss limited to diphtheria A chain, nonbinding active fragments of of membrane integrity as indicated by, e.g., propidium iodide diphtheria toxin, exotoxin A chain (from Pseudomonas (PI), trypan blue or 7AAD uptake may be assessed relative to aeruginosa), ricin. A chain, abrin A chain, modeccin. A chain, control. API uptake assay can be performed in the absence of alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phy complement and immune effector cells. OX40 expressing tolaca americana proteins (PAPI, PAPII, and PAP-S), cells are incubated with medium alone or medium containing momordica charantia inhibitor, curcin, crotin, Sapaonaria of the appropriate monoclonal antibody at e.g., about 10 officinalis inhibitor, gelonin, mitogellin, restrictocin, pheno ug/ml. The cells are incubated for a time period (e.g., 1 or 3 mycin, enomycin, and the tricothecenes. days). Following each treatment, cells are washed and ali 0358. In another embodiment, an immunoconjugate com quoted. In some embodiments, cells are aliquoted into 35 mm prises an antibody as described herein conjugated to a radio strainer-capped 12x75 tubes (1 ml per tube, 3 tubes per treat active atom to form a radioconjugate. A variety of radioactive ment group) for removal of cell clumps. Tubes then receive PI isotopes are available for the production of radioconjugates. (10 g/ml). Samples may be analyzed using a FACSCANTM Examples include At'', I'', I'', Y', Re, Re', sm', flow cytometer and FACSCONVERTTM CellOuest software Bi', P°, Pb’’ and radioactive isotopes of Lu. When the (Becton Dickinson). radioconjugate is used for detection, it may comprise a radio 0352 Cells for use in any of the above in vitro assays active atom for Scintigraphic studies, for exampletc99m or include cells or cell lines that naturally express OX40 or that I123, or a spin label for nuclear magnetic resonance (NMR) have been engineered to express OX40. Such cells include imaging (also known as magnetic resonance imaging, mri). activated T cells, Treg cells and activated memory T cells that Such as iodine-123 again, iodine-131, indium-111, fluorine naturally express OX40. Such cells also include cell lines that 19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manga express OX40 and cell lines that do not normally express nese or iron. OX40 but have been transfected with nucleic acid encoding 0359 Conjugates of an antibody and cytotoxic agent may OX40. Exemplary cell lines provided herein for use in any of be made using a variety of bifunctional protein coupling the above in vitro assays include transgenic BT474 cells (a agents such as N-Succinimidyl-3-(2-pyridyldithio) propi human breast cancer cell line) that express human OX40 onate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclo 0353. It is understood that any of the above assays may be hexane-1-carboxylate (SMCC), iminothiolane (IT), bifunc carried out using an immunoconjugate of the invention in tional derivatives of imidoesters (such as dimethyl place of or in addition to an anti-OX40 antibody. adipimidate HCl), active esters (such as disuccinimidyl Sub 0354. It is understood that any of the above assays may be erate), aldehydes (such as glutaraldehyde), bis-azido com carried out using anti-OX40 antibody and an additional thera pounds (such as bis(p-azidobenzoyl) hexanediamine), bis peutic agent. diazonium derivatives (such as bis-(p-diazoniumbenzoyl)- ethylenediamine), diisocyanates (such as toluene 2,6- D. Immunoconjugates diisocyanate), and bis-active fluorine compounds (such as 0355 The invention also provides immunoconjugates 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immu comprising an anti-OX40 antibody herein conjugated to one notoxin can be prepared as described in Vitetta et al., Science or more cytotoxic agents, such as chemotherapeutic agents or 238:1098 (1987). Carbon-14-labeled 1-isothiocyanatoben drugs, growth inhibitory agents, toxins (e.g., protein toxins, Zyl-3-methyldiethylene triaminepentaacetic acid (MX enzymatically active toxins of bacterial, fungal, plant, orani DTPA) is an exemplary chelating agent for conjugation of mal origin, or fragments thereof), or radioactive isotopes. radionucleotide to the antibody. See WO94/11026. The linker 0356. In one embodiment, an immunoconjugate is an anti may be a “cleavable linker facilitating release of a cytotoxic body-drug conjugate (ADC) in which an antibody is conju drug in the cell. For example, an acid-labile linker, peptidase gated to one or more drugs, including but not limited to a sensitive linker, photolabile linker, dimethyl linker or disul maytansinoid (see U.S. Pat. Nos. 5.208,020, 5,416,064 and fide-containing linker (Chari et al., Cancer Res. 52:127-131 European Patent EP 0 425 235 B1); an auristatin such as (1992); U.S. Pat. No. 5,208,020) may be used. monomethylauristatin drug moieties DE and DF (MMAE and 0360. The immunuoconjugates or ADCs herein expressly MMAF) (see U.S. Pat. Nos. 5,635,483 and 5,780,588, and contemplate, but are not limited to such conjugates prepared 7,498,298); a dolastatin; a calicheamicin orderivative thereof with cross-linker reagents including, but not limited to, (see U.S. Pat. Nos. 5,712.374, 5,714,586, 5,739,116, 5,767, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, 285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hin SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, man et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo Cancer Res. 58:2925-2928 (1998)); an anthracycline such as SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinyl daunomycin or doxorubicin (see Kratz et al., Current Med. Sulfone)benzoate) which are commercially available (e.g., Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. from Pierce Biotechnology, Inc., Rockford, Ill., U.S.A). Chem. Letters 16:358-362 (2006); Torgov et al., Bioconi. E. Methods and Compositions for Diagnostics and Detection Chem. 16:717-721 (2005): Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. 0361. In certain embodiments, any of the anti-OX40 anti Chem. Letters 12:1529-1532 (2002); King et al., J. Med. bodies provided herein is useful for detecting the presence of US 2015/0307617 A1 Oct. 29, 2015 37 OX40 in a biological sample. The term “detecting as used tional modifications of that sequence. In a particular embodi herein encompasses quantitative or qualitative detection. In ment, the VH comprises one, two or three HVRs selected certain embodiments, a biological sample comprises a cell or from: (a) HVR-H1 comprising the amino acid sequence of tissue, such as a sample of a tumor (e.g., NSCLC or breast SEQ ID NO:2, (b) HVR-H2 comprising the amino acid tumor). sequence of SEQID NO:3, and (c) HVR-H3 comprising the 0362. In one embodiment, an anti-OX40 antibody for use amino acid sequence of SEQ ID NO:4. In some embodi in a method of diagnosis or detection is provided. In a further ments, the antibody comprises a light chain variable domain aspect, a method of detecting the presence of OX40 in a (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, biological sample is provided. In certain embodiments, the 97%.98%, 99%, or 100% sequence identity to the amino acid method comprises contacting the biological sample with an sequence of SEQID NO:179. In certain embodiments, a VL anti-OX40 antibody as described herein under conditions sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, permissive for binding of the anti-OX40 antibody to OX40, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., and detecting whether a complex is formed between the anti conservative Substitutions), insertions, or deletions relative to OX40 antibody and OX40. Such method may bean in vitro or the reference sequence, but an anti-human OX40 agonist in vivo method. In one embodiment, an anti-OX40 antibody is antibody comprising that sequence retains the ability to bind used to select subjects eligible for therapy with an anti-OX40 to OX40. In certain embodiments, a total of 1 to 10 amino antibody, e.g. where OX40 is a biomarker for selection of acids have been substituted, inserted and/or deleted in SEQ patients. ID NO: 179. In certain embodiments, the substitutions, inser 0363. In some embodiments, the anti-OX40 antibody for tions, or deletions occur in regions outside the HVRS (i.e., in use in a method of diagnosis or detection is an anti-human the FRs). Optionally, the anti-human OX40 agonistantibody OX40 antibody comprising at least one, two, three, four, five, comprises the VL sequence in SEQID NO: 179, including or six HVRs selected from (a) HVR-H1 comprising the post-translational modifications of that sequence. In a par amino acid sequence of SEQ ID NO:2; (b) HVR-H2 com ticular embodiment, the VL comprises one, two or three prising the amino acid sequence of SEQID NO:3; (c) HVR HVRs selected from (a) HVR-L1 comprising the amino acid H3 comprising the amino acid sequence of SEQID NO:4; (d) sequence of SEQ ID NO:5; (b) HVR-L2 comprising the HVR-L1 comprising the amino acid sequence of SEQ ID amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 NO:5; (e) HVR-L2 comprising the amino acid sequence of comprising the amino acid sequence of SEQID NO:7. SEQ ID NO:6; and (f) HVR-L3 comprising the amino acid 0364. In some embodiments, the anti-OX40 antibody used sequence of SEQID NO:7. In some embodiments, the anti in the method of diagnosis or detection is an anti-human OX40 antibody comprises (a) a VH domain comprising at OX40 antibody comprising at least one, two, three, four, five, least one, at least two, or all three VH HVR sequences or six HVRs selected from (a) HVR-H1 comprising the selected from (i) HVR-H1 comprising the amino acid amino acid sequence of SEQID NO:29; (b) HVR-H2 com sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the prising the amino acid sequence of SEQID NO:30; (c) HVR amino acid sequence of SEQ ID NO:3, and (iii) HVR-H3 H3 comprising the amino acid sequence of SEQID NO:31: comprising an amino acid sequence selected from SEQ ID (d) HVR-L1 comprising the amino acid sequence of SEQID NO:4; and (b) a VL domain comprising at least one, at least NO:37; (e) HVR-L2 comprising the amino acid sequence of two, or all three VL HVR sequences selected from (i) HVR SEQID NO:39; and (f) HVR-L3 comprising the amino acid L1 comprising the amino acid sequence of SEQID NO:5, (ii) sequence of SEQID NO:42. In some embodiments, the anti HVR-L2 comprising the amino acid sequence of SEQ ID OX40 antibody comprises (a) a VH domain comprising at NO:6, and (c) HVR-L3 comprising the amino acid sequence least one, at least two, or all three VH HVR sequences of SEQID NO:7. In some embodiments, the OX40 antibody selected from (i) HVR-H1 comprising the amino acid comprises (a) HVR-H1 comprising the amino acid sequence sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 sequence of SEQ ID NO:3; (c) HVR-H3 comprising the comprising an amino acid sequence selected from SEQ ID amino acid sequence of SEQID NO:4; (d) HVR-L1 compris NO:31; and (b) a VL domain comprising at least one, at least ing the amino acid sequence of SEQID NO:5; (e) HVR-L2 two, or all three VL HVR sequences selected from (i) HVR comprising the amino acid sequence of SEQID NO:6; and (f) L1 comprising the amino acid sequence of SEQID NO:37, HVR-L3 comprising an amino acid sequence selected from (ii) HVR-L2 comprising the amino acid sequence of SEQID SEQID NO:7. In some embodiments, the antibody comprises NO:39, and (c) HVR-L3 comprising the amino acid sequence a heavy chain variable domain (VH) sequence having at least of SEQ ID NO:42. In some embodiments, the anti-OX40 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or antibody comprises (a) HVR-H1 comprising the amino acid 100% sequence identity to the amino acid sequence of SEQ sequence of SEQ ID NO:29; (b) HVR-H2 comprising the IDNO: 180. In certain embodiments, a VH sequence having at amino acid sequence of SEQ ID NO:30; (c) HVR-H3 com least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or prising the amino acid sequence of SEQID NO:31; (d) HVR 99% identity contains substitutions (e.g., conservative substi L1 comprising the amino acid sequence of SEQID NO:37; tutions), insertions, or deletions relative to the reference (e) HVR-L2 comprising the amino acid sequence of SEQID sequence, but an anti-human OX40 agonist antibody com NO:39; and (f) HVR-L3 comprising an amino acid sequence prising that sequence retains the ability to bind to OX40. In selected from SEQ ID NO:42. In some embodiment, the certain embodiments, a total of 1 to 10amino acids have been anti-OX40 antibody comprises a heavy chain variable substituted, inserted and/or deleted in SEQ ID NO: 180. In domain (VH) sequence having at least 90%, 91%, 92%, 93%, certain embodiments, Substitutions, insertions, or deletions 94%. 95%, 96%,97%.98%, 99%, or 100% sequence identity occur in regions outside the HVRs (i.e., in the FRs). Option to the amino acid sequence of SEQ ID NO:182. In certain ally, the anti-human OX40 agonist antibody comprises the embodiments, a VH sequence having at least 90%, 91%, 92%, VH sequence in SEQ ID NO:180, including post-transla 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains US 2015/0307617 A1 Oct. 29, 2015 Substitutions (e.g., conservative Substitutions), insertions, or (HRP), alkaline phosphatase, B-galactosidase, glucoamylase, deletions relative to the reference sequence, but an anti-hu lysozyme, Saccharide oxidases, e.g., glucose oxidase, galac man OX40 agonistantibody comprising that sequence retains tose oxidase, and glucose-6-phosphate dehydrogenase, het the ability to bind to OX40. In certain embodiments, a total of erocyclic oxidases Such as uricase and Xanthine oxidase, 1 to 10 amino acids have been substituted, inserted and/or coupled with an enzyme that employs hydrogen peroxide to deleted in SEQID NO:182. In certain embodiments, substi oxidize a dye precursor such as HRP, lactoperoxidase, or tutions, insertions, or deletions occur in regions outside the microperoxidase, biotin/avidin, spin labels, bacteriophage HVRs (i.e., in the FRs). Optionally, the anti-human OX40 labels, stable free radicals, and the like. agonist antibody comprises the VH sequence in SEQ ID 0368. In one aspect, the invention provides diagnostic NO:182, including post-translational modifications of that methods, e.g. for identifying a cancer patient who is likely to sequence. In a particular embodiment, the VH comprises one, respond to treatment with an anti-human OX40 agonist anti two or three HVRs selected from: (a) HVR-H1 comprising body. the amino acid sequence of SEQ ID NO:29, (b) HVR-H2 0369. In some embodiments, methods are provided for comprising the amino acid sequence of SEQID NO:30, and identifying patients who are likely to respond to treatment (c) HVR-H3 comprising the amino acid sequence of SEQID with anti-human OX40 agonist antibody, the methods com NO:31. In some embodiments, the anti-OX40 antibody com prising (i) determining presence or absence or amount (e.g., prises a light chain variable domain (VL) having at least 90%, number per given sample size) of cells expressing FcR in a 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sample of cancer from the patient, and (ii) identifying the sequence identity to the amino acid sequence of SEQ ID patient as likely to respond if the sample comprises cells NO:181. In certain embodiments, a VL sequence having at expressing FcR (e.g., high number of cells expressing FcR). least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or Methods for detecting cells that express FcRare well known 99% identity contains substitutions (e.g., conservative substi in the art, including, e.g., by IHC. In some embodiments, FcR tutions), insertions, or deletions relative to the reference is FcyR. In some embodiments, FcR is an activating FcyR. In sequence, but an anti-human OX40 agonist antibody com Some embodiments, the cancer is any cancer described prising that sequence retains the ability to bind to OX40. In herein. In some embodiments, the cancer is non-small cell certain embodiments, a total of 1 to 10amino acids have been lung cancer (NSCLC), glioblastoma, neuroblastoma, mela substituted, inserted and/or deleted in SEQ ID NO: 181. In noma, breast carcinoma (e.g. triple-negative breast cancer), certain embodiments, the Substitutions, insertions, or dele gastric cancer, colorectal cancer (CRC), or hepatocellular tions occur in regions outside the HVRs (i.e., in the FRs). carcinoma. In some embodiments, the method is an in vitro Optionally, the anti-human OX40agonistantibody comprises method. In some embodiments, the methods further comprise the VL sequence in SEQID NO: 181, including post-trans (iii) recommending treatment with the anti-human OX40 lational modifications of that sequence. In a particular agonist antibody (e.g., any of the anti-human OX40 agonist embodiment, the VL comprises one, two or three HVRs antibodies described herein). In some embodiments, the selected from (a) HVR-L1 comprising the amino acid methods further comprise (iv) treating the patient with the sequence of SEQ ID NO:37; (b) HVR-L2 comprising the anti-human OX40 agonist antibody. amino acid sequence of SEQ ID NO:39; and (c) HVR-L3 0370. In some embodiments, methods are provided for comprising the amino acid sequence of SEQID NO:42. identifying patients who are likely to respond to treatment 0365. In some embodiments, the anti-OX40 antibody with anti-human OX40 agonist antibody, the methods com comprises a VH sequence of SEQ ID NO: 180. In some prising (i) determining presence or absence or amount (e.g., embodiments, the anti-OX40 antibody comprises a VL number per given sample size) of human effector cells (e.g., sequence of SEQ ID NO: 179. In some embodiments, the infiltrating effector cells) in a sample of cancer from the anti-OX40 antibody comprises a VH sequence of SEQ ID patient, and (ii) identifying the patient as likely to respond if NO:180 and a VL sequence of SEQ ID NO: 179. In some the sample comprises effector cells (e.g., high number of embodiments, the anti-OX40 antibody comprises a VH effector cells). Methods for detecting infiltrating human sequence of SEQ ID NO: 182. In some embodiments, the effector cells are well known in the art, including, e.g., by anti-OX40 antibody comprises a VL sequence of SEQ ID IHC. In some embodiments, human effector cells are one or NO: 181. In some embodiments, the anti-OX40 antibody more of NK cells, macrophages, monocytes. In some embodi comprises a VH sequence of SEQ ID NO:182 and a VL ments, the effector cells express activating FcyR. In some sequence of SEQID NO: 181. embodiments, the method is an in vitro method. In some 0366 Exemplary disorders that may be diagnosed using embodiments, the cancer is any cancer described herein. In an antibody of the invention include cancer. Some embodiments, the cancer is non-Small cell lung cancer 0367. In certain embodiments, labeled anti-OX40 anti (NSCLC), glioblastoma, neuroblastoma, melanoma, breast bodies are provided. Labels include, but are not limited to, carcinoma (e.g. triple-negative breast cancer), gastric cancer, labels or moieties that are detected directly (such as fluores colorectal cancer (CRC), or hepatocellular carcinoma. In cent, chromophoric, electron-dense, chemiluminescent, and Some embodiments, the methods further comprise (iii) rec radioactive labels), as well as moieties, such as enzymes or ommending treatment with the anti-human OX40 agonist ligands, that are detected indirectly, e.g., through an enzy antibody (e.g., any of the anti-human OX40 agonist antibod matic reaction or molecular interaction. Exemplary labels ies described herein). In some embodiments, the methods include, but are not limited to, the radioisotopes 'P.C. 'I, further comprise (iv) treating the patient with the anti-human H, and 'I, fluorophores such as rare earth chelates or fluo OX40 agonistantibody. rescein and its derivatives, rhodamine and its derivatives, 0371 Provided are methods of providing a cancer diagno dansyl, umbelliferone, luceriferases, e.g., firefly luciferase sis comprising: (i) measuring FcR expressing cells (e.g., the and bacterial luciferase (U.S. Pat. No. 4,737,456), luciferin, level or presence or absence of or prevalence (e.g., percentage 2,3-dihydrophthalazinediones, horseradish peroxidase of cells expressing FcR, e.g., by IHC) of FcR) in a sample US 2015/0307617 A1 Oct. 29, 2015 39 from the patient; (ii) diagnosing the patient as having cancer bic acid and methionine; preservatives (such as octade comprising FcR biomarker (e.g., high FcR biomarker) when cyldimethylbenzyl ammonium chloride; hexamethonium the sample has FcR biomarker expression. In some embodi chloride; benzalkonium chloride; benzethonium chloride; ments, the method further comprises (iii) selecting a therapy phenol, butyl or benzyl alcohol; alkyl parabens such as comprising (a) anti-human OX40 agonist antibody or (b) methyl or propyl paraben; catechol; resorcinol; cyclohex recommending a therapy comprising anti-human OX40 ago anol: 3-pentanol; and m-cresol); low molecular weight (less nist antibody for the patient. In some embodiments, the than about 10 residues) polypeptides; proteins, such as serum method is an in vitro method. albumin, gelatin, or immunoglobulins; hydrophilic polymers 0372 Provided are methods of providing a cancer diagno Such as polyvinylpyrrolidone; amino acids Such as glycine, sis comprising: (i) measuring human effector cells (e.g., the glutamine, asparagine, histidine, arginine, or lysine; level or presence or absence of or prevalence (e.g., percentage monosaccharides, disaccharides, and other carbohydrates of human effector cells) of human effector cells) in a sample including glucose, mannose, or dextrins; chelating agents from the patient; (ii) diagnosing the patient as having cancer Such as EDTA; Sugars such as Sucrose, mannitol, trehalose or comprising human effector cells (e.g., high human effector Sorbitol; salt-forming counter-ions such as sodium; metal cells) when the sample has human effector cell biomarker. In complexes (e.g. Zn-protein complexes); and/or non-ionic Sur some embodiments, the method further comprises (iii) select factants such as polyethylene glycol (PEG). Exemplary phar ing a therapy comprising (a) anti-human OX40 agonist anti maceutically acceptable carriers hereinfurther include inster body or (b) recommending a therapy comprising anti-human Stitial drug dispersion agents such as soluble neutral-active OX40 agonistantibody for the patient. In some embodiments, hyaluronidase glycoproteins (shASEGP), for example, the method is an in vitro method. human soluble PH-20 hyaluronidase glycoproteins, such as 0373) Provided are methods of recommending a treatment rHuPH20 (HYLENEX(R), Baxter International, Inc.). Certain to a cancer patient comprising: (i) measuring FcR expressing exemplary shASEGPs and methods of use, including cells (e.g., the level or presence or absence of or prevalence rHuPH20, are described in US Patent Publication Nos. 2005/ (e.g., percentage of cells expressing FcR) of FcR) in a sample 0260186 and 2006/0104968. In one aspect, a shASEGP is from the patient; (ii) recommending treatment with an anti combined with one or more additional glycosaminoglyca human OX40 agonist antibody when the sample has FcR nases such as chondroitinases. expressing cells (in Some embodiments, high FcR expressing 0377. In some embodiments, a “histidine buffer is a cells). In some embodiments, the method further comprises buffer comprising histidine ions. Examples of histidine buff (iii) selectingatherapy comprising anti-human OX40 agonist ers include histidine chloride, histidine acetate, histidine antibody for the patient. In some embodiments, the method is phosphate, histidine sulfate. The preferred histidine buffer an in vitro method. identified in the examples herein was found to be histidine 0374 Provided are methods of recommending a treatment acetate. In the preferred embodiment, the histidine acetate to a cancer patient comprising: (i) measuring human effector buffer is prepared by titrating L-histidine (free base, solid) cells (e.g., the level or presence or absence of or prevalence with acetic acid (liquid). In some embodiments, the histidine (e.g., percentage of human effector cells) of human effector buffer or histidine-acetate buffer is at pH 5.0 to 6.0, in some cells) in a sample from the patient; (ii) recommending treat embodiments, pH 5.3 to 5.8. ment with an anti-human OX40 agonist antibody when the 0378. In some embodiments, a “saccharide’ herein com sample has human effector cells (in some embodiments, high prises the general composition (CH2O)n and derivatives human effector cells). In some embodiments, the method thereof, including monosaccharides, disaccharides, trisac further comprises (iii) selecting a therapy comprising anti charides, polysaccharides, Sugar alcohols, reducing Sugars, human OX40 agonist antibody for the patient. In some nonreducing Sugars, etc. Examples of Saccharides herein embodiments, the method is an in vitro method. include glucose, Sucrose, trehalose, lactose, fructose, mal 0375. In some embodiments of any of the inventions pro tose, dextran, glycerin, dextran, erythritol, glycerol, arabitol, vided herein, the sample is obtained prior to treatment with sylitol, Sorbitol, mannitol, mellibiose, melezitose, raffinose, anti-human OX40 agonist antibody. In some embodiments, mannotriose, stachyose, maltose, lactulose, maltulose, gluci the sample is obtained prior to treatment with a cancer medi tol, maltitol, lactitol, iso-maltulose, etc. In some embodi cament. In some embodiments, the sample is obtained after ments, the saccharide is a nonreducing disaccharide. Such as the cancer has metastasized. In some embodiments, the trehalose or Sucrose. sample is formalin fixed and paraffin embedded (FFPE). In 0379. In some embodiments herein, a “surfactant” refers Some embodiments, the sample is of a biopsy (e.g., a core to a surface-active agent, preferably a nonionic Surfactant. biopsy), a Surgical specimen (e.g., a specimen from a Surgical Examples of surfactants herein include polysorbate (for resection), or a fine needle aspirate. example, polysorbate 20 and polysorbate 80); poloxamer (e.g. poloxamer 188); Triton; sodium dodecyl sulfate (SDS); F. Pharmaceutical Formulations Sodium laurel Sulfate; sodium octyl glycoside; lauryl-, myri 0376 Pharmaceutical formulations of an anti-OX40 anti styl-, linoleyl-, or Stearyl-Sulfobetaine; lauryl-, myristyl-, body as described herein are prepared by mixing such anti linoleyl- or Stearyl-sarcosine; linoleyl-, myristyl-, or cetyl body having the desired degree of purity with one or more betaine; lauroamidopropyl-, cocamidopropyl-, linoleami optional pharmaceutically acceptable carriers (Remington's dopropyl-, myristamidopropyl-, palmidopropyl-, or isos Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), tearamidopropyl-betaine (e.g. lauroamidopropyl); in the form of lyophilized formulations or aqueous Solutions. myristamidopropyl-, palmidopropyl-, or isostearamidopro Pharmaceutically acceptable carriers are generally nontoxic pyl-dimethylamine; sodium methyl cocoyl-, or disodium to recipients at the dosages and concentrations employed, and methyl oleyl-taurate; and the MONAQUATTM series (Mona include, but are not limited to: buffers such as phosphate, Industries, Inc., Paterson, N.J.); polyethylglycol, polypropyl citrate, and other organic acids; antioxidants including ascor glycol, and copolymers of ethylene and propylene glycol (e.g. US 2015/0307617 A1 Oct. 29, 2015 40 Pluronics, PF68 etc); etc. In some embodiments, the surfac embodiments, the disaccharide is trehalose. In some embodi tant is polysorbate 20. In some embodiments, the Surfactant is ments, the disaccharide is Sucrose. polysorbate 80. 0389. In some embodiments of any of the formulations, 0380 Exemplary lyophilized antibody formulations are the histidine buffer is at a concentration of about 1 mM to described in U.S. Pat. No. 6,267,958. Aqueous antibody for about 50 mM (e.g. about 1 mM to about 25 mM). In some mulations include those described in U.S. Pat. No. 6,171,586 embodiments, the histidine buffer is at a concentration of and WO2006/044908, the latterformulations including a his about 10 mM. In some embodiments, the histidine buffer is at tidine-acetate buffer. a concentration of about 20 mM. In some embodiments, the 0381. The formulation herein may also contain more than histidine buffer is at a concentration of about 30 mM. In some one active ingredients as necessary for the particular indica embodiments, the histidine buffer is histidine acetate. tion being treated, preferably those with complementary 0390. In some embodiments of any of the formulations, activities that do not adversely affect each other. For example, the Surfactant is polysorbate (e.g., polysorbate 20 or polysor it may be desirable to further provide an additional medica bate 40), poloxamer (e.g. poloxamer 188); Triton; sodium ment (examples of which are provided herein). Such active dodecyl sulfate (SDS); sodium laurel sulfate; or sodium octyl ingredients are Suitably present in combination in amounts glycoside. that are effective for the purpose intended. 0391. In some embodiments of any of the formulations, 0382 Active ingredients may be entrapped in microcap the Surfactant is polysorbate. In some embodiments, the Sules prepared, for example, by coacervation techniques orby polysorbate is present at a concentration of about 0.005% to interfacial polymerization, for example, hydroxymethylcel about 0.1%. In some embodiments, the polysorbate is present lulose or gelatin-microcapsules and poly-(methylmethacy at a concentration of about 0.005%. In some embodiments, late) microcapsules, respectively, in colloidal drug delivery the polysorbate is present at a concentration of about 0.02%. systems (for example, liposomes, albumin microspheres, In some embodiments, the polysorbate is presentata concen microemulsions, nano-particles and nanocapsules) or in mac tration of about 0.04%. In some embodiments, the polysor roemulsions. Such techniques are disclosed in Remington's bate is present at a concentration of about 0.06%. In some Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). embodiments, the polysorbate is polysorbate 20. In some 0383 Sustained-release preparations may be prepared. embodiments, the polysorbate is polysorbate 80. Suitable examples of Sustained-release preparations include 0392. In some embodiments of any of the formulations, semipermeable matrices of solid hydrophobic polymers con the formulation is diluted with a diluent (e.g., 0.9% NaCl). In taining the antibody, which matrices are in the form of shaped some embodiments, the anti-human OX40 agonist antibody articles, e.g. films, or microcapsules. is present at a concentration of about 1 mg/mL. 0393. In particular, provided herein are pharmaceutical 0384 The formulations to be used for in vivo administra formulations comprising (a) any of the anti-human OX40 tion are generally sterile. Sterility may be readily accom agonist antibodies described herein, (b) a polysorbate, plished, e.g., by filtration through sterile filtration mem wherein the polysorbate concentration is about 0.005% to branes. about 0.1%; and (c) a histidine buffer (e.g., a histidine buffer 0385. In some embodiments, provided herein are pharma at a pH between 5.0 and 6.0). ceutical formulations comprising: (a) any of the anti-human 0394. In some embodiments, the pharmaceutical formula OX40 agonist antibodies described herein; (b) a histidine tion comprises (a) any of the anti-human OX40 agonist anti buffer at pH 5.0-6.0. bodies described herein (e.g., at a concentration between 0386. In some embodiments, provided herein are pharma about 10 mg/mL and about 100 mg/mL), (b) a polysorbate, ceutical formulations comprising: (a) any of the anti-human wherein the polysorbate concentration is about 0.02% to OX40 agonist antibodies described herein; (b) a histidine about 0.06%; (c) a histidine buffer (e.g., a histidine buffer at buffer at pH 5.0-6.0; (c) a saccharide; and (d) a surfactant. pH 5.0 to 6.0); and a saccharide, wherein the saccharide 0387. In some embodiments of any of the formulations, concentration is about 120 mM to about 320 mM. In some the anti-human OX40 agonist antibody is present at a con embodiments, the saccharide is Sucrose. centration between about 10 mg/mL and about 100 mg/mL 0395. In some embodiments, the pharmaceutical formula (e.g. about 15 mg/mL, 18 mg/mL, 20 mg/mL, 60 mg/mL, and tion comprises (a) any of the anti-human OX40 agonist anti 75 mg/mL). In some embodiments, the anti-human OX40 bodies described herein at a concentration between about 10 agonist antibody is present at a concentration of about 20 mg/mL and about 100 mg/mL, (b) a polysorbate, wherein the mg/mL. In some embodiments, the anti-human OX40agonist polysorbate concentration is about 0.02% to about 0.06%, antibody is present at a concentration of about 50 mg/mL. In wherein the polysorbate is polysorbate 20 or polysorbate 40: Some embodiments, the anti-human OX40 agonist antibody (c) a histidine acetate buffer at pH 5.0 to 6.0; and a saccharide is present at a concentration of about 60 mg/mL. In some (e.g., Sucrose) at a concentration of about 120 mM to about embodiments, the anti-human OX40 agonist antibody is 320 mM. present at a concentration of about 70 mg/mL. 0396. In some embodiments, the pharmaceutical formula 0388. In some embodiments of any of the formulations, tion comprises (a) any of the anti-human OX40 agonist anti the saccharide is presentata concentration of about 75 mM to bodies described herein, (b) polysorbate 20, wherein the about 360 mM (e.g., about 100 mM, about 120 mM, about polysorbate concentration is about 0.02% to about 0.06%; (c) 240 mM, about 320 mM to about 360 mM). In some embodi a histidine acetate buffer (e.g., a histidine acetate buffer at pH ments, the saccharide is present at a concentration of about 5.0 to 6.0); and (d) sucrose, wherein the sucrose concentration 120 mM. In some embodiments, the saccharide is presentata is about 120 mM to about 320 mM. concentration of about 240 mM. In some embodiments, the 0397. In some embodiments, the pharmaceutical formula saccharide is present at a concentration of about 320 mM. In tion comprises (a) any of the anti-human OX40 agonist anti Some embodiments, the saccharide is a disaccharide. In some bodies described herein, (b) polysorbate 40, wherein the US 2015/0307617 A1 Oct. 29, 2015 polysorbate concentration is about 0.02% to about 0.06%; (c) to minimize aggregation and/or maintain stability upon long a histidine acetate buffer (e.g., a histidine acetate buffer at a term storage and/or during administration (e.g., after dilution pH between 5.0 and 6.0); and sucrose, wherein the sucrose in an IV bag). In some embodiments, the polysorbate concen concentration is about 120 mM to about 320 mM. tration is about 0.005% w/v, about 0.02% w/v, about 0.04% 0398. In some embodiments, the pharmaceutical formula w/v and less than about 0.1% w/v. In some embodiments, the tion comprises (a) any of the anti-human OX40 agonistanti polysorbate concentration is greater than 0.01% w/v and less bodies described herein, (b) polysorbate 20, wherein the than about 0.1% w/v. In some embodiments, the polysorbate polysorbate concentration is about 0.02%; (c) a histidine concentration is about any of 0.005% w/v. about 0.02% w/v. acetate buffer at pH 6.0; and (d) sucrose, wherein the sucrose 0.03% w/v, 0.04% w/v, or 0.05% w/v. In some embodiments, concentration is about 320 mM. the polysorbate is present at a concentration of about 0.04% 0399. In some embodiments, the pharmaceutical formula w/v. In some embodiments, the polysorbate is present at a tion comprises (a) any of the anti-human OX40 agonistanti concentration of about 0.02% w/v. bodies described herein, (b) polysorbate 20, wherein the 0406. The pharmaceutical formulation preferably com polysorbate concentration is about 0.02%; (c) a histidine prises a saccharide. Saccharides include monosaccharides, acetate buffer at pH 5.5; and (d) sucrose, wherein the sucrose disaccharides, trisaccharides, polysaccharides, Sugar alco concentration is about 240 mM. hols, reducing Sugars, nonreducing Sugars, etc. Further 0400. In some embodiments, the pharmaceutical formula examples of Saccharides include, but are not limited to, glu tion comprises (a) any of the anti-human OX40 agonistanti cose, Sucrose, trehalose, lactose, fructose, maltose, dextran, bodies described herein, (b) polysorbate 20, wherein the glycerin, dextran, erythritol, glycerol, arabitol, Sylitol, Sorbi polysorbate concentration is about 0.04%; (c) a histidine tol, mannitol, mellibiose, melezitose, raffinose, mannotriose, acetate buffer at pH 6.0; and (d) sucrose, wherein the sucrose stachyose, maltose, lactulose, maltulose, glucitol, maltitol, concentration is about 120 mM. lactitol, iso-maltulose, etc. In some embodiments, the saccha 04.01. In some embodiments, the pharmaceutical formula ride is a disaccharide. In some embodiments, the Saccharide is tion comprises (a) any of the anti-human OX40 agonistanti a nonreducing disaccharide. In some embodiments, the sac bodies described herein, (b) polysorbate 40, wherein the charide is trehalose. polysorbate concentration is about 0.04%; (c) a histidine 0407. The saccharide is generally included in an amount acetate buffer at pH 5.0; and (d) sucrose, wherein the sucrose which reduces aggregate formation. In some embodiments of concentration is about 240 mM. any of the pharmaceutical formulations described herein, the 0402. In some embodiments, the pharmaceutical formula saccharide is presentata concentration of between about any tion comprises (a) any of the anti-human OX40 agonistanti of 50 mM to 250 mM, 75 mM to 200 mM, 75 mM to 150 mM, bodies described herein, (b) polysorbate 40, wherein the 100 mM to 150 mM, or 110 mM to 130 mM, or 100 mM to polysorbate concentration is about 0.04%; (c) a histidine 320 mM, or 240 mM to 320 mM, or 240 mM to 400 mM. In acetate buffer at pH 6.0; and (d) sucrose, wherein the sucrose Some embodiments, the Saccharide is present at a concentra concentration is about 120 mM. tion greater than about any of 50 mM, 75 mM, 100 mM, 110 0403. In some embodiments, the pharmaceutical formula mM, or 115 mM. In some embodiments, the saccharide is tion is a liquid pharmaceutical formulation. In some embodi presentata concentration of about any of 100 mM, 110 mM, ments, the pharmaceutical formulation is a stable pharmaceu 120 mM, 130 mM, or 140 mM. In some embodiments, the tical formulation. In some embodiments, the pharmaceutical saccharide is present at a concentration of about 120 mM. In formulation is a stable liquid pharmaceutical formulation. Some embodiments of any of the formulations, the saccharide 04.04. In some embodiments of any of the pharmaceutical is presentata concentration of about 75 mM to about 360 mM formulations described herein, the anti-human OX40 agonist (e.g., about 100 mM, about 120 mM, about 240 mM, about antibody of the pharmaceutical formulation is present at a 320 mM to about 360 mM). In some embodiments, the sac concentration between about 10 mg/mL and about 100 charide is present at a concentration of about 240 mM. In mg/mL. In some embodiments, the concentration of the Some embodiments, the Saccharide is present at a concentra human OX40 agonist antibody is between about any of 10 tion of about 320 mM. mg/mL to 50 mg/mL, 10 mg/mL to 75 mg/mL, 25 mg/mL to 0408. The pharmaceutical formulation preferably com 75 mg/mL, 50 mg/mL to 100 mg/mL, 50 mg/mL to 75 prises a histidine buffer. Examples of histidine buffers mg/mL, and/or 75 mg/mL to 100 mg/mL. In some embodi include, but are not limited to, histidine chloride, histidine ments, the concentration of the human OX40 agonist anti Succinate, histidine acetate, histidine phosphate, histidine body is greater than about any of 20 mg/mL, 30 mg/mL, 40 sulfate. In some embodiments, the histidine buffer is histidine mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, or 100 mg/mL. acetate. In some embodiments of any of the pharmaceutical 04.05 The pharmaceutical formulation preferably com formulations described herein, the histidine buffer concentra prises a polysorbate. The polysorbate is generally included in tion is between about any of 1 mM to 50 mM, 1 mM to 35 an amount which reduces aggregate formation (such as that mM, 1 mM to 25 mM, 1 mM to 20 mM, 7.5 mM to 12.5 mM, which occurs upon shaking or shipping). Examples of or 5 mM to 15 mM, 20 mM to 30 mM, 25 mM to 35 mM. In polysorbate include, but are not limited to, polysorbate 20 some embodiments, the histidine buffer concentration is (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 about any of 5 mM, 7.5 mM, 10 mM, 12.5 mM, 15 mM, 20 (polyoxyethylene (20) Sorbitan monopalmitate), polysorbate mM, 25 mM, 30 mM, 35 mM or 40 mM. In some embodi 60 (polyoxyethylene (20) sorbitan monostearate), and/or ments, the histidine buffer concentration is about 10 mM. In polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). some embodiments, the histidine buffer concentration is In some embodiments, the polysorbate is polysorbate 20 about 20 mM. In some embodiments, the histidine buffer (polyoxyethylene (20) Sorbitan monolaurate). In some concentration is about 30 mM. In some embodiments, the embodiments of any of the pharmaceutical formulations histidine buffer concentration is about 40 mM. In some described herein, the polysorbate concentration is sufficient embodiments of any of the pharmaceutical formulations US 2015/0307617 A1 Oct. 29, 2015 42 described herein, the histidine buffer is at a pH of between pH embodiments, depletion is by phagocytosis. Provided is an 5.0 and 6.0, for example, about any of pH 5.0, pH 5.1, pH 5.2, anti-human OX40 agonistantibody for treating an individual pH 5.3, pH 5.4, pH 5.5, pH 5.6, pH 5.7, pH 5.8, pH 5.9 or pH having tumor immunity. 6.0. In some embodiments, the pH is between pH 4.9 to pH 0415. In further aspects, an anti-human OX40 agonist 6.3. antibody for use in treating infection (e.g., with a bacteria or 04.09. The pharmaceutical formulation herein may also virus or other pathogen) is provided. In certain embodiments, contain more than one active compound as necessary for the the invention provides an anti-human OX40 agonistantibody particular indication being treated, preferably those with for use in a method of treating an individual having an infec complementary activities that do not adversely affect each tion comprising administering to the individual an effective other. Such molecules are suitably present in combination in amount of the anti-human agonist OX40 antibody. In some amounts that are effective for the purpose intended. embodiments, the infection is with a virus and/or a bacteria. 0410. Further, provided herein are vials and methods of In some embodiments, the infection is with a pathogen. filing a vial comprising a pharmaceutical formulation 0416) Inafurther aspect, the invention provides for the use described herein. In some embodiments, the pharmaceutical of an anti-OX40 antibody in the manufacture or preparation formulation is provided inside a vial with a stopper pierceable of a medicament. In one embodiment, the medicament is for by a syringe, preferably in aqueous form. The vial is desirably treatment of cancer. In a further embodiment, the medicament stored at about 2-8°C. as well as up to 30°C. for 24 hours until is for use in a method of treating cancer comprising admin it is administered to a subject in need thereof. The vial may for istering to an individual having cancer an effective amount of example be a 15 cc vial (for example for a 200 mg dose). the medicament. In one such embodiment, the method further 0411. The pharmaceutical formulation for administration comprises administering to the individual an effective is preferably a liquid formulation (not lyophilized) and has amount of at least one additional therapeutic agent, e.g., as not been subjected to prior lyophilization. While the pharma described below. ceutical formulation may be lyophilized, preferably it is not. 0417. In one aspect, the medicament is for use in enhanc In some embodiments of any of the pharmaceutical formula ing immune function (e.g., by upregulating cell-mediated tions, the pharmaceutical formulation, the pharmaceutical immune responses) in an individual having cancer compris formulation is a lyophilized pharmaceutical formulation. In ing administering to the individual an effective amount of the Some embodiments, the pharmaceutical formulation is a liq medicament. In one aspect, the medicament is for use in uid formulation. In some embodiments, the pharmaceutical enhancing T cell function in an individual having cancer formulation does not contain a tonicifying amount of a salt comprising administering to the individual an effective Such as Sodium chloride. In some embodiments of any of the amount of the medicament. In some embodiments, the T cell pharmaceutical formulations, the pharmaceutical formula dysfunctional disorder is cancer. In one aspect, the medica tion is diluted. ment is for use in depleting human OX40-expressing cells (e.g., cell expressing high OX40, e.g., OX40 expressing T G. Therapeutic Methods and Compositions cells) comprising administering to the individual an effective 0412. Any of the anti-human OX40 antibodies provided amount of the medicament. In some embodiments, depletion herein may be used in therapeutic methods. is by ADCC. In some embodiments, depletion is by phago 0413. In one aspect, an anti-human OX40 agonist anti cytosis. In one aspect, the medicament is for treating an body for use as a medicament is provided. In further aspects, individual having tumor immunity. an anti-human OX40 agonist antibody for use in treating 0418. In further aspects, the medicament is for use in cancer is provided. In certain embodiments, an anti-human treating infection (e.g., with a bacteria or virus or other patho OX40 agonist antibody for use in a method of treatment is gen) is provided. In certain embodiments, the medicament is provided. In certain embodiments, the invention provides an for use in a method of treating an individual having an infec anti-human OX40 agonist antibody for use in a method of tion comprising administering to the individual an effective treating an individual having cancer comprising administer amount of the medicament. In some embodiments, the infec ing to the individual an effective amount of the anti-human tion is with virus and/or bacteria. In some embodiments, the agonist OX40 antibody. In one such embodiment, the method infection is with a pathogen. further comprises administering to the individual an effective 0419. In a further aspect, the invention provides a method amount of at least one additional therapeutic agent, e.g., as for treating a cancer. In one embodiment, the method com described below. prises administering to an individual having Such cancer an 0414. In one aspect, provided is an anti-human OX40 ago effective amount of an anti-OX40 antibody. In one such nistantibody for use in enhancing immune function (e.g., by embodiment, the method further comprises administering to upregulating cell-mediated immune responses) in an indi the individual an effective amount of at least one additional vidual having cancer comprising administering to the indi therapeutic agent, as described below. An “individual vidual an effective amount of the anti-human agonist OX40 according to any of the above embodiments may be a human. antibody. In one aspect, provided is an anti-human OX40 0420. In one aspect, provided is a method for enhancing agonist antibody for use in enhancing T cell function in an immune function (e.g., by upregulating cell-mediated individual having cancer comprising administering to the immune responses) in an individual having cancer compris individual an effective amount of the anti-human agonist ing administering to the individual an effective amount of the OX40 antibody. In one aspect, provided are an anti-human anti-humanagonist OX40 antibody. In one aspect, provided is OX40 agonist antibody for use in depleting human OX40 a method for enhancing T cell function in an individual hav expressing cells (e.g., OX40 expressing T cells, e.g., OX40 ing cancer comprising administering to the individual an expressing Treg) comprising administering to the individual effective amount of the anti-human agonist OX40 antibody. an effective amount of the anti-human agonist OX40 anti In one aspect, provided are a method for depleting human body. In some embodiments, depletion is by ADCC. In some OX40-expressing cells (e.g., cells that express high level of US 2015/0307617 A1 Oct. 29, 2015 OX40, e.g., OX40 expressing T cells) comprising adminis macroglobulinemia, h) acute lymphocytic leukemia (ALL), tering to the individual an effective amount of the anti-human chronic lymphocytic leukemia (CLL)/small lymphocytic agonist OX40 antibody. In some embodiments, depletion is lymphoma (SLL). B cell prolymphocytic leukemia, i) plasma by ADCC. In some embodiments, depletion is by phagocy cell neoplasms, plasma cell myeloma, multiple myeloma, tosis. Provided is an anti-human OX40 agonist antibody for plasmacytoma, and/orj) Hodgkin’s disease. treating an individual having tumor immunity. 0423. In some embodiments of any of the methods, the 0421. In some embodiments, examples of cancer further cancer is a B-cell proliferative disorder. In some embodi include, but are not limited to, B-cell lymphoma (including ments, the B-cell proliferative disorder is lymphoma, non low grade/follicular non-Hodgkin’s lymphoma (NHL); small Hodgkins lymphoma (NHL), aggressive NHL, relapsed lymphocytic (SL) NHL; intermediate grade/follicular NHL: aggressive NHL, relapsed indolent NHL, refractory NHL, intermediate grade diffuse NHL; high grade immunoblastic refractory indolent NHL, chronic lymphocytic leukemia NHL: high grade lymphoblastic NHL; high grade small non (CLL), Small lymphocytic lymphoma, leukemia, hairy cell cleaved cell NHL; bulky disease NHL; mantle cell lym leukemia (HCL), acute lymphocytic leukemia (ALL), or phoma; AIDS-related lymphoma; and Waldenstrom's Mac mantle cell lymphoma. In some embodiments, the B-cell roglobulinemia); chronic lymphocytic leukemia (CLL); proliferative disorder is NHL, such as indolent NHL and/or acute lymphoblastic leukemia (ALL); Hairy cell leukemia; aggressive NHL. In some embodiments, the B-cell prolifera chronic myeloblastic leukemia; and post-transplant lym tive disorder is indolent follicular lymphoma or diffuse large phoproliferative disorder (PTLD), as well as abnormal vas B-cell lymphoma. cular proliferation associated with phakomatoses, edema 0424. In a further aspect, the invention provides pharma (such as that associated with brain tumors), B-cell prolifera ceutical formulations comprising any of the anti-OX40 anti tive disorders, and Meigs' syndrome. More specific examples bodies provided herein, e.g., for use in any of the above include, but are not limited to, relapsed or refractory NHL, therapeutic methods. In one embodiment, a pharmaceutical front line low grade NHL, Stage III/IV NHL, chemotherapy formulation comprises any of the anti-OX40 antibodies pro resistant NHL, precursor B lymphoblastic leukemia and/or vided herein and a pharmaceutically acceptable carrier. In lymphoma, Small lymphocytic lymphoma, B-cell chronic another embodiment, a pharmaceutical formulation com lymphocytic leukemia and/or prolymphocytic leukemia and/ prises any of the anti-OX40 antibodies provided herein and at or Small lymphocytic lymphoma, B-cell prolymphocytic least one additional therapeutic agent, e.g., as described lymphoma, immunocytoma and/or lymphoplasmacytic lym below. phoma, lymphoplasmacytic lymphoma, marginal Zone B-cell 0425. In some embodiments of any of the methods of the lymphoma, splenic marginal Zone lymphoma, extranodal invention, the anti-human OX40 agonist antibodies inhibits marginal Zone-MALT lymphoma, nodal marginal Zone lym tumor immunity by inhibiting Treg function (e.g., inhibiting phoma, hairy cell leukemia, plasmacytoma and/or plasma the Suppressive function of Tregs), killing OX40 expressing cell myeloma, low grade/follicular lymphoma, intermediate cells (e.g., cells that express high levels of OX40), increasing grade/follicular NHL, mantle cell lymphoma, follicle center effector T cell function and/or increasing memory T cell lymphoma (follicular), intermediate grade diffuse NHL, dif function. In some embodiments of any of the methods of the fuse large B-cell lymphoma, aggressive NHL (including invention, the anti-human OX40 agonistantibodies treat can aggressive front-line NHL and aggressive relapsed NHL). cer by inhibiting Treg function (e.g., inhibiting the Suppres NHL relapsing after or refractory to autologous stem cell sive function of Tregs), killing OX40 expressing cells (e.g., transplantation, primary mediastinal large B-cell lymphoma, cells that express high levels of OX40), increasing effector T primary effusion lymphoma, high grade immunoblastic cell function and/or increasing memory T cell function. In NHL, high grade lymphoblastic NHL, high grade small non some embodiments of any of the methods of the invention, the cleaved cell NHL, bulky disease NHL, Burkitt's lymphoma, anti-human OX40 agonist antibodies enhance immune func precursor (peripheral) large granular lymphocytic leukemia, tion by inhibiting Treg function (e.g., inhibiting the Suppres mycosis fungoides and/or Sezary syndrome, skin (cutaneous) sive function of Tregs), killing OX40 expressing cells (e.g., lymphomas, anaplastic large cell lymphoma, angiocentric cells that express high levels of OX40), increasing effector T lymphoma. cell function and/or increasing memory T cell function. In 0422. In some embodiments, examples of cancer further some embodiments of any of the methods of the invention, the include, but are not limited to, B-cell proliferative disorders, anti-human OX40 agonistantibodies enhance T cell function which further include, but are not limited to, lymphomas by inhibiting Treg function (e.g., inhibiting the Suppressive (e.g., B-Cell Non-Hodgkin’s lymphomas (NHL)) and lym function of Tregs), killing OX40 expressing cells (e.g., cells phocytic leukemias. Such lymphomas and lymphocytic leu that express high levels of OX40), increasing effector T cell kemias include e.g. a) follicular lymphomas, b) Small Non function and/or increasing memory T cell function. Cleaved Cell Lymphomas/Burkitt's lymphoma (including 0426 In some embodiments of any of the methods, the endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma anti-human OX40 agonistantibody is a depleting anti-human and Non-Burkitt's lymphoma), c) marginal Zone lymphomas agonist antibody. In some embodiments, treatment with the (including extranodal marginal Zone B-cell lymphoma (Mu anti-human OX40 agonist antibody results in cell depletion cosa-associated lymphatic tissue lymphomas, MALT), nodal (e.g., depletion of OX40-expressing cells, e.g., depletion of marginal Zone B-cell lymphoma and splenic marginal Zone cells that express high levels of OX40). In some embodi lymphoma), d) Mantle cell lymphoma (MCL), e) Large Cell ments, depletion is by ADCC. In some embodiments, deple Lymphoma (including B-cell diffuse large cell lymphoma tion is by phagocytosis. (DLCL). Diffuse Mixed Cell Lymphoma, Immunoblastic 0427. In some embodiments of any of the methods, the Lymphoma, Primary Mediastinal B-Cell Lymphoma, Angio anti-human OX40 agonist antibody inhibits Treg function, centric Lymphoma-Pulmonary B-Cell Lymphoma), f) hairy e.g., by inhibiting Treg Suppression of effector and/or cell leukemia, g) lymphocytic lymphoma, Waldenstrom's memory T cell function (in some embodiments, effector T US 2015/0307617 A1 Oct. 29, 2015 44 cell and/or memory T cell proliferation and/or cytokine secre (e.g., a DANA or N297G mutation) does not possess substan tion), relative to Treg function prior to administration of the tial activity (e.g., CD4+ effector T cell function, e.g., prolif OX40 agonist antibody. In some embodiments of any of the eration). methods, the anti-human OX40 agonist antibody increases 0431. In some embodiments of any of the methods of the effector T cell proliferation, relative to effector T cell prolif invention, antibody cross-linking is required for anti-human eration prior to administration of the OX40 agonistantibody. OX40 agonist antibody function. In some embodiments, In some embodiments of any of the methods, the anti-human function is stimulation of CD4+ effector T cell proliferation. OX40 agonist antibody increases memory T cell prolifera In some embodiments, antibody cross-linking is determined tion, relative to memory T cell proliferation prior to admin by providing anti-human OX40 agonistantibody adhered on istration of the OX40 agonistantibody. In some embodiments a Solid Surface (e.g., a cell culture plate). In some embodi of any of the methods, the anti-human OX40 agonistantibody ments, antibody cross-linking is determined by introducing a increases effector T cell cytokine production (e.g., gamma mutation in the antibody’s IgG1 Fc portion (e.g., a DANA or interferon production), relative to effector T cell cytokine N297S mutation) and testing function of the mutant antibody. production prior to administration of the OX40 agonist anti 0432. In some embodiments of any of the methods, the body. In some embodiments of any of the methods, the anti memory T cells in the individual have enhanced proliferation human OX40 agonist antibody increases memory T cell and/or cytokine secretion relative to prior to the administra cytokine production (e.g., gamma interferon production), tion of the anti-human OX40 agonist antibody. In some relative to memory T cell cytokine production prior to admin embodiments, the number of memory T cells is elevated istration of the OX40 agonistantibody. In some embodiments relative to prior to administration of the anti-human OX40 of any of the methods, the anti-human OX40 agonistantibody agonist antibody. In some embodiments, memory T cell increases CD4+ effector T cell proliferation and/or CD8+ cytokine secretion (level) is elevated relative to prior to effector T cell proliferation relative to CD4+ effector T cell administration of the anti-human OX40 agonist antibody. In proliferation and/or CD8+ effector T cell proliferation prior some embodiments of any of the methods, the Treg in the to administration of the OX40 agonist antibody. In some individual have decreased inhibition of effector T cell func embodiments of any of the methods, the anti-human OX40 tion (e.g., proliferation and/or cytokine secretion) relative to agonistantibody increases memory T cell proliferation (e.g., prior to the administration of the anti-human OX40 agonist CD4+ memory T cell proliferation), relative to memory T cell antibody. In some embodiments, the number of effector T proliferation prior to administration of the OX40 agonistanti cells is elevated relative to prior to administration of the body. In some embodiments, the CD4+ effector T cells in the anti-human OX40 agonist antibody. In some embodiments, individual have enhanced proliferation, cytokine secretion effector T cell cytokine secretion (level) is elevated relative to and/or cytolytic activity relative to proliferation, cytokine prior to administration of the anti-human OX40 agonistanti secretion and/or cytolytic activity prior to the administration body. of the anti-human OX40 agonist antibody. 0433. In some embodiments of any of the methods of the 0428. In some embodiments of any of the methods of the invention, the number of intratumoral (infiltrating) CD4+ invention, the number of CD4+ effector T cells is elevated effector T cells (e.g., total number of CD4+ effector T cells, or relative to prior to administration of the anti-human OX40 e.g., percentage of CD4+ cells in CD45+ cells) is elevated agonistantibody. In some embodiments, CD4+ effector T cell relative to prior to administration of the anti-human OX40 cytokine secretion is elevated relative to prior to administra agonistantibody. In some embodiments of any of the methods tion of the anti-human OX40 agonist antibody. In some of the invention, number of intratumoral (infiltrating) CD4+ embodiments of any of the methods, the CD8+ effector T effector T cells that express gamma interferon (e.g., total cells in the individual have enhanced proliferation, cytokine gamma interferon expressing CD4+ cells, or e.g., percentage secretion and/or cytolytic activity relative to prior to the of gamma interferon expressing CD4+ cells in total CD4+ administration of the anti-human OX40 agonist antibody. In cells) is elevated relative to prior to administration anti-hu some embodiments, the number of CD8+ effector T cells is man OX40 agonist antibody. elevated relative to prior to administration of the anti-human 0434 In some embodiments of any of the methods of the OX40 agonistantibody. In some embodiments, CD8+ effec invention, the number of intratumoral (infiltrating) CD8+ tor T cell cytokine secretion is elevated relative to prior to effector T cells (e.g., total number of CD8+ effector T cells, or administration of the anti-human OX40 agonist antibody. e.g., percentage of CD8+ in CD45+ cells) is elevated relative 0429. In some embodiments of any of the methods of the to prior to administration of anti-human OX40 agonist anti invention, the anti-human OX40 agonist antibody binds body. In some embodiments of any of the methods of the human effector cells, e.g., binds FcyR expressed by human invention, number of intratumoral (infiltrating) CD8+ effec effector cells. In some embodiments, the human effector cell tor T cells that express gamma interferon (e.g., percentage of performs ADCC effector function. In some embodiments, the CD8+ cells that express gamma interferon in total CD8+ human effector cell performs phagocytosis effector function. cells) is increased relative to prior to administration of anti 0430. In some embodiments of any of the methods of the human OX40 agonist antibody. invention, the anti-human OX40 agonistantibody comprising 0435. In some embodiments of any of the methods of the a variant IgG1 Fc polypeptide comprising a mutation that invention, the number of intratumoral (infiltrating) Treg (e.g., eliminates binding to human effector cells (e.g., a DANA or total number of Treg or e.g., percentage of Fox3p-- cells in N297G mutation) has diminished activity (e.g., CD4+ effec CD4+ cells) is reduced relative to prior to administration of tor T cell function, e.g., proliferation), relative to anti-human anti-human OX40 agonist antibody. OX40 agonist antibody comprising native sequence IgG1 Fc 0436. In some embodiments of any of the methods of the portion. In some embodiment, the anti-human OX40 agonist invention, administration of anti-human OX40 agonist anti antibody comprising a variant IgG1 Fc polypeptide compris body is in combination with administration of a tumor anti ing a mutation that eliminates binding to human effector cells gen. In some embodiments, the tumor antigen comprises US 2015/0307617 A1 Oct. 29, 2015 protein. In some embodiments, the tumor antigen comprises Pfizer), Afinitor (everolimus, Novartis). Nexavar (Sorafenib, nucleic acid. In some embodiments, the tumor antigen is a Onyx/Bayer). Votrient, Pazopanib, axitinib, IMA-901, AGS tumor cell. 003, cabozantinib, Vinflunine, Hsp90 inhibitor (e.g., apa 0437. In some embodiments of any of the methods of the torsin), Ad-GM-CSF (CT-0070), Temazolomide, IL-2, IFNa, invention, the cancer displays human effector cells (e.g., is vinblastine, Thalomid, dacarbazine, cyclophosphamide, infiltrated by human effector cells). Methods for detecting lenalidomide, azacytidine, lenalidomide, bortezomid (VEL human effector cells are well known in the art, including, e.g., CADE), amrubicine, carfilzomib, pralatrexate, and/or enZas by IHC. In some embodiments, the cancer display high levels taurin. of human effector cells. In some embodiments, human effec tor cells are one or more of NK cells, macrophages, mono 0444. In some embodiments, an anti-human OX40 agonist cytes. In some embodiments, the cancer is any cancer antibody may be administered in conjunction with a PD-1 described herein. In some embodiments, the cancer is non axis binding antagonist. A PD-1 axis binding antagonist small cell lung cancer (NSCLC), glioblastoma, neuroblas includes but is not limited to a PD-1 binding antagonist, a toma, melanoma, breast carcinoma (e.g. triple-negative PD-L1 binding antagonist and a PD-L2 binding antagonist. breast cancer), gastric cancer, colorectal cancer (CRC), or Alternative names for “PD-1 include CD279 and SLEB2. hepatocellular carcinoma. Alternative names for “PD-L1 include B7-H1, B7-4, 0438. In some embodiments of any of the methods of the CD274, and B7-H. Alternative names for “PD-L2 include invention, the cancer displays cells expressing FcR (e.g., is B7-DC, Btdc, and CD273. In some embodiments, PD-1, PD infiltrated by cells expressing FcR). Methods for detecting L1, and PD-L2 are human PD-1, PD-L1 and PD-L2. In some FcR are well known in the art, including, e.g., by IHC. In embodiments, the PD-1 binding antagonist is a molecule that Some embodiments, the cancer display high levels of cells inhibits the binding of PD-1 to its ligand binding partners. In expressing FcR. In some embodiments, FcR is FcyR. In some a specific aspect the PD-1 ligand binding partners are PD-L1 embodiments, FcR is activating FcyR. In some embodiments, and/or PD-L2. In another embodiment, a PD-L1 binding the cancer is non-Small cell lung cancer (NSCLC), glioblas antagonist is a molecule that inhibits the binding of PD-L1 to toma, neuroblastoma, melanoma, breast carcinoma (e.g. its binding partners. In a specific aspect, PD-L1 binding part triple-negative breast cancer), gastric cancer, colorectal can ners are PD-1 and/or B7-1. In another embodiment, the PD cer (CRC), or hepatocellular carcinoma. L2 binding antagonist is a molecule that inhibits the binding 0439. An “individual' according to any of the above of PD-L2 to its binding partners. In a specific aspect, a PD-L2 embodiments is preferably a human. binding partner is PD-1. The antagonist may be an antibody, 0440 Antibodies of the invention can be used either alone an antigen binding fragment thereof, an immunoadhesin, a or in combination with other agents in a therapy. For instance, fusion protein, or oligopeptide. In some embodiments, the an antibody of the invention may be co-administered with at PD-1 binding antagonist is an anti-PD-1 antibody (e.g., a least one additional therapeutic agent. human antibody, a humanized antibody, or a chimeric anti 0441 Such combination therapies noted above encompass body). In some embodiments, the anti-PD-1 antibody is combined administration (where two or more therapeutic selected from the group consisting of MDX-1 106 (nivol agents are included in the same or separate formulations), and umab, OPDIVO), Merck 3475 (MK-3475, pembrolizumab, separate administration, in which case, administration of the KEYTRUDA) and CT-011 (Pidilizumab). In some embodi antibody of the invention can occur prior to, simultaneously, ments, the PD-1 binding antagonist is an immunoadhesin and/or following, administration of the additional therapeutic (e.g., an immunoadhesin comprising an extracellular or PD-1 agent or agents. In one embodiment, administration of the binding portion of PD-L1 or PD-L2 fused to a constant region anti-OX40 antibody and administration of an additional (e.g., an Fc region of an immunoglobulin sequence). In some therapeutic agent occur within about one month, or within embodiments, the PD-1 binding antagonist is AMP-224. In about one, two or three weeks, or within about one, two, three, Some embodiments, the PD-L1 binding antagonist is anti four, five, or six days, of each other. Antibodies of the inven PD-L1 antibody. In some embodiments, the anti-PD-L1 bind tion can also be used in combination with radiation therapy. ing antagonist is selected from the group consisting of 0442. In some embodiments, an anti-human OX40agonist YW243.55.S70, MPDL3280A, MEDI4736 and MDX-1105. antibody may be administered in conjunction with a chemo MDX-1105, also known as BMS-93.6559, is an anti-PD-L1 therapy or chemotherapeutic agent. In some embodiments, an antibody described in WO2007/005874. Antibody YW243. anti-human OX40 agonist antibody may be administered in 55.S70 (heavy and light chain variable region sequences conjunction with a radiation therapy or radiotherapeutic shown in SEQID Nos. 20 and 21, respectively) is an anti-PD agent. In some embodiments, an anti-human OX40 agonist L1 described in WO 2010/077634 A1. MDX-1 106, also antibody may be administered in conjunction with a targeted known as MDX-1 106-04, ONO-4538, BMS-936558 or niv therapy or targeted therapeutic agent. In some embodiments, olumab, is an anti-PD-1 antibody described in WO2006/ an anti-human OX40 agonist antibody may be administered 121168. Merck 3475, also known as MK-3475, SCH-900475 in conjunction with an immunotherapy or immunotherapeu or pembrolizumab, is an anti-PD-1 antibody described in tic agent, for example a monoclonal antibody. WO2009/114335. CT-011, also known as hBAT, hEBAT-1 or 0443) In some embodiments, an anti-human OX40agonist pidilizumab, is an anti-PD-1 antibody described in WO2009/ antibody may be administered in conjunction with a PARP 101611. AMP-224, also known as B7-DCIg, is a PD-L2-Fc inhibitor (e.g., Olaparanib, Rucaparib, Niraparib, Cediranib, fusion soluble receptor described in WO2010/027827 and BMN673, Veliparib), Trabectedin, nab-paclitaxel (albumen WO2011/066342. In some embodiments, the anti-PD-1 anti bound paclitaxel, ABRAXANE), Trebananib, Pazopanib, body is MDX-1106. Alternative names for “MDX-1106” Cediranib, Palbociclib, everolimus, fluoropyrimidine (e.g., include MDX-1 106-04, ONO-4538, BMS-936558 or nivol FOLFOX, FOLFIRI), IFL, regorafenib, Reolysin, Alimta, umab. In some embodiments, the anti-PD-1 antibody is niv Zykadia, Sutent, Torisel (temsirolimus), Inlyta (axitinib, olumab (CAS Registry Number: 94.6414-94-4). US 2015/0307617 A1 Oct. 29, 2015 46 0445. In some embodiments, an anti-human OX40agonist human OX40 agonist antibody may be administered in antibody may be administered in conjunction with an agonist conjunction with an antagonist directed against CD38. In directed against an activating co-stimulatory molecule. In Some embodiments, an anti-human OX40 agonist antibody Some embodiments, an activating co-stimulatory molecule may be administered in conjunction with daratumumab. may include CD40, CD226, CD28, GITR, CD137, CD27, HVEM, or CD127. In some embodiments, the agonist 0449 In some embodiments, an anti-human OX40agonist directed against an activating co-stimulatory molecule is an antibody may be administered in conjunction with an agonist agonist antibody that binds to CD40, CD226, CD28, OX40, directed against CD137 (also known as TNFRSF9, 4-1 BB, or GITR, CD137, CD27, HVEM, or CD127. In some embodi ILA), e.g., an activating antibody. In some embodiments, an ments, an anti-human OX40 agonistantibody may be admin anti-human OX40 agonist antibody may be administered in istered in conjunction with an antagonist directed against an conjunction with urelumab (also known as BMS-663.513). In inhibitory co-stimulatory molecule. In some embodiments, Some embodiments, an anti-human OX40 agonist antibody an inhibitory co-stimulatory molecule may include CTLA-4 may be administered in conjunction with an agonist directed (also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG against CD40, e.g., an activating antibody. In some embodi 3, B7-H3, B7-H4, IDO, TIGIT, MICA/B, or arginase. In some ments, an anti-human OX40 agonistantibody may be admin embodiments, the antagonist directed against an inhibitory istered in conjunction with CP-870893. In some embodi co-stimulatory molecule is an antagonist antibody that binds ments, an anti-human OX40 agonist antibody may be to CTLA-4, PD-1, TIM-3, BTLA, VISTA, LAG-3 (e.g., administered in conjunction with an agonist directed against LAG-3-IgG fusion protein (IMP321)), B7-H3, B7-H4, IDO, OX40 (also known as CD134), e.g., an activating antibody. In TIGIT, MICA/B, or arginase. Some embodiments, an anti-human OX40 agonist antibody 0446. In some embodiments, an anti-human OX40agonist may be administered in conjunction with a different anti antibody may be administered in conjunction with an antago OX40 antibody (e.g., AgonCX). In some embodiments, an nist directed against CTLA-4 (also known as CD152), e.g., a anti-human OX40 agonist antibody may be administered in blocking antibody. In some embodiments, an anti-human OX40 agonist antibody may be administered in conjunction conjunction with an agonist directed against CD27, e.g., an with ipilimumab (also known as MDX-010, MDX-101, or activating antibody. In some embodiments, an anti-human Yervoy(R). In some embodiments, an anti-human OX40 ago OX40 agonist antibody may be administered in conjunction nistantibody may be administered in conjunction with trem with CDX-1127. In some embodiments, an anti-human elimumab (also known as ticilimumab or CP-675.206). In OX40 agonist antibody may be administered in conjunction Some embodiments, an anti-human OX40 agonist antibody with an antagonist directed against indoleamine-2,3-dioxy may be administered in conjunction with an antagonist genase (IDO). In some embodiments, with the IDO antago directed against B7-H3 (also known as CD276), e.g., a block nist is 1-methyl-D-tryptophan (also known as 1-D-MT). ing antibody. In some embodiments, an anti-human OX40 0450. In some embodiments, an anti-human OX40agonist agonist antibody may be administered in conjunction with antibody may be administered in conjunction with an agonist MGA271. In some embodiments, an anti-human OX40 ago directed against CD137 (also known as TNFRSF9, 4-1 BB, or nist antibody may be administered in conjunction with an ILA), e.g., an activating antibody. In some embodiments, an antagonist directed against a TGF beta, e.g., metelimumab anti-human OX40 agonist antibody may be administered in (also known as CAT-192), fresolimumab (also known as conjunction with urelumab (also known as BMS-663.513). In GC1008), or LY21572.99. Some embodiments, an anti-human OX40 agonist antibody 0447. In some embodiments, an anti-human OX40agonist may be administered in conjunction with an agonist directed antibody may be administered in conjunction with a treat against CD40, e.g., an activating antibody. In some embodi ment comprising adoptive transfer of a T cell (e.g., a cytotoxic ments, an anti-human OX40 agonistantibody may be admin T cellor CTL) expressing a chimericantigen receptor (CAR). istered in conjunction with CP-870893 or RO7009789. In In some embodiments, an anti-human OX40 agonistantibody Some embodiments, an anti-human OX40 agonist antibody may be administered in conjunction with UCART19. In some may be administered in conjunction with an agonist directed embodiments, an anti-human OX40 agonistantibody may be against OX40 (also known as CD134), e.g., an activating administered in conjunction with WT128Z. In some embodi antibody). In some embodiments, an anti-human OX40 ago ments, an anti-human OX40 agonistantibody may be admin nist antibody may be administered in conjunction with an istered in conjunction with KTE-C19 (Kite). In some embodi agonist directed against CD27, e.g., an activating antibody. In ments, an anti-human OX40 agonist antibody may be Some embodiments, an anti-human OX40 agonist antibody administered in conjunction with CTL019 (Novartis). In may be administered in conjunction with CDX-1127 (also Some embodiments, an anti-human OX40 agonist antibody known as Varlilumab). In some embodiments, an anti-human may be administered in conjunction with a treatment com OX40 agonist antibody may be administered in conjunction prising adoptive transfer of a T cell comprising a dominant with an antagonist directed against indoleamine-2,3-dioxy negative TGFbeta receptor, e.g., a dominant-negative TGF genase (IDO). In some embodiments, with the IDO antago beta type II receptor. In some embodiments, an anti-human nist is 1-methyl-D-tryptophan (also known as 1-D-MT). In OX40 agonist antibody may be administered in conjunction Some embodiments, the IDO antagonist is an IDO antagonist with a treatment comprising a HERCREEM protocol (see, shown in WO2010/005958 (the contents of which are e.g., ClinicalTrials.gov Identifier NCT00889954). expressly incorporated by record herein). In some embodi 0448. In some embodiments, an anti-human OX40agonist ments the IDO antagonist is 4-(2-(Aminosulfonyl)aminol antibody may be administered in conjunction with an antago ethylamino)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-1.2, nist directed against CD19. In some embodiments, an anti 5-oxadiazole-3-carboximidamide (e.g., as described in human OX40 agonist antibody may be administered in con Example 23 of WO2010/005958). In some embodiments the junction with MOR00208. In some embodiments, an anti IDO antagonist is US 2015/0307617 A1 Oct. 29, 2015 47 Some embodiments, an anti-human OX40 agonist antibody OH F may be administered in conjunction with a VEGF Receptor N fusion protein. In some embodiments, an anti-human OX40 agonist antibody may be administered in conjunction with HN1N1\-1W N OC Br. aflibercept. In some embodiments, an anti-human OX40 ago nist antibody may be administered in conjunction with Ziv N No1 N aflibercept (also known as VEGF Trap or Zaltrap(R). In some embodiments, an anti-human OX40 agonistantibody may be administered in conjunction with a bispecific antibody In some embodiments, the IDO antagonist is INCB24360. In directed against VEGF and Ang2. In some embodiments, an some embodiments, the IDO antagonist is Indoximod (the D anti-human OX40 agonist antibody may be administered in isomer of 1-methyl-tryptophan). In some embodiments, an conjunction with RG7221 (also known as Vanucizumab). In anti-human OX40 agonist antibody may be administered in Some embodiments, an anti-human OX40 agonist antibody conjunction with an antibody-drug conjugate. In some may be administered in conjunction with an angiogenesis embodiments, the antibody-drug conjugate comprises mer inhibitor and in conjunction with a PD-1 axis binding antago tansine or monomethyl auristatin E (MMAE). In some nist (e.g., a PD-1 binding antagonist Such as an anti-PD-1 embodiments, an anti-human OX40 agonistantibody may be antibody, a PD-L1 binding antagonist such as an anti-PD-L1 administered in conjunction with an anti-NaPi2b antibody antibody, and a PD-L2 binding antagonist Such as an anti-PD MMAE conjugate (also known as DNIB0600A, RG7599 or L2 antibody). In some embodiments, an anti-human OX40 lifastuzumab vedotin). In some embodiments, an anti-human agonist antibody may be administered in conjunction with OX40 agonist antibody may be administered in conjunction bevacizumab and a PD-1 axis binding antagonist (e.g., a PD-1 with trastuzumab emtansine (also known as T-DM1, ado binding antagonist such as an anti-PD-1 antibody, a PD-L1 trastuzumab emtansine, or KADCYLAR), Genentech). In binding antagonist Such as an anti-PD-L1 antibody, and a Some embodiments, an anti-human OX40 agonist antibody PD-L2 binding antagonist such as an anti-PD-L2 antibody). may be administered in conjunction with an anti-MUC16 In some embodiments, an anti-human OX40 agonistantibody antibody-MMAE conjugate, DMUC5754A. In some may be administered in conjunction with bevacizumab and embodiments, an anti-human OX40 agonistantibody may be MDX-1106 (nivolumab, OPDIVO). In some embodiments, administered in conjunction with an anti-MUC16 antibody an anti-human OX40 agonist antibody may be administered MMAE conjugate, DMUC4064A. In some embodiments, an in conjunction with bevacizumab and Merck 3475 (MK anti-human OX40 agonist antibody may be administered in 3475, pembrolizumab, KEYTRUDA). In some embodi conjunction with an antibody-drug conjugate targeting the ments, an anti-human OX40 agonistantibody may be admin endothelin B receptor (EDNBR), e.g., an antibody directed istered in conjunction with bevacizumab and CT-011 against EDNBR conjugated with MMAE. In some embodi (Pidilizumab). In some embodiments, an anti-human OX40 ments, an anti-human OX40 agonistantibody may be admin agonist antibody may be administered in conjunction with istered in conjunction with an antibody-drug conjugate tar bevacizumab and YW243.55.S70. In some embodiments, an geting the lymphocyte antigen 6 complex, locus E (Ly6E), anti-human OX40 agonist antibody may be administered in e.g., an antibody directed against Ly6E conjugated with conjunction with bevacizumab and MPDL3280A. In some MMAE, (also known as DLYE5953A). In some embodi embodiments, an anti-human OX40 agonistantibody may be ments, an anti-human OX40 agonistantibody may be admin administered in conjunction with bevacizumab and istered in conjunction with polatuZumab vedotin. In some MEDI4736. In some embodiments, an anti-human OX40 embodiments, an anti-human OX40 agonistantibody may be agonist antibody may be administered in conjunction with administered in conjunction with an antibody-drug conjugate bevacizumab and MDX-1105. targeting CD30. In some embodiments, an anti-human OX40 0452. In some embodiments, an anti-human OX40agonist agonist antibody may be administered in conjunction with antibody may be administered in conjunction with an antine ADCETRIS (also known as brentuximab vedotin). In some oplastic agent. In some embodiments, an anti-human OX40 embodiments, an anti-human OX40 agonistantibody may be agonistantibody may be administered in conjunction with an administered in conjunction with polatuZumab vedotin. agent targeting CSF-1R (also known as M-CSFR or CD115). 0451. In some embodiments, an anti-human OX40agonist In some embodiments, an anti-human OX40 agonistantibody antibody may be administered in conjunction with an angio may be administered in conjunction with anti-CSF-1R anti genesis inhibitor. In some embodiments, an anti-human body (also known as IMC-CS4 or LY3022855) In some OX40 agonist antibody may be administered in conjunction embodiments, an anti-human OX40 agonistantibody may be with an antibody directed against a VEGF, e.g., VEGF-A. In administered in conjunction with anti-CSF-1R antibody, Some embodiments, an anti-human OX40 agonist antibody RG7155 (also known as RO5509554 or emactuzumab). In may be administered in conjunction with bevacizumab (also Some embodiments, an anti-human OX40 agonist antibody known as AVASTINR), Genentech). In some embodiments, may be administered in conjunction with an interferon, for an anti-human OX40 agonist antibody may be administered example interferon alpha or interferon gamma. In some in conjunction with an antibody directed againstangiopoietin embodiments, an anti-human OX40 agonistantibody may be 2 (also known as Ang2). In some embodiments, an anti administered in conjunction with Rolferon-A (also known as human OX40 agonist antibody may be administered in con recombinant Interferon alpha-2a). In some embodiments, an junction with MEDI3617. In some embodiments, an anti anti-human OX40 agonist antibody may be administered in human OX40 agonist antibody may be administered in conjunction with GM-CSF (also known as recombinant conjunction with an antibody directed against VEGFR2. In human granulocyte macrophage colony stimulating factor, Some embodiments, an anti-human OX40 agonist antibody rhu GM-CSF, sargramostim, or Leukine(R). In some embodi may be administered in conjunction with ramucirumab. In ments, an anti-human OX40 agonistantibody may be admin US 2015/0307617 A1 Oct. 29, 2015 48 istered in conjunction with IL-2 (also known as aldesleukin or nist. In some embodiments, an anti-human OX40 agonist Proleukin R). In some embodiments, an anti-human OX40 antibody may be administered in conjunction with an ICOS agonist antibody may be administered in conjunction with agonist, e.g., by administration of ICOS-L or an agonistic IL-12. In some embodiments, an anti-human OX40 agonist antibody directed against ICOS. In some embodiments, an antibody may be administered in conjunction with IL27. In anti-human OX40 agonist antibody may be administered in Some embodiments, an anti-human OX40 agonist antibody conjunction with a treatment targeting CX3CL1. In some may be administered in conjunction with IL-15. In some embodiments, an anti-human OX40 agonistantibody may be embodiments, an anti-human OX40 agonistantibody may be administered in conjunction with a treatment targeting administered in conjunction with ALT-803. In some embodi CXCL9. In some embodiments, an anti-human OX40 agonist ments, an anti-human OX40 agonistantibody may be admin antibody may be administered in conjunction with a treat istered in conjunction with an antibody targeting CD20. In ment targeting CXCL10. In some embodiments, an anti-hu some embodiments, the antibody targeting CD20 is obinutu man OX40 agonistantibody may be administered in conjunc Zumab (also known as GA101 or Gazy vaR) or rituximab. In tion with a treatment targeting CCL5. In some embodiments, Some embodiments, an anti-human OX40 agonist antibody an anti-human OX40 agonist antibody may be administered may be administered in conjunction with an antibody target in conjunction with an LFA-1 or ICAM1 agonist. In some ing GITR. In some embodiments, the antibody targeting embodiments, an anti-human OX40 agonistantibody may be GITR is TRX518. In some embodiments, the antibody tar administered in conjunction with a Selectin agonist. geting GITR is MK04166 (Merck). 0456. In some embodiments, an anti-human OX40agonist 0453. In some embodiments, an anti-human OX40agonist antibody may be administered in conjunction with an inhibi antibody may be administered in conjunction with an inhibi tor of B-Raf. In some embodiments, an anti-human OX40 tor of Bruton's tyrosine kinase (BTK). In some embodiments, agonist antibody may be administered in conjunction with an anti-human OX40 agonist antibody may be administered vemurafenib (also known as ZelborafR). In some embodi in conjunction with ibrutinib. In some embodiments, an anti ments, an anti-human OX40 agonistantibody may be admin human OX40 agonist antibody may be administered in con istered in conjunction with dabrafenib (also known as Tafin junction with an inhibitor of Isocitrate dehydrogenase 1 lar R). In some embodiments, an anti-human OX40 agonist (IDH1) and/or Isocitrate dehydrogenase 2 (IDH2). In some antibody may be administered in conjunction with embodiments, an anti-human OX40 agonistantibody may be encorafenib (LGX818). administered in conjunction with AG-120 (Agios). 0457. In some embodiments, an anti-human OX40agonist 0454. In some embodiments, an anti-human OX40agonist antibody may be administered in conjunction with an EGFR antibody may be administered in conjunction with obinutu inhibitor. In some embodiments, an anti-human OX40 ago Zumab and a PD-1 axis binding antagonist (e.g., a PD-1 nist antibody may be administered in conjunction with erlo binding antagonist such as an anti-PD-1 antibody, a PD-L1 tinib (also known as Tarceva(R). In some embodiments, an binding antagonist Such as an anti-PD-L1 antibody, and a anti-human OX40 agonist antibody may be administered in PD-L2 binding antagonist such as an anti-PD-L2 antibody). conjunction with an inhibitor of EGFR-T790M. In some 0455. In some embodiments, an anti-human OX40agonist embodiments, an anti-human OX40 agonistantibody may be antibody may be administered in conjunction with a cancer administered in conjunction with gefitinib. In some embodi vaccine. In some embodiments, the cancer vaccine is a pep ments, an anti-human OX40 agonistantibody may be admin tide cancer vaccine, which in some embodiments is a person istered in conjunction with afatinib. In some embodiments, an alized peptide vaccine. In some embodiments the peptide anti-human OX40 agonist antibody may be administered in cancer vaccine is a multivalent long peptide, a multi-peptide, conjunction with cetuximab (also known as ErbituxR). In a peptide cocktail, a hybrid peptide, or a peptide-pulsed den Some embodiments, an anti-human OX40 agonist antibody dritic cell vaccine (see, e.g., Yamada et al., Cancer Sci, 104: may be administered in conjunction with panitumumab (also 14-21, 2013). In some embodiments, an anti-human OX40 known as VectibiX(R). In some embodiments, an anti-human agonistantibody may be administered in conjunction with an OX40 agonist antibody may be administered in conjunction adjuvant. In some embodiments, an anti-human OX40 ago with rociletinib. In some embodiments, an anti-human OX40 nist antibody may be administered in conjunction with a agonist antibody may be administered in conjunction with treatment comprising a TLR agonist, e.g., Poly-ICLC (also AZD9291. In some embodiments, an anti-human OX40 ago known as Hiltono1R), LPS, MPL, or CpG ODN. In some nist antibody may be administered in conjunction with an embodiments, an anti-human OX40 agonistantibody may be inhibitor of a MEK, such as MEK1 (also known as MAP2K1) administered in conjunction with tumor necrosis factor and/or MEK2 (also known as MAP2K2). In some embodi (TNF) alpha. In some embodiments, an anti-human OX40 ments, an anti-human OX40 agonistantibody may be admin agonist antibody may be administered in conjunction with istered in conjunction with cobimetinib (also known as GDC IL-1. In some embodiments, an anti-human OX40 agonist 0973 or XL-518). In some embodiments, an anti-human antibody may be administered in conjunction with HMGB1. OX40 agonist antibody may be administered in conjunction In some embodiments, an anti-human OX40 agonistantibody with trametinib (also known as Mekinist(R). In some embodi may be administered in conjunction with an IL-10 antagonist. ments, an anti-human OX40 agonistantibody may be admin In some embodiments, an anti-human OX40 agonistantibody istered in conjunction with binimetinib. may be administered in conjunction with an IL-4 antagonist. 0458 In some embodiments, an anti-human OX40agonist In some embodiments, an anti-human OX40 agonistantibody antibody may be administered in conjunction an inhibitor of may be administered in conjunction with an IL-13 antagonist. B-Raf (e.g., venurafenib or dabrafenib) and an inhibitor of In some embodiments, an anti-human OX40 agonistantibody MEK (e.g., MEK1 and/or MEK2 (e.g., cobimetinib or trame may be administered in conjunction with an IL-17 antagonist. tinib). In some embodiments, an anti-human OX40 agonist In some embodiments, an anti-human OX40 agonistantibody antibody may be administered in conjunction with an inhibi may be administered in conjunction with an HVEM antago tor of ERK (e.g., ERK1/2). In some embodiments, an anti US 2015/0307617 A1 Oct. 29, 2015 49 human OX40 agonist antibody may be administered in con junction with temsirolimus (also known as CCI-779 or junction with GDC-0994). In some embodiments, an anti Torisel(R). In some embodiments, an anti-human OX40 ago human OX40 agonist antibody may be administered in nist antibody may be administered in conjunction with conjunction with an inhibitor of B-Raf, an inhibitor of MEK, everolimus (also known as RAD001). In some embodiments, and an inhibitor of ERK1/2. In some embodiments, an anti an anti-human OX40 agonist antibody may be administered human OX40 agonist antibody may be administered in con in conjunction with ridaforolimus (also known as AP-23573, junction with an inhibitor of EGFR, an inhibitor of MEK, and MK-8669, or deforolimus). In some embodiments, an anti an inhibitor of ERK1/2. In some embodiments, an anti-hu human OX40 agonist antibody may be administered in con man OX40 agonistantibody may be administered in conjunc junction with OSI-027. In some embodiments, an anti-human tion with one or more MAP kinase pathway inhibitor. In some OX40 agonist antibody may be administered in conjunction embodiments, an anti-human OX40 agonistantibody may be with AZD8055. In some embodiments, an anti-human OX40 administered in conjunction with CK127. In some embodi agonist antibody may be administered in conjunction with ments, an anti-human OX40 agonistantibody may be admin INK128. In some embodiments, an anti-human OX40 agonist istered in conjunction with an inhibitor of K-Ras. antibody may be administered in conjunction with a dual PI3K/mTOR inhibitor. In some embodiments, an anti-human 0459. In some embodiments, an anti-human OX40agonist OX40 agonist antibody may be administered in conjunction antibody may be administered in conjunction with an inhibi with XL765. In some embodiments, an anti-human OX40 tor of c-Met. In some embodiments, an anti-human OX40 agonist antibody may be administered in conjunction with agonist antibody may be administered in conjunction with GDC-0980. In some embodiments, an anti-human OX40 onartuzumab (also known as MetMAb). In some embodi agonist antibody may be administered in conjunction with ments, an anti-human OX40 agonistantibody may be admin BEZ235 (also known as NVP-BEZ235). In some embodi istered in conjunction with an inhibitor of anaplatic lym ments, an anti-human OX40 agonistantibody may be admin phoma kinase (ALK). In some embodiments, an anti-human istered in conjunction with BGT226. In some embodiments, OX40 agonist antibody may be administered in conjunction an anti-human OX40 agonist antibody may be administered with AF802 (also known as CH5424802 or alectinib). In in conjunction with GSK2126458. In some embodiments, an Some embodiments, an anti-human OX40 agonist antibody anti-human OX40 agonist antibody may be administered in may be administered in conjunction with crizotinib. In some conjunction with PF-0469 1502. In some embodiments, an embodiments, an anti-human OX40 agonistantibody may be anti-human OX40 agonist antibody may be administered in administered in conjunction with ceritinib. In some embodi ments, an anti-human OX40 agonistantibody may be admin conjunction with PF-05212384 (also known as PKI-587). istered in conjunction with an inhibitor of a phosphatidyli 0460. In some embodiments, an anti-human OX40agonist nositol 3-kinase (PI3K). In some embodiments, an anti antibody may be administered in conjunction with an agent human OX40 agonist antibody may be administered in that selectively degrades the estrogen receptor. In some conjuction with buparlisib (BKM-120). In some embodi embodiments, an anti-human OX40 agonistantibody may be ments, an anti-human OX40 agonistantibody may be admin administered in conjunction with GDC-0927. In some istered in conjunction with pictilisib (also known as GDC embodiments, an anti-human OX40 agonistantibody may be 0941). In some embodiments, an anti-human OX40 agonist administered in conjunction with an inhibitor of HERS. In antibody may be administered in conjunction with buparlisib Some embodiments, an anti-human OX40 agonist antibody (also known as BKM-120). In some embodiments, an anti may be administered in conjunction with duligotuZumab. In human OX40 agonist antibody may be administered in con Some embodiments, an anti-human OX40 agonist antibody junction with perifosine (also known as KRX-0401). In some may be administered in conjunction with an inhibitor of embodiments, an anti-human OX40 agonistantibody may be LSD1. In some embodiments, an anti-human OX40 agonist administered in conjunction with a delta-selective inhibitor of antibody may be administered in conjunction with an inhibi a phosphatidylinositol 3-kinase (PI3K). In some embodi tor of MDM2. In some embodiments, an anti-human OX40 ments, an anti-human OX40 agonistantibody may be admin agonistantibody may be administered in conjunction with an istered in conjunction with idelalisib (also known as GS-1 101 inhibitor of BCL2. In some embodiments, an anti-human or CAL-101). In some embodiments, an anti-human OX40 OX40 agonist antibody may be administered in conjunction agonist antibody may be administered in conjunction with with Venetoclax. In some embodiments, an anti-human OX40 taselisib (also known as GDC-0032). In some embodiments, agonistantibody may be administered in conjunction with an an anti-human OX40 agonist antibody may be administered inhibitor of CHK1. In some embodiments, an anti-human in conjunction with BYL-719. In some embodiments, an OX40 agonist antibody may be administered in conjunction anti-human OX40 agonist antibody may be administered in with GDC-0575. In some embodiments, an anti-human conjunction with an inhibitor of an Akt. In some embodi OX40 agonist antibody may be administered in conjunction ments, an anti-human OX40 agonistantibody may be admin with an inhibitor of activated hedgehog signaling pathway. In istered in conjunction with MK2206. In some embodiments, Some embodiments, an anti-human OX40 agonist antibody an anti-human OX40 agonist antibody may be administered may be administered in conjunction with ERIVEDGE. in conjunction with GSK690693. In some embodiments, an 0461. In some embodiments, an anti-human OX40agonist anti-human OX40 agonist antibody may be administered in antibody may be administered in conjunction with radiation conjunction with ipatasertib (also known as GDC-0068). In therapy. In some embodiments, an anti-human OX40 agonist Some embodiments, an anti-human OX40 agonist antibody antibody may be administered in conjunction with gemcitab may be administered in conjunction with an inhibitor of ine. In some embodiments, an anti-human OX40 agonistanti mTOR. In some embodiments, an anti-human OX40 agonist body may be administered in conjunction with nab-paclitaxel antibody may be administered in conjunction with Sirolimus (ABRAXANE). In some embodiments, an anti-human OX40 (also known as rapamycin). In some embodiments, an anti agonist antibody may be administered in conjunction with human OX40 agonist antibody may be administered in con trastuzumab. In some embodiments, an anti-human OX40 US 2015/0307617 A1 Oct. 29, 2015 50 agonist antibody may be administered in conjunction with The antibody need not be, but is optionally formulated with TVEC. In some embodiments, an anti-human OX40 agonist one or more agents currently used to prevent or treat the antibody may be administered in conjunction with IL27. In disorder in question. The effective amount of such other Some embodiments, an anti-human OX40 agonist antibody agents depends on the amount of antibody present in the may be administered in conjunction with cyclophosphamide. formulation, the type of disorder or treatment, and other fac In some embodiments, an anti-human OX40 agonistantibody tors discussed above. These are generally used in the same may be administered in conjunction with an agent that dosages and with administration routes as described herein, recruits T cells to the tumor. In some embodiments, an anti or about from 1 to 99% of the dosages described herein, or in human OX40 agonist antibody may be administered in con any dosage and by any route that is empirically/clinically junction with lirilumab (IPH2102/BMS-986015). In some determined to be appropriate. embodiments, an anti-human OX40 agonistantibody may be 0466 For the prevention or treatment of disease, the administered in conjunction with Idelalisib. In some embodi appropriate dosage of an antibody of the invention (when ments, an anti-human OX40 agonistantibody may be admin used alone or in combination with one or more other addi istered in conjunction with an antibody that targets CD3 and tional therapeutic agents) will depend on the type of disease to CD20. In some embodiments, an anti-human OX40 agonist be treated, the type of antibody, the severity and course of the antibody may be administered in conjunction with disease, whether the antibody is administered for preventive REGN 1979. In some embodiments, an anti-human OX40 or therapeutic purposes, previous therapy, the patient's clini agonistantibody may be administered in conjunction with an cal history and response to the antibody, and the discretion of antibody that targets CD3 and CD19. In some embodiments, the attending physician. The antibody is Suitably adminis an anti-human OX40 agonist antibody may be administered tered to the patient at one time or over a series of treatments. in conjunction with blinatumomab. Depending on the type and severity of the disease, about 1 0462. In some embodiments, an anti-human OX40agonist ug/kg to 40 mg/kg of antibody can be an initial candidate antibody may be administered in conjunction with an onco dosage for administration to the patient, whether, for lytic virus. In some embodiments, an anti-human OX40 ago example, by one or more separate administrations, or by nist antibody may be administered in conjunction with car continuous infusion. One typical daily dosage might range boplatin and nab-paclitaxel. In some embodiments, an anti from about 1 lug/kg to 100 mg/kg or more, depending on the human OX40 agonist antibody may be administered in factors mentioned above. For repeated administrations over conjunction with carboplatin and paclitaxel. In some embodi several days or longer, depending on the condition, the treat ments, an anti-human OX40 agonistantibody may be admin ment would generally be Sustained until a desired suppression istered in conjunction with cisplatin and pemetrexed. In some of disease symptoms occurs. Such doses may be administered embodiments, an anti-human OX40 agonistantibody may be intermittently, e.g. every week or every three weeks (e.g. Such administered in conjunction with cisplatin and gemcitabine. that the patient receives from about two to about twenty, or In some embodiments, an anti-human OX40 agonistantibody e.g. about six doses of the antibody). An initial higher loading may be administered in conjunction with FOLFOX. In some dose, followed by one or more lower doses may be adminis embodiments, an anti-human OX40 agonistantibody may be tered. However, other dosage regimens may be useful. The administered in conjunction with FOLFIRI. progress of this therapy is easily monitored by conventional 0463 Such combination therapies noted above encompass techniques and assays. combined administration (where two or more therapeutic 0467. It is understood that any of the above formulations agents are included in the same or separate formulations), and or therapeutic methods may be carried out using an immuno separate administration, in which case, administration of the conjugate of the invention in place of or in addition to an antibody of the invention can occur prior to, simultaneously, anti-OX40 antibody. and/or following, administration of the additional therapeutic agent and/or adjuvant. Antibodies of the invention can also be III. COMBINATION THERAPY COMPRISING used in combination with radiation therapy. ANTI-ANGIOGENESIS AGENTS AND OX40 0464 An antibody of the invention (and any additional BINDING AGONISTS therapeutic agent) can be administered by any suitable means, 0468. Also provided herein are methods treating or delay including parenteral, intrapulmonary, and intranasal, and, if ing progression of cancer in an individual comprising admin desired for local treatment, intralesional administration. istering to the individual an effective amount of an anti Parenteral infusions include intramuscular, intravenous, angiogenesis agent and an OX40 binding agonist. intraarterial, intraperitoneal, or Subcutaneous administration. 0469. In some embodiments, “sustained response' refers Dosing can be by any suitable route, e.g. by injections, such as to the Sustained effect on reducing tumor growth after cessa intravenous or Subcutaneous injections, depending in part on tion of a treatment. For example, the tumor size may remain whether the administration is brief or chronic. Various dosing to be the same or Smaller as compared to the size at the schedules including but not limited to single or multiple beginning of the administration phase. In some embodiments, administrations over various time-points, bolus administra the Sustained response has a duration at least the same as the tion, and pulse infusion are contemplated herein. treatment duration, at least 1.5.x, 2.0x, 2.5x, or 3.0x length of 0465 Antibodies of the invention would be formulated, the treatment duration. dosed, and administered in a fashion consistent with good 0470. In some embodiments, the terms “cancer and “can medical practice. Factors for consideration in this context cerous' further include but are not limited to, carcinoma, include the particular disorder being treated, the particular lymphoma, blastoma, sarcoma, and leukemia. More particu mammal being treated, the clinical condition of the individual lar examples of Such cancers include epithelial ovarian can patient, the cause of the disorder, the site of delivery of the cer, fallopian tube cancer, primary peritoneal cancer, squa agent, the method of administration, the scheduling of admin mous cell cancer, lung cancer (including Small-cell lung istration, and other factors known to medical practitioners. cancer, non-Small cell lung cancer, adenocarcinoma of the US 2015/0307617 A1 Oct. 29, 2015 lung, and squamous carcinoma of the lung), cancer of the composition may or may not be achieved in conjunction with peritoneum, hepatocellular cancer, gastric or stomach cancer another drug, compound, or pharmaceutical composition. (including gastrointestinal cancer), pancreatic cancer, glio Thus, an “effective amount may be considered in the context blastoma, cervical cancer, ovarian cancer (including platinum of administering one or more therapeutic agents, and a single sensitive and platinum resistant ovarian cancer), liver cancer, agent may be considered to be given in an effective amount if, bladder cancer, hepatoma, neuroblastoma, melanoma, breast in conjunction with one or more other agents, a desirable cancer, colon cancer, colorectal cancer, fallopian tube, peri result may be or is achieved. toneal, endometrial or uterine carcinoma, gynecologic can 0472. In some embodiments, “in conjunction with refers cers (e.g., ovarian, peritoneal, fallopian tube, cervical, to administration of one treatment modality in addition to endometrial, vaginal, and Vulvar cancer), salivary gland car another treatment modality. As such, “in conjunction with cinoma, kidney or renal cancer, liver cancer, prostate cancer, refers to administration of one treatment modality before, Vulval cancer, thyroid cancer, soft-tissue sarcoma, kaposi's during, or after administration of the other treatment modality sarcoma, carcinoid carcinoma, mesothelioma, multiple to the individual. For example, an anti-angiogenesis agent myeloma, hepatic carcinoma and various types of head and may be administered in conjunction with an OX40 binding neck cancer, as well as B-cell lymphoma (including low agonist. An anti-angiogenesis agent and an OX40 binding grade/follicular non-Hodgkin’s lymphoma (NHL); small agonist may be administered in conjunction with another a lymphocytic (SL) NHL; intermediate grade/follicular NHL: chemotherapeutic agent. intermediate grade diffuse NHL; high grade immunoblastic 0473. In some embodiments, an "anti-angiogenesis agent' NHL: high grade lymphoblastic NHL; high grade small non or “angiogenesis inhibitor refers to a small molecular weight cleaved cell NHL; bulky disease NHL; mantle cell lym Substance, a polynucleotide, a polypeptide, an isolated pro phoma; AIDS-related lymphoma; and Waldenstrom's Mac tein, a recombinant protein, an antibody, or conjugates or roglobulinemia); chronic lymphocytic leukemia (CLL); fusion proteins thereof, that inhibits angiogenesis, vasculo acute lymphoblastic leukemia (ALL); Hairy cell leukemia; genesis, or undesirable vascular permeability, either directly chronic myeloblastic leukemia; and post-transplant lym or indirectly. It should be understood that the anti-angiogen phoproliferative disorder (PTLD), as well as abnormal vas esis agent includes those agents that bind and block the angio cular proliferation associated with phakomatoses, edema genic activity of the angiogenic factor or its receptor. For (such as that associated with brain tumors), and Meigs' Syn example, an anti-angiogenesis agent is an antibody or other drome. In some embodiments, included in this definition are antagonist to an angiogenic agent as defined throughout the benign and malignant cancers. specification or known in the art, e.g., but are not limited to, 0471. In some embodiments, an “effective amount” is at antibodies to VEGF-A or to the VEGF-A receptor (e.g., KDR least the minimum amount required to effect a measurable receptor or Flt-1 receptor), VEGF-trap, anti-PDGFR inhibi improvement or prevention of a particular disorder. An effec tors such as GleevecTM (Imatinib Mesylate). Anti-angiogen tive amount herein may vary according to factors such as the esis agents also include native angiogenesis inhibitors, e.g., disease state, age, sex, and weight of the patient, and the angiostatin, endostatin, etc. See, e.g., Klagsbrun and ability of the antibody to elicit a desired response in the D'Amore, Annu. Rev. Physiol., 53:217-39 (1991); Streit and individual. An effective amount is also one in which any toxic Detmar. Oncogene, 22:3172-3179 (2003) (e.g., Table 3 list or detrimental effects of the treatment are outweighed by the ing anti-angiogenic therapy in malignant melanoma); Ferrara therapeutically beneficial effects. For prophylactic use, ben & Alitalo, Nature Medicine 5:1359–1364 (1999); Tonini et eficial or desired results include results such as eliminating or al. Oncogene, 22:6549-6556 (2003) (e.g., Table 2 listing reducing the risk, lessening the severity, or delaying the onset known antiangiogenic factors); and Sato. Int. J. Clin. Oncol., of the disease, including biochemical, histological and/or 8:200-206 (2003) (e.g., Table 1 lists anti-angiogenic agents behavioral symptoms of the disease, its complications and used in clinical trials). intermediate pathological phenotypes presenting during 0474. In some embodiments, the term “VEGF or development of the disease. For therapeutic use, beneficial or “VEGF-A' is used to refer to the 165-amino acid human desired results include clinical results such as decreasing one vascular endothelial cell growth factor and related 121-, 145-. or more symptoms resulting from the disease, increasing the 189-, and 206-amino acid human vascular endothelial cell quality of life of those Suffering from the disease, decreasing growth factors, as described by, e.g., Leung et al. Science, the dose of other medications required to treat the disease, 246:1306 (1989), and Houck et al. Mol. Endocrin. 5:1806 enhancing effect of another medication Such as via targeting, (1991), together with the naturally occurring allelic and pro delaying the progression of the disease, and/or prolonging cessed forms thereof. VEGF-A is part of a gene family includ Survival. In the case of cancer or tumor, an effective amount of ing VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and the drug may have the effect in reducing the number of cancer P1GF. VEGF-A primarily binds to two high affinity receptor cells; reducing the tumor size; inhibiting (i.e., slow to some tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/ extent or desirably stop) cancer cell infiltration into periph KDR), the latter being the major transmitter of vascular eral organs; inhibit (i.e., slow to some extent and desirably endothelial cell mitogenic signals of VEGF-A. Additionally, stop) tumor metastasis; inhibiting to some extent tumor neuropilin-1 has been identified as a receptor for heparin growth; and/or relieving to some extent one or more of the binding VEGF-A isoforms, and may play a role in vascular symptoms associated with the disorder. An effective amount development. The term “VEGF or “VEGF-A'also refers to can be administered in one or more administrations. For pur VEGFs from non-human species such as mouse, rat, or pri poses of this invention, an effective amount of drug, com mate. Sometimes the VEGF from a specific species is indi pound, orpharmaceutical composition is an amount Sufficient cated by terms such as hVEGF for human VEGF or mVEGF to accomplish prophylactic or therapeutic treatment either for murine VEGF. Typically, VEGF refers to human VEGF. directly or indirectly. As is understood in the clinical context, The term “VEGF is also used to refer to truncated forms or an effective amount of a drug, compound, or pharmaceutical fragments of the polypeptide comprising amino acids 8 to 109 US 2015/0307617 A1 Oct. 29, 2015 52 or 1 to 109 of the 165-amino acid human vascular endothelial EYLEAR, and Ziv-aflibercept (VEGF Trap; ZALTRAPR)), cell growth factor. Reference to any such forms of VEGF may bispecific VEGF antibodies (e.g., MP-0250, Vanucizumab be identified in the application, e.g., by “VEGF (8-109). (VEGF-ANG2), and bispecific antibodies disclosed in US “VEGF (1-109) or “VEGF165.” The amino acid positions 2001/0236388), bispecific antibodies including combina for a “truncated native VEGF are numbered as indicated in tions of two of anti-VEGF, anti-VEGFR1, and anti-VEGFR2 the native VEGF sequence. For example, amino acid position arms, anti-VEGFA antibodies (e.g., bevacizumab. Sevaci 17 (methionine) in truncated native VEGF is also position 17 Zumab), anti-VEGFB antibodies, anti-VEGFC antibodies (methionine) in native VEGF. The truncated native VEGF has (e.g., VGA-400), anti-VEGFD antibodies, and nonpeptide binding affinity for the KDR and Flt-1 receptors comparable Small molecule VEGFantagonists (e.g., paZopanib, axitinib, to native VEGF. Vandetanib, stivarga, cahozantinib, lenvatinib, nintedanib, 0475. In some embodiments, a “chimeric VEGF receptor orantinib, tellatinib, dovitinig, cediranib, motesanib, apatinib, protein’ is a VEGF receptor molecule having amino acid foretinib, famitinib, and tivo Zanib). sequences derived from at least two different proteins, at least 0478. In some embodiments, an “anti-VEGF antibody” is one of which is a VEGF receptor protein. In certain embodi an antibody that binds to VEGF with sufficient affinity and ments, the chimeric VEGF receptor protein is capable of specificity. In certain embodiments, the antibody will have a binding to and inhibiting the biological activity of VEGF. sufficiently high binding affinity for VEGF, for example, the 0476. In some embodiments, a “VEGF antagonist' or antibody may bind hVEGF with a K value of between 100 “VEGF-specific antagonist” refers to a molecule capable of nM-1 pM. Antibody affinities may be determined, e.g., by a binding to VEGF, reducing VEGF expression levels, or neu Surface plasmon resonance based assay (Such as the BIAcore tralizing, blocking, inhibiting, abrogating, reducing, or inter assay as described in PCT Application Publication No. fering with VEGF biological activities, including, but not WO2005/012359): enzyme-linked immunoabsorbent assay limited to, VEGF binding to one or more VEGF receptors, (ELISA); and competition assays (e.g., RIA's). In certain VEGF signaling, and VEGF mediated angiogenesis and embodiments, the anti-VEGF antibody can be used as a thera endothelial cell survival or proliferation. For example, a mol peutic agent in targeting and interfering with diseases or ecule capable of neutralizing, blocking, inhibiting, abrogat conditions wherein the VEGF activity is involved. Also, the ing, reducing, or interfering with VEGF biological activities antibody may be subjected to other biological activity assays, can exert its effects by binding to one or more VEGF receptor e.g., in order to evaluate its effectiveness as a therapeutic. (VEGFR) (e.g., VEGFR1, VEGFR2, VEGFR3, membrane Such assays are known in the art and depend on the target bound VEGF receptor (mbVEGFR), or soluble VEGF recep antigen and intended use for the antibody. Examples include tor (sVEGFR)). Included as VEGF-specific antagonists use the HUVEC inhibition assay; tumor cell growth inhibition ful in the methods of the invention are polypeptides that assays (as described in WO 89/06692, for example); anti specifically bind to VEGF, anti-VEGF antibodies and anti body-dependent cellular cytotoxicity (ADCC) and comple gen-binding fragments thereof, receptor molecules and ment-mediated cytotoxicity (CDC) assays (U.S. Pat. No. derivatives which bind specifically to VEGF thereby seques 5.500,362); and agonistic activity or hematopoiesis assays tering its binding to one or more receptors, fusions proteins (see WO95/27062). An anti-VEUF antibody will usually not (e.g., VEGF-Trap (Regeneron)), and VEGF-gelonin (Per bind to other VEGF homologues such as VEGF-B or VEGF egrine). VEGF-specific antagonists also include antagonist C, nor other growth factors such as P1GF, PDGF, or bFGF. In variants of VEGF polypeptides, antisense nucleobase oligo one embodiment, anti-VEGF; antibody is a monoclonal anti mers complementary to at least a fragment of a nucleic acid body that binds to the same epitope as the monoclonal anti molecule encoding a VEGF polypeptide; small RNAs VEGF antibody A4.6.1 produced by hybridoma ATCC HB complementary to at least a fragment of a nucleic acid mol 10709. In another embodiment, the anti-VEGF antibody is a ecule encoding a VEGF polypeptide; ribozymes that target recombinant humanized anti-VEGF monoclonal antibody VEGF; peptibodies to VEGF; and VEGF aptamers, VEGF generated according to Presta et al. (1997) Cancer Res. antagonists also include polypeptides that bind to VEGFR, 57:4593-4599, including but not limited to the antibody anti-VEGFR antibodies, and antigen-binding fragments known as bevacizumab (BY: AVASTINR). thereof, and derivatives which bind to VEGFR thereby block 0479. In some embodiments, the anti-VEGF antibody ing, inhibiting, abrogating, reducing, or interfering with “Bevacizumab (BV), also known as “rhuMAb VEGF or VEGF biological activities (e.g., VEGF signaling), or fusions “AVASTINR, is a recombinant humanized anti-VEGF proteins. VEGF-specific antagonists also include nonpeptide monoclonal antibody generated according to Presta et al. Small molecules that bind to VEGF or VEGFR and are (1997) Cancer Res. 57:4593-4599. It comprises mutated capable of blocking, inhibiting, abrogating, reducing, or human IgG1 framework regions and antigen-binding interfering with VEGF biological activities. Thus, the term complementarity-determining regions from the murine anti “VEGF activities” specifically includes VEGF mediated bio hVEGF monoclonal antibody A.4.6.1 that blocks binding of logical activities of VEGF. In certain embodiments, the human VEGF to its receptors. Approximately 93% of the VEGF antagonist reduces or inhibits, by at least 10%, 20%, amino acid sequence of bevacizumab, including most of the 30%, 40%, 50%, 60%, 70%, 80%, 90% or more, the expres framework regions, is derived from human IgG1, and about sion level or biological activity of VEGF, In some embodi 7% of the sequence is derived from the murine antibody ments, the VEGF inhibited by the VEGF-specificantagonist A4.6.1 Bevacizumab has a molecular mass of about 149,000 is VEGF (8-109), VEGF (1-109), or VEGFs. daltons and is glycosylated. Bevacizumab and other human 0477. In some embodiments, as used herein, VEGF ized anti-VEGF antibodies are further described in U.S. Pat. antagonists can include, but are not limited to, anti-VEGFR2 No. 6,884,879 issued Feb. 26, 2005, the entire disclosure of antibodies and related molecules (e.g., ramucirumab, tani which is expressly incorporated herein by reference. Addi birumab, aflibercept), anti-VEGFR1 antibodies and related tional preferred antibodies include the G6 or B20 series anti molecules (e.g., icrucumab, aflibercept (VEGF Trap-Eye: bodies (e.g., G6-31, B20-4.1), as described in PCT Applica US 2015/0307617 A1 Oct. 29, 2015 tion Publication No. WO 2005/O12359. For additional stance, a polynucleotide, a polypeptide, an isolated protein, a preferred antibodies see U.S. Pat. Nos. 7,060,269, 6,582,959, recombinant protein, an antibody, or conjugates or fusion 6,703,020; 6,054,297; WO98/.45332: WO 96/30046; WO94/ proteins thereof. In some embodiments, the anti-angiogen 10202; EP 0666868B1; U.S. Patent Application Publication esis agent is an anti-VEGFR2 antibody; an anti-VEGFR1 NoS. 2006009360, 20050186208, 20030206899, antibody; a VEGF-trap; a bispecific VEGF antibody; a bispe 20030190317, 20030203409, and 20050112126; and Popkov cific antibody comprising a combination of two arms selected et al., Journal of Immunological Methods 288:149-164 from an anti-VEGF arm, an anti-VEGFR1 arm, and an anti (2004). Other preferred antibodies include those that bind to VEGFR2 arm; an anti-VEGF-A antibody (e.g., an anti-KDR a functional epitope on human VEGF comprising of residues receptor or anti-Flt-1 receptor antibody); an anti-VEGFB F17, M18, D19, Y21, Y25, Q89, 191, K101, E103, and C104 antibody; an anti-VEGFC antibody; an anti-VEGFD anti or, alternatively, comprising residues F 17, Y21, Q22, Y25, body; a nonpeptide Small molecule VEGF antagonist; an D63, 183, and Q89. anti-PDGFR inhibitor; or a native angiogenesis inhibitor. In 0480. In some embodiments, the “epitope A4.6.1 refers certain embodiments, the anti-angiogenesis agent is ramucir to the epitope recognized by the anti-VEGF antibody beva umab, tanibirumab, aflibercept (e.g., VEGF Trap-Eye: cizumab (AVASTINR) (see Mullery et al., Structure 15 Sep. EYLEAR), icrucumab, Ziv-aflibercept (e.g., VEGF ZAL 1998, 6:1153-1167). In certain embodiments of the invention, TRAPR), MP-0250, Vanucizumab, sevacizumab, VGX-100, the anti-VEGF antibodies include, but are not limited to, a paZopanib, axitinib, Vandetanib, Stivarga, caboZantinib, len monoclonal antibody that binds to the same epitope as the Vatinib, nintedanib, orantinib, tellatinib, dovitinig, cediranib, monoclonal anti-VEGF antibody A4.6.1 produced by hybri motesanib, sulfatinib, apatinib, foretinib, famitinib, imatinib doma ATCC HB 10709; a recombinant humanized anti (e.g., Imatinib Mesylate: GleevecTM), and tivo Zanib. VEGF monoclonal antibody generated according to Presta et 0489. In some embodiments, the anti-angiogenesis agent al. (1997) Cancer Res. 57:4593-4599. is an anti-angiogenesis antibody. Descriptions of antibodies 0481. In some embodiments, by “standard of care herein and methods for generating antibodies are further provided is intended the anti-tumor agent or agents that are routinely infra. In some embodiments, the anti-angiogenesis antibody used to treat a particular form of cancer. For example, for is a monoclonal antibody. In some embodiments, the anti platinum-resistant ovarian cancer, a standard of care is topo angiogenesis antibody is a human or humanized antibody tecan or liposomal doxorubicin. (described in more detail below). 0482 In some embodiments, by “platinum-based chemo 0490. In some embodiments, the anti-angiogenesis agent therapeutic agent' or “platin' is meant an antineoplastic drug is a VEGFantagonist. For example, VEGFantagonists of the that is a coordination complex of platinum. Examples of present disclosure may include without limitation polypep platinum-based chemotherapeutic agents include carbopl tides that specifically bind to VEGF, anti-VEGF antibodies atin, cisplatin, and oxaliplatinum. and antigen-binding fragments thereof; receptor molecules 0483. In some embodiments, by “platinum-based chemo and derivatives which bind specifically to VEGF, thereby therapy' is meant therapy with one or more platinum-based sequestering its binding to one or more receptors; fusion chemotherapeutic agent, optionally in combination with one proteins VEGF-Trap (Regeneron)), VEGF-gelonin (Per or more other chemotherapeutic agents. egrine), antagonist variants of VEGF polypeptides, antisense 0484. In some embodiments, by “chemotherapy-resis nucleobase oligomers complementary to at least a fragment tant cancer is meant cancer in a patient that has progressed of a nucleic acid molecule encoding a VEGF polypeptide: while the patient is receiving a chemotherapy regimen (i.e., Small RNAS complementary to at least afragment of a nucleic the patient is “chemotherapy refractory'), or the patient has acid molecule encoding a VEGF polypeptide (e.g., an RNAi, progressed within 12 months (for instance, within 6 months) siRNA, shRNA, or miRNA); ribozymes that target VEGF; after completing a chemotherapy regimen. peptibodies to VEGF: VEGF aptamers; polypeptides that 0485. In some embodiments, by "platinum-resistant can bind to VEGFR: anti-VEGFR antibodies and antigen-binding cer is meant cancer in a patient that has progressed while fragments thereof; derivatives which bind to VEGFR thereby receiving platinum-based chemotherapy (i.e., the patient is blocking, inhibiting, abrogating, reducing, or interfering with “platinum refractory'), or the patient has progressed within VEGF biological activities (e.g., VEGF signaling); fusion 12 months (for instance, within 6 months) after completing a proteins; and nonpeptide small molecules that bind to VEGF platinum-based chemotherapy regimen. or VEGFR and are capable of blocking, inhibiting, abrogat 0486 In some embodiments, by “radiation therapy” is ing, reducing, or interfering with VEGF biological activities. meant the use of directed gamma rays or beta rays to induce 0491. In certain embodiments, the VEGF antagonist Sufficient damage to a cell So as to limit its ability to function reduces or inhibits, by at least 10%, 20%, 30%, 40%, 50%, normally or to destroy the cell altogether. It will be appreci 60%, 70%, 80%, 90% or more, the expression level or bio ated that there will be many ways known in the art to deter logical activity of VEGF, For example, in some embodiments, mine the dosage and duration of treatment. Typical treatments the VEGF antagonist may reduce or inhibit the expression are given as a one-time administration and typical dosages level or biological activity of VEGF by at least 10%, at least range from 10 to 200 units (Grays) per day. 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least A. Anti-Angiogenesis Agents 60%, at least 65%, at least 70%, at least 75%, at least 80%, at 0487. Provided herein are methods treating or delaying least 85%, at least 90%, or at least 95%. In some embodi progression of cancer in an individual comprising adminis ments, the VEGF inhibited by the VEGF-specific antagonist tering to the individual an effective amount of an anti-angio is VEGF (8-109), VEGF (1-109), or VEGFs. genesis agent and an OX40 binding agonist. 0492 Certain aspects of the methods, uses, and kits of the 0488. As described Supra, an anti-angiogenesis agent may present disclosure are based, at least in part, on the Surprising include a compound Such as a small molecular weight Sub discovery that anti-VEGF treatment can improve the func US 2015/0307617 A1 Oct. 29, 2015 54 tional phenotype of tumoral dendritic cells (e.g., by leading to significant F4/80 and Gr1 expression. In some embodiments, increased expression of MHC Class II and/or OX40L). With myeloid dendritic cells are dendritic cells that express out wishing to be bound to theory, this property, inter alia, CD11b, and non-myeloid dendritic cells are dendritic cells may make combination therapies including an anti-angiogen that lack significant CD11b expression. For further descrip esis agent and an OX40 binding agonist particularly advan tions of myeloid and non-myeloid dendritic cells, see, e.g., tageous for the treatment of cancer, e.g., by resulting in Steinman, R.M. and Inaba, K. (1999).J. Leukoc. Biol. 66:205 enhanced anti-tumor responses such as anti-tumoral T cell 8 responses. 0497. 1. VEGF Receptor Molecules 0493. Therefore, in some embodiments, the VEGF 0498. In some embodiments, the anti-angiogenesis agent antagonistincreases MHC class II expression on intratumoral is a VEGF antagonist. In some embodiments, the VEGF dendritic cells, e.g., as compared to MHC class II expression antagonist comprises a soluble VEGF receptor or a soluble on dendritic cells from a tumor treated with a control antibody VEGF receptor fragment that specifically binds to VEGF. The (e.g., an isotype control). MHC class II is known as a family two best characterized VEGF receptors are VEGFR1 (also of related molecules (typically heterodimers containing alpha known as Flt-1) and VEGFR2 (also known as KDR and and beta chains) that present antigen to T cells. As used FLK-1 for the murine homolog). The specificity of each herein, MHC class II expression may refer to expression of receptor for each VEGF family member varies but VEGF-A any MHC class II molecule or chain, including without limi binds to both Flt-1 and KDR. Both Flt-I and KDR belong to tation a polypeptide encoded by the human genes HLA-DM the family of receptor tyrosine kinases (RTKs). The RTKs alpha (e.g., NCBI Gene ID No. 3108), HLA-DM beta (e.g., comprise a large family of transmembrane receptors with NCBI Gene ID No. 3109), HLA-DO alpha (e.g., NCBIGene diverse biological activities. At least nineteen (19) distinct ID No. 3111), HLA-DO beta (e.g., NCBIGene ID No.3112), RTK subfamilies have been identified. The receptor tyrosine HLA-DP alpha 1 (e.g., NCBI Gene ID No. 3113), HLA-DP kinase (RTK) family includes receptors that are crucial for the beta 1 (e.g., NCBIGene ID No. 3115), HLA-DQ alpha 1 (e.g., growth and differentiation of a variety of cell types (Yarden NCBI Gene ID No. 31.17), HLA-DQ alpha 2 (e.g., NCBI and Ullrich (1988) Ann. Rev. Biochem. 57:433-478; Ullrich Gene ID No.3118), HLA-DQ beta1 (e.g., NCBIGene ID No. and Schlessinger (1990) Cell 61:243-254). The intrinsic func 3119), HLA-DQ beta 2 (e.g., NCBI Gene ID No. 3120), tion of RTKs is activated upon ligand binding, which results HLA-DR alpha (e.g., NCBI Gene ID No. 3122), HLA-DR in phosphorylation of the receptor and multiple cellular sub beta 1 (e.g., NCBI Gene ID No. 3123), HLA-DR beta 3 (e.g., strates, and Subsequently in a variety of cellular responses NCBI Gene ID No. 3125), HLA-DR beta 4 (e.g., NCBIGene (Ullrich & Schlessinger (1990) Cell 61:203-212). Thus, ID No. 3126), or HLA-DR beta 5 (e.g., NCBI Gene ID No. receptor tyrosine kinase mediated signal transduction is ini 3127). It will be appreciated by one of skill in the art that tiated by extracellular interaction with a specific growth fac MHC genes are highly variable across populations, and thus tor (ligand), typically followed by receptor dimerization, the specific genes and sequences listed are merely exemplary stimulation of the intrinsic protein tyrosine kinase activity and in no way intended to be limiting. and receptor trans-phosphorylation. Binding sites are thereby 0494. In some embodiments, the VEGF antagonist created for intracellular signal transduction molecules and increases OX40L expression on intratumoral dendritic cells, lead to the formation of complexes with a spectrum of cyto e.g., as compared to OX40L expression on dendritic cells plasmic signaling molecules that facilitate the appropriate from a tumor treated with a control antibody (e.g., an isotype cellular response. (e.g., cell division, differentiation, meta control). OX40L (also known as tumor necrosis factor ligand bolic effects, changes in the extracellular microenvironment) superfamily member 4 or CD252) is known as the binding see, Schlessinger and Ullrich (1992) Neuron 9:1-20. Struc partner or ligand of OX40. Examples of OX40L polypeptides turally, both Flt-1 and KDR have seven immunoglobulin-like including without limitation polypeptides having the amino domains in the extracellular domain, a single transmembrane acid sequence represented by UniProt Accession No. P43488 region, and a consensus tyrosine kinase sequence which is and/or a polypeptide encoded by gene TNFSF4 (e.g., NCBI interrupted by a kinase-insert domain. Matthews et al. (1991) Gene ID No. 7292). PNAS USA 88:9026-9030; Terman et al. (1991) Oncogene 0495 Methods for measuring MHC class II or OX40L 6:1677-1683. The extracellular domain is involved in the expression are known in the art and may include without binding of VEGF and the intracellular domain is involved in limitation FACS, Western blot, ELISA, immunoprecipita signal transduction. tion, immunohistochemistry, immunofluorescence, radioim 0499 VEGF receptor molecules, or fragments thereof, munoassay, dot blotting, immunodetection methods, HPLC, that specifically bind to VEGF can be used in the methods of Surface plasmon resonance, optical spectroscopy, mass spec the invention to bind to and sequester the VEGF protein, trometery, HPLC, qPCR, RT-qPCR, multiplex qPCR or RT thereby preventing it from signaling. In certain embodiments, qPCR, RNA-seq microarray analysis, SAGE, Mass ARRAY the VEGF receptor molecule, or VEGF binding fragment technique, and FISH, and combinations thereof. thereof, is a soluble form, such as slt-1. A soluble form of the 0496. In some embodiments, the dendritic cells are receptor exerts an inhibitory effect on the biological activity myeloid dendritic cells. In other embodiments, the dendritic of the VEGF protein by binding to VEGF, thereby preventing cells are non-myeloid dendritic cells (e.g., lymphoid or plas it from binding to its natural receptors present on the Surface macytoid dendritic cells). The cell-surface antigens of target cells. Also included are VEGF receptor fusion pro expressed by dendritic cells, and those that distinguish teins, examples of which are described below. myeloid and non-myeloid dendritic cells, are known in the 0500. In some embodiments, the VEGF antagonist is a art. For example, dendritic cells may be identified by expres chimeric VEGF receptor protein. A chimeric VEGF receptor sion of CD45, CD11c, and MHC class II. They may be dis protein is a receptor molecule having amino acid sequences tinguished from other cell types (e.g., macrophages, neutro derived from at least two different proteins, at least one of phils, and granulocytic myeloid cells) by their lack of which is a VEGF receptor protein (e.g., the filt-1 or KDR US 2015/0307617 A1 Oct. 29, 2015 receptor), that is capable of binding to and inhibiting the Chem 262:44294432 (1987); and Wagner et al., Proc. Natl. biological activity of VEGF. In certain embodiments, the Acad. Sci. USA 87:3410-3414 (1990). For review of the cur chimeric VEGF receptor proteins of the invention consist of rently known gene marking and gene therapy protocols see amino acid sequences derived from only two different VEGF Anderson et al., Science 256:808–813 (1992). See also WO receptor molecules; however, amino acid sequences compris 93/25673 and the references cited therein. ing one, two, three, four, five, six, or all seven Ig-like domains 0503 2. Anti-VEGF Antibodies from the extracellular ligand-binding region of the filt-1 and/ 0504. In some embodiments, the anti-angiogenesis agent or KDR receptor can be linked to amino acid sequences from is a VEGF antagonist. In some embodiments, the VEGF other unrelated proteins, for example, immunoglobulin antagonist is an anti-VEGF antibody. In some embodiments, sequences. Other amino acid sequences to which Ig-like the anti-VEGF antibody may be a human or humanized anti domains are combined will be readily apparent to those of body. In some embodiments, the anti-VEGF antibody may be ordinary skill in the art. Examples of chimeric VEGF receptor a monoclonal antibody. Exemplary descriptions, methods of proteins include, e.g., soluble Flt-1/Fc, KDR/Fc, or FLt-1/ making and use, and features of antibodies are described KDR/Fc (also known as VEGF Trap). (See for example PCT above in sections II.A1-7, B, D, and F with respect to anti Application Publication No. WO97/.44453). OX40 antibodies (e.g., anti-human agonist OX40 antibodies). 0501) A soluble VEGF receptor protein orchimeric VEGF One of skill in the art will appreciate that general descriptions, receptor proteins of the invention includes VEGF receptor methods, and features related to antibodies may apply to proteins which are not fixed to the surface of cells via a anti-OX40 and anti-VEGF antibodies. transmembrane domain. As such, soluble forms of the VEGF (0505. The VEGF antigen to be used for production of receptor, including chimeric receptor proteins, while capable VEGF antibodies may be, e.g., the VEGFs molecule as well of binding to and inactivating VEGF, do not comprise a trans as other isoforms of VEGF or a fragment thereof containing membrane domain and thus generally do not become associ the desired epitope. In one embodiment, the desired epitope is ated with the cell membrane of cells in which the molecule is the one recognized by bevacizumab, which binds to the same expressed. epitope as the monoclonal anti-VEGF antibody A4.6.1 pro 0502. In some embodiments, the VEGF antagonist (I, an duced by hybridoma ATCC HB 10709 (known as “epitope anti-VEGF antibody, such as bevacizumab) is administered A.4.6.1' defined herein). Other forms of VEGF useful for by gene therapy. See, for example, WO 96/07321 published generating anti-VEGF antibodies of the invention will be Mar. 14, 1996 concerning the use of gene therapy to generate apparent to those skilled in the art. intracellular antibodies. There are two major approaches to (0506 Human VEGF was obtained by first screening a getting the nucleic acid (optionally contained in a vector) into cDNA library prepared from human cells, using bovine the patient’s cells; in vivo and ex vivo. For in vivo delivery the VEGF cDNA as a hybridization probe. Leung et al. (1989) nucleic acid is injected directly into the patient, usually at the Science, 246: 1306. One cDNA identified thereby encodes a site where the antibody is required. For ex vivo treatment, the 165-amino acid protein having greater than 95% homology to patient’s cells are removed, the nucleic acid is introduced into bovine VEGF; this 165-amino acid protein is typically these isolated cells and the modified cells are administered to referred to as human VEGF (hVEGF) or VEGFs. The mito the patient either directly or, for example, encapsulated genic activity of human VEGF was confirmed by expressing within porous membranes which are implanted into the the human VEGF cDNA in mammalian host cells. Media patient (see, e.g. U.S. Pat. Nos. 4,892,538 and 5,283,187). conditioned by cells transfected with the human VEGF cDNA There are a variety of techniques available for introducing promoted the proliferation of capillary endothelial cells, nucleic acids into viable cells. The techniques vary depending whereas control cells did not. Leung et al. (1989) Science, upon whether the nucleic acid is transferred into cultured supra. Further efforts were undertaken to clone and express cells in vitro, or in vivo in the cells of the intended host. VEGF via recombinant DNA techniques. (See, e.g., Ferrara, Techniques suitable for the transfer of nucleic acid into mam Laboratory Investigation 72:615-618 (1995), and the refer malian cells in vitro include the use of liposomes, electropo ences cited therein). ration, microinjection, cell fusion, DEAE-dextran, the cal 0507 VEGF is expressed in a variety of tissues as multiple cium phosphate precipitation method, etc. A commonly used homodimeric forms (121, 145, 165, 189, and 206 amino acids vector for ex vivo delivery of the gene is a retrovirus. The per monomer) resulting from alternative RNA splicing. currently preferred in vivo nucleic add transfer techniques VEGF is a soluble mitogen that does not bind heparin; the include transfection with viral vectors such as adenovirus, longerforms of VEGF bind heparin with progressively higher Herpes simplex I virus, or adeno-associated virus) and lipid affinity. The heparin-binding forms of VEGF can be cleaved based systems (useful lipids for lipid-mediated transfer of the in the carboxy terminus by plasmin to release a diffusible gene are DOTMA, DOPE and DC-Chol, for example). In form(s) of VEGF. Amino acid sequencing of the carboxy Some situations it is desirable to provide the nucleic acid terminal peptide identified after plasmin cleavage is Argo Source with an agent that targets the target cells, such as an Ala. Amino terminal “core” protein, VEGF (1-110) iso antibody specific for a cell surface membrane protein or the lated as a homodimer, binds neutralizing monoclonal anti target cell, a ligand for a receptor on the target cell, etc. Where bodies (such as the antibodies referred to as 4.6.1 and 3.2E3. liposomes are employed, proteins which bind to a cell Surface 1.1) and soluble forms of VEGF receptors with similar membrane protein associated with endocytosis may be used affinity compared to the intact VEGFs homodimer. for targeting and/or to facilitate uptake, e.g. capsid proteins or (0508. Several molecules structurally related to VEGF fragments thereoftropic for a particular cell type, antibodies have also been identified recently, including placenta growth for proteins which undergo internalization in cycling, and factor (P1GF), VEGF-B, VEGF-C, VEGF-D and VEGF-E. proteins that target intracellular localization and enhance Ferrara and Davis-Smyth (1987) Endocr. Rev., supra; Ogawa intracellular half-life. The technique of receptor-mediated et al. J. Biological Chem. 273:31273-31281 (1998); Meyeret endocytosis is described, for example, by Wu et al., J. Biol. al. EMBO.J., 18:363-374 (1999). A receptor tyrosine kinase, US 2015/0307617 A1 Oct. 29, 2015 56 Flt-4 (VEGFR-3), has been identified as the receptor for prising of residues F17, M18, D19, Y21, Y25, Q89, I191, VEGF-C and VEGF-D. Joukov et al. EMBO. J. 15:1751 K101, E 103, and C104 or, alternatively, comprising residues (1996); Lee etal. PNAS USA 93:1988-1992 (1996); Achenet F17, Y21, Q22, Y25, D63, I83 and Q89. al. (1998) PNAS USA95:548-553. VEGF-C has been shown 0514. In one embodiment of the invention, the anti-VEGF to be involved in the regulation of lymphatic angiogenesis. antibody has a light chain variable region comprising the Jeltsch et al. Science 276:1423-1425 (1997). following amino acid sequence: DIQMTQSPSS LSAS 0509. Two VEGF receptors have been identified, Flt-1 VGDRVTITCSASQDIS NYLNWYQQKPGKAPKVLIYF (also called VEGFR-1) and KDR (also called VEGFR-2). TSSLHSGVPS RFSGSGSGTD FTLTISSLQP EDFATYY Shibuya et al. (1990) Oncogene 8:519-527; de Vries et al. CQQYSTVPWTFGQGTKVEIKR. (SEQID NO:214); and/ (1992) Science 255:989-991; Terman et al. (1992) Biochem. or a heavy chain variable region comprising the following Biophys. Res. Commun. 187: 1579-1586. Neuropilin-1 has amino acid sequence: EVOLVESGGG LVOPGGSLRL been shown to be a selective VEGF receptor, able to bind the SCAASGYTFT NYGMNWVRQA PGKGLEWVGW heparin-binding VEGF isoforms (Soker et al. (1998) Cell INTYTGEPTY AADFKRRFTFSLDTSKSTAY LOMNSL 92:735-45). RAEDTAVYYCAKYPHYYGSSHWYF DVWGQGTLVT 0510 Anti-VEGF antibodies that are useful in the meth VSS (SEQID NO:215). ods of the invention include any antibody, or antigen binding 0515. In some embodiments, the anti-VEGF antibody fragment thereof, that bind with sufficient affinity and speci comprises one, two, three, four, five, or six hyperVariable ficity to VEGF and can reduce or inhibit the biological activ region (HVR) sequences of bevacizumab, in some embodi ity of VEGF. An anti-VEGF antibody will usually not bind to ments, the anti-VEGF antibody comprises one, two, three, other VEGF homologues such as VEGF-B or VEGF-C, nor four, five, or six hypervariable region (HVR) sequences of other growth factors such as P1GF, PDGF, or bFGF. selected from (a) HVR-H1 comprising the amino acid 0511. In certain embodiments of the invention, the anti sequence of GYTFTNYGMN (SEQID NO:216); (b) HVR VEGF antibodies include, but are not limited to, a mono H2 comprising the amino acid sequence of WINTYT clonal antibody that binds to the same epitope as the mono GEPTYAADFKR (SEQID NO:217); (c) HVR-H3 compris clonal anti-VEGF antibody A4.6.1 produced by hybridoma ing the amino acid sequence ofYPHYYGSSHWYFDV (SEQ ATCC HB 10709; a recombinant humanized anti-VEGF ID NO:218); (d) HVR-L1 comprising the amino acid monoclonal antibody generated according to Presta et al. sequence of SASQDISNYLN (SEQID NO:219); (e) HVR (1997) Cancer Res. 57:4593-4599. In one embodiment, the L2 comprising the amino acid sequence of FTSSLHS (SEQ anti-VEGF antibody is “bevacizumab (BV), also known as ID NO:220); and (f) HVR-L3 comprising the amino acid “rhuMAb VEGF or “AVASTINR. It comprises mutated sequence of QQYSTVPWT (SEQ ID NO:221). In some human IgG1 framework regions and antigen-binding embodiments, the anti-VEGF antibody comprises one, two, complementarity-determining regions from the murine anti three, four, five, or six hypervariable region (HVR) sequences hVEGF monoclonal antibody A.4.6.1 that blocks binding of of an antibody described in U.S. Pat. No. 6,884.879. In some human VEGF to its receptors. Approximately 93% of the embodiments, the anti-VEGF antibody comprises one, two, amino acid sequence of bevacizumab, including most of the or three hypervariable region (HVR) sequences of a light framework regions, is derived from human IgG1, and about chain variable region comprising the following amino acid 7% of the sequence is derived from the murine antibody sequence: DIQMTQSPSS LSASVGDRVT ITCSASQDIS A4.6.1. NYLNWYQQKP GKAPKVLIYF TSSLHSGVPS 0512 Bevacizumab (AVASTINR) was the first anti-an RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT giogenesis therapy approved by the FDA and is approved for FGQ GTKVEIKR. (SEQ ID NO:214) and/or one, two, or the treatment metastatic colorectal cancer (first- and second three hypervariable region (HVR) sequences of a heavy chain line treatment in combination with intravenous 5-FU-based variable region comprising the following amino acid chemotherapy), advanced non-squamous, non-Small cell sequence: EVOLVESGGG LVOPGGSLRLSCAASGYTFT lung cancer (NSCLC) (first-line treatment of unresectable, NYGMNWVRQAPGKGLEWVGW INTYTGEPTY AAD locally advanced, recurrent or metastatic NSCLC in combi FKRRFTF SLDTSKSTAY LOMNSLRAED TAVYY nation with carboplatin and paclitaxel) and metastatic HER2 CAKYP HYYGSSHWYF DVWGQGTLVT VSS (SEQ ID negative breast cancer (previously untreated, metastatic NO:215). HER2-negative breast cancer in combination with pacli 0516 A "G6 series antibody' according to this invention, taxel). is an anti-VEGF antibody that is derived from a sequence of 0513 Bevacizumab and other humanized anti-VEGF anti a G6 antibody or G6-derived antibody according to any one of bodies are further described in U.S. Pat. No. 6,884.879 issued FIGS. 7, 24-26, and 34-35 of PCT Publication No. WO2005/ Feb. 26, 2005. Additional antibodies include the G6 or B20 012359, the entire disclosure of which is expressly incorpo series antibodies (e.g., G6-31, B20-4.1), as described in PCT rated herein by reference. See also PCT Publication No. Publication No. WO2005/012359, PCT Publication No. WO2005/044853, the entire disclosure of which is expressly WO2005/044853, and U.S. Patent Application 60/991,302, incorporated herein by reference. In one embodiment, the G6 the content of these patent applications are expressly incor series antibody binds to a functional epitope on human VEGF porated herein by reference. For additional antibodies see comprising residues F17, Y21, Q22, Y25, D63, I83 and Q89. U.S. Pat. Nos. 7,060,269, 6,582,959, 6,703,020; 6,054,297; 0517 A“B20 series antibody' according to this invention WO98/.45332:WO 96/30046; WO94/10202; EP 0666868B1; is an anti-VEGF antibody that is derived from a sequence of U.S. Patent Application Publication Nos. 2006009360, the B20 antibody or a B20-derived antibody according to any 20050186208, 20030206899, 20030190317, 20030203409, one of FIGS. 27-29 of PCT Publication No. WO2005/ and 20050112126; and Popkov et al., Journal of Immunologi 012359, the entire disclosure of which is expressly incorpo cal Methods 288:149-164 (2004). Other antibodies include rated herein by reference. See also PCT Publication No. those that bind to a functional epitope on human VEGF com WO2005/044853, and U.S. Patent Application 60/991,302, US 2015/0307617 A1 Oct. 29, 2015 57 the content of these patent applications are expressly incor antibody), an OX40L agonist fragment, an OX40 oligomeric porated herein by reference. In one embodiment, the B20 receptor, and an OX40 immunoadhesin. In some embodi series antibody binds to a functional epitope on human VEGF ments, the OX40 binding agonist is a trimeric OX40L-Fc comprising residues F17, M18, D19, Y21, Y25, Q89, I91, protein. In some embodiments, the OX40 binding agonist is K101, E103, and C104. an OX40L agonist fragment comprising one or more extra cellular domains of OX40L. In some embodiments, the OX40 0518. A “functional epitope' according to this invention agonist antibody is a full-length human IgG1 antibody. Any refers to amino acid residues of an antigen that contribute of the OX40 binding agonists (e.g., anti-human OX40 agonist energetically to the binding of an antibody. Mutation of any antibodies) described herein may be used in any of the meth one of the energetically contributing residues of the antigen ods, uses, and/or kits described herein. (for example, mutation of wild-type VEGF by alanine or 0522. In some embodiments, the anti-human OX40 ago homolog mutation) will disrupt the binding of the antibody nist antibody is a human or humanized antibody. In some such that the relative affinity ratio (IC50 mutant VEGF/ embodiments, the OX40 binding agonist (e.g., an OX40 ago IC50wild-type VEGF) of the antibody will be greater than 5 nist antibody) is not MEDI6383. In some embodiments, the (see Example 2 of WO2005/012359). In one embodiment, the OX40 binding agonist (e.g., an OX40 agonistantibody) is not relative affinity ratio is determined by a solution binding MEDIO562. phage displaying ELISA. Briefly, 96-well Maxisorp immu 0523. In some embodiments, the OX40 agonistantibody is noplates (NUNC) are coated overnight at 4°C. with an Fab an anti-human OX40 agonist antibody described in U.S. Pat. form of the antibody to be tested at a concentration of 2 ug/ml No. 7.550,140, which is incorporated herein by reference in in PBS, and blocked with PBS, 0.5% BSA, and 0.05% its entirety. In some embodiments, the anti-human OX40 Tween20 (PBT) for 2 hat room temperature. Serial dilutions agonist antibody comprises a heavy chain comprising the of phage displaying hVEGF alanine point mutants (residues sequence of EVOLVESGGGLVOPGGSLRLSCAASG 8-109 form) or wild type hVEGF (8-109) in PBT are first FTFSNYTMNWVRQAPGKGLEWV incubated on the Fab-coated plates for 15 min at room tem SAISGSGGSTYYADSV KGRFTISRDNSKNT perature, and the plates are washed with PBS, 0.05% LYLQMNSLRAEDTAVYYCAKDRYSQVHYALDYWGQ Tween20 (PBST). The bound phage is detected with an anti GTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALG M13 monoclonal antibody horseradish peroxidase (Amer CLVKDYFPEPVTVSWNSGALTSGVHTF sham Pharmacia) conjugate diluted 1:5000 in PBT, devel PAVLQSSGLYSLSSVVTVPS SSLGTQTYICNVNH oped with 3.3',5,5'-tetramethylbenzidine (TMB, Kirkegaard KPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF & Perry Labs, Gaithersburg, Md.) substrate for approxi LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW mately 5 min, quenched with 1.0 MH3PO4, and read spec YVDGVEVHNAKTKPREEQYNSTYRVVSV trophotometrically at 450 nm. The ratio of IC50 values (IC50, LTVLHQDWLNGKEY KCKVSNKALPAPIEK ala/IC50, wt) represents the fold of reduction in binding affin TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG ity (the relative binding affinity). FYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALH NHYTQK 0519 Assays for identifying anti-VEGF antibodies are SLSLSPGK (SEQID NO:183) and/or a light chain compris known in the art. For example, antibody affinities may be ing the Sequence of determined by a surface plasmon resonance based assay DIVMTQSPDSLPVTPGEPASISCRSSQS (such as the BIAcore assay as described in PCT Application LLHSNGYNYLDWYLQKAGQSPQLLIYLG Publication No. WO2005/012359): enzyme-linked immuno SNRASGVPDRF SGSGSGTDFTLKISRVEAEDVGVYY absorbent assay (ELISA); and competition assays (e.g. CQQYYNHPTTFGQGTKLEIKRTVAAPSVFIFPPSDEQL RIA's), for example. In certain embodiments, the anti-VEGF KSGT ASVVCLLNNFYPREAKVQWKVDNALQS antibody of the invention can be used as a therapeutic agent in GNSQESVTEQDSKDSTYSLSSTLTL targeting and interfering with diseases or conditions wherein SKADYEKHKVYA CEVTHQGLSSPVTKSFNRGEC the VEGF activity is involved. Also, the antibody may be (SEQID NO:184). In some embodiments, the antibody com Subjected to other biological activity assays, e.g., in order to prises at least one, two, three, four, five, or six hyperVariable evaluate its effectiveness as a therapeutic. Such assays are region (HVR) sequences of antibody 008 as described in U.S. known in the art and depend on the target antigen and Pat. No. 7,550,140. In some embodiments, the antibody com intended use for the antibody. Examples include the HUVEC prises a heavy chain variable region sequence and/or a light inhibition assay; tumor cell growth inhibition assays (as chain variable region sequence of antibody 008 as described described in WO 89/06692, for example); antibody-depen in U.S. Pat. No. 7,550,140. dent cellular cytotoxicity (ADCC) and complement-medi 0524. In some embodiments, the OX40 agonistantibody is ated cytotoxicity (CDC) assays (U.S. Pat. No. 5,500,362); an anti-human OX40 agonist antibody described in U.S. Pat. and agonistic activity or hematopoiesis assays (see WO No. 7,550,140. In some embodiments, the anti-human OX40 95/27062). agonist antibody comprises the sequence of DIQMTQSPD B.OX40 Binding Agonists for Use in Conjunction with Anti SLPVTPGEPASISCRSSQSLLHSNGY Angiogenesis Agents NYLDWYLQKAGQSPQLLIYLGSNRASGVPDRF 0520 Provided herein are methods treating or delaying SGSGSGTDFTLKISRVEAEDVGVYYC progression of cancer in an individual comprising adminis QQYYNHPTTFGQGTKLEIKRTVAAPS tering to the individual an effective amount of an anti-angio VFIFPPSDEQLKSGT ASVVCLLNN genesis agent and an OX40 binding agonist. FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY 0521. In some embodiments, an OX40 binding agonist for SLSSTLTLSKADYEKHKVYA CEVTHQGLSSPVTKS use in conjunction with an anti-angiogenesis agent may FNRGEC (SEQID NO:185). In some embodiments, the anti include any of the OX40 binding agonists described in section body comprises at least one, two, three, four, five, or six II. A above. An OX40 binding agonist includes, for example, hypervariable region (HVR) sequences of antibody an OX40 agonistantibody (e.g., an anti-human OX40 agonist SCO2008 as described in U.S. Pat. No. 7,550, US 2015/0307617 A1 Oct. 29, 2015 140. In some embodiments, the antibody comprises a heavy NAKNSLYLQMNSLRAEDTALYYCAKDQSTADYYFY chain variable region sequence and/or a light chain variable YGMDVWGQGTTVTVSS (SEQID NO:190) and/or a light region sequence of antibody SCO2008 as described in U.S. chain variable region comprising the sequence of EIVVTOS Pat. No. 7,550,140. PATLSLSPGERATLSCRASQSVSSYLAW 0525. In some embodiments, the OX40 agonistantibody is YQQKPGQAPRLLIYDASNRATGIPARFSGSGS GTD an anti-human OX40 agonist antibody described in U.S. Pat. FTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK No. 7,550,140. In some embodiments, the anti-human OX40 (SEQID NO:191). In some embodiments, the antibody com agonist antibody comprises a heavy chain comprising the prises at least one, two, three, four, five, or six hyperVariable sequence of EVOLVESGGGLVHPGGSLRLSCAGSG region (HVR) sequences of antibody 18D8 as described in FTFSSYAMHWVRQAPGKGLEWV U.S. Pat. No. 7,960,515. In some embodiments, the antibody SAIGTGGGTYYADSV MGRFTISRDNSKNT comprises a heavy chain variable region sequence and/or a LYLQMNSLRAEDTAVYYCARYDNVMGLYWFDYWG light chain variable region sequence of antibody 18D8 as QGTLVTVSSASTKGP SVFPLAPSSKSTSGGTAALG described in U.S. Pat. No. 7,960,515. CLVKDYFPEPVTVSWNSGALTSGVHTF 0528. In some embodiments, the OX40 agonistantibody is PAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNH an anti-human OX40 agonist antibody described in WO KPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF 2012/027328, which is incorporated herein by reference in its LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW entirety. In some embodiments, the anti-human OX40 agonist YVDGVEVHNAKTKPREEQYNSTYRVVSV antibody comprises aheavy chain variable region comprising LTVLHQDWLNGKE YKCKVSNKALPAPIEK the sequence of QVOLVQSGSELKKPGASVKVSCKAS TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG GYTFTDYSMHWVRQAPGQGLKWMGWIN FYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLY TETGEPTYAD DFKGRFVFSLDTSVSTAYLOISSL SKLTVDKSRWQQGNVFSCSVMHEALH KAEDTAVYYCANPYYDYVSYYAMDYWGQGTTVTV NHYTQKSLSLSPGK (SEQID NO:186) and/or a light chain SS (SEQ ID NO:192) and/or a light chain variable region comprising the sequence of EIVLTQSPATLSLSPGER comprising the sequence of DIOMTQSPSSLSAS ATLSCRASQSVSSYLAWYQQK VGDRVTITCKASQDVSTAVAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGS GTD PGKAPKLLIYSASYLYTGVPSRFSGSG SGTDFTFTISS FTLTISSLEPEDFAVYYCQQRSNWPPAFGGGTKVEIKR LQPEDIATYYCQQHYSTPRTFGQGTKLEIK (SEQ ID TVAAPSVFIFPPSDEQLKSGTASVVC LLNN NO:193). In some embodiments, the antibody comprises at FYPREAKVQWKVDNALQSGNSQESVTE least one, two, three, four, five, or six hyperVariable region QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH (HVR) sequences of antibody hu106-222 as described in WO QGLSSPVTKSFNRGEC (SEQ ID NO:187). In some 2012/027328. In some embodiments, the antibody comprises embodiments, the antibody comprises at least one, two, three, a heavy chain variable region sequence and/or a light chain four, five, or six hypervariable region (HVR) sequences of variable region sequence of antibody hu106-222 as described antibody 023 as described in U.S. Pat. No. 7,550,140. In some in WO 2012/O27328. embodiments, the antibody comprises a heavy chain variable 0529. In some embodiments, the OX40 agonistantibody is region sequence and/or a light chain variable region sequence an anti-human OX40 agonist antibody described in WO of antibody 023 as described in U.S. Pat. No. 7,550,140. 2012/027328. In some embodiments, the anti-human OX40 0526 In some embodiments, the OX40 agonistantibody is agonist antibody comprises a heavy chain variable region an anti-human OX40 agonist antibody described in U.S. Pat. comprising the sequence of EVOLVESGGGLVOPGGSL No. 7,960,515, which is incorporated herein by reference in RLSCAASEYEFPSHDMSWVRQAPGK its entirety. In some embodiments, the anti-human OX40 GLELVAAINSDGGSTYYPDTM ERRFTISRD agonist antibody comprises a heavy chain variable region NAKNSLYLQMNSLRAEDTAVYYCARHYDDYYAWFA comprising the sequence of EVOLVESGGGLVOPGGSL YWGQGTMVTVSS (SEQID NO:194) and/or a light chain RLSCAASGFTFSSYSMNWVRQAPGK variable region comprising the sequence of EIVLTQS GLEWVSYISSSSSTIDYADSVK GRFTISRD PATLSLSPGERATLSCRASKSVSTS NAKNSLYLQMNSLRDEDTAVYYCARESGWYLFDYW GYSYMHWYQQKPGQAPRLLIYLASNLESGVPARFS GQGTLVTVSS (SEQID NO:188) and/or a light chain vari GSGSGTDFTLTISSLEPEDFAVYYCQH able region comprising the sequence of DIQMTQSPSSL SRELPLTFGGGTKVEIK (SEQ ID NO:195). In some SASVGDRVTITCRASQGISSWLAWYQQK embodiments, the antibody comprises at least one, two, three, PEKAPKSLIYAASSLQSGVPSRFSGSGS four, five or six hypervariable region (HVR) sequences of GTDFTLTISSLQPEDFATYYCQQYN antibody Hu1 19-122 as described in WO 2012/027328. In SYPPTFGGGTKVEIK (SEQID NO:189). In some embodi Some embodiments, the antibody comprises a heavy chain ments, the antibody comprises at least one, two, three, four, variable region sequence and/or a light chain variable region five, or six hypervariable region (HVR) sequences of anti sequence of antibody Hu1 19-122 as described in WO 2012/ body 1 1D4 as described in U.S. Pat. No. 7,960,515. In some O27328. embodiments, the antibody comprises a heavy chain variable 0530. In some embodiments, the OX40 agonistantibody is region sequence and/or a light chain variable region sequence an anti-human OX40 agonist antibody described in WO of antibody 1 1D4 as described in U.S. Pat. No. 7,960,515. 2013/028231, which is incorporated herein by reference in its 0527. In some embodiments, the OX40 agonistantibody is entirety. In some embodiments, the anti-human OX40 agonist an anti-human OX40 agonist antibody described in U.S. Pat. antibody comprises a heavy chain comprising the sequence of No. 7,960,515. In some embodiments, the anti-human OX40 MYLGLNYVFIV agonist antibody comprises a heavy chain variable region FLLNGVQSEVKLEESGGGLVQPGGSMKLSCAASGFT comprising the sequence of EVOLVESGGGLVOPGRSL FSDAWMDWVRQSPEKGL EWVAEIRSKAN RLSCAASGFTFDDYAMHWVRQAPGK NHATYYAESVNGRFTISRDDSKSS GLEWVSGISWNSGSIGYADSV KGRFTISRD US 2015/0307617 A1 Oct. 29, 2015 59 GEVFYFDYW GQGTTLTVSSASTKGPSVF VKISCKTSGYTFKDYTMHWVKQSHGK PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL SLEWIGGIYPNNGGSTYNQNF TSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTY KDKATITVDKSSSTAYMEFRSLTSED ITCNVNHKPSNTKVDKKVEPKSCDKTH SAVYYCARMGYHGPHLDFDVWGAGTTVTVSP (SEQ TCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCV ID NO:202) and/or a light chain variable region comprising VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY the sequence of DIVMTQSHKFMSTSLGDRVSITCK NSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL ASQDVGAAVAWYQQKPGQSPKLLIY VKGFYPSDIAVEWESNGQPENNYKTTP WASTRHTGVPDRFTG GGSGTDFTLTISNVQSEDLT PVLDSDGSFFLYSKLTVDKSRWQQGNVF DYFCQQYINYPLTFGGGTKLEIKR (SEQID NO:203). In SCSVMHEAL HNHYTQKSLSLSPGK (SEQ ID NO:196) Some embodiments, the antibody comprises at least one, two, and/or a light chain comprising the sequence of MRPSIQ three, four, five, or six hypervariable region (HVR) sequences FLGLLLFWLHGAQCDIQMTQSPSSL of antibody clone 12H3 as described in WO 2013/038191. In SASLGGKVTITCKSSQDINKYIAWYQHKPGKGPRL Some embodiments, the antibody comprises a heavy chain LIHYTSTLQPGIPSRFSGSGSGRDYSF variable region sequence and/or a light chain variable region SISNLEPEDIATYYCLOYDNLLTF sequence of antibody clone 12H3 as described in WO 2013/ GAGTKLELKRTVAAPSV FIFPPSDEQLKSGTASV O381.91. VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTL SKADYEKHKVY 0533. In some embodiments, the OX40 agonistantibody is ACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:197). In an anti-human OX40 agonist antibody described in WO Some embodiments, the anti-human OX40 agonist antibody 2014/148895A1, which is incorporated herein by reference in comprises a heavy chain variable region comprising the its entirety. In some embodiments, the anti-human OX40 Sequence of MYLGLNYVFIV agonist antibody comprises a heavy chain variable region FLLNGVQSEVKLEESGGGLVQPGGSMKLSCAASGFT comprising the sequence of QVOLVOSGAEVKKPGAS FSDAWMDWVRQSPEKGL EWVAEIRSKAN VKVSCKASGYTFTSYVMHWVRQAPGQR NHATYYAESVNGRFTISRDDSKSS LEWMGYINPYNDGTKYNE KFKGRVTITSDTSAS VYLQMNSLRAEDTGIYYCTWGEVFYFDYW GQGT TAYMELSSLRSEDTAVYYCANYYGSSLSMDYWGQG TLTVSS (SEQ ID NO:198) and/or a light chain variable TLVTVSS (SEQ ID NO:204) and/or a light chain variable region comprising the sequence of MRPSIQFLGLLLFWL region comprising the sequence of DIQMTQSPSSLSAS HGAQCDIQMTQSPSSLSASLG VGDRVTITCRASQDISNYLNWYQQK GKVTITCKSSQDINKYIAWYQHKPGKGPRL LIHYT PGKAPKLLIYYTSRLHSGVPSRFSGSGS GTDYTLTISS STLQPGIPSRFSGSGSGRDYSFSISNLEPEDIATYYCLO LQPEDFATYYCQQGNTLPWTFGQGTKVEIKR (SEQID YDNLLTFGAGTKLELK (SEQ ID NO:199). In some NO:205). In some embodiments, the antibody comprises at embodiments, the antibody comprises at least one, two, three, least one, two, three, four, five, or six hyperVariable region four, five, or six hypervariable region (HVR) sequences of (HVR) sequences of antibody clone 20E.5as described in WO antibody Mab CH 119-43-1 as described in WO 2013/ 2014/148895A1. In some embodiments, the antibody com 028231. In some embodiments, the antibody comprises a prises a heavy chain variable region sequence and/or a light heavy chain variable region sequence and/or a light chain chain variable region sequence of antibody clone 20E5 as variable region sequence of antibody Mab CH 119-43-1 as described in WO 2014/148895A1. described in WO 2013/028231. 0534. In some embodiments, the OX40 agonistantibody is 0531. In some embodiments, the OX40 agonistantibody is an anti-human OX40 agonist antibody described in WO an anti-human OX40 agonist antibody described in WO 2014/148895A1. In some embodiments, the anti-human 2013/038.191, which is incorporated herein by reference in its OX40 agonist antibody comprises a heavy chain variable entirety. In some embodiments, the anti-human OX40agonist region comprising the sequence of QVOLVOSGAEVKKP antibody comprises aheavy chain variable region comprising GASVKVSCKASGYTFTSYVMH the sequence of EVOLOQSGPELVKPGASVKMSCKAS WVRQAPGQRLEWMGYINPYNDGTKYNE GYTFTSYVMHWVKQKPGQGLEWIGYIN KFKGRVTITSDTSASTAYMELSSLRSED PYNDGTKYNEK FKGKATLTSDKSSSTAYMELSSLT TAVYYCANYYGSSLSMDYWGQGTLVTVSS (SEQ ID SEDSAVYYCANYYGSSLSMDYWGQGTSVTVSS (SEQ NO:204) and/or a light chain variable region comprising the ID NO:200) and/or a light chain variable region comprising Sequence of DIQMTQSPSSLSASVGDRVTIT the sequence of DIQMTQTTSSLSASLGDRVTIS CRASQDISNYLNWYQQK CRASQDISNYLNWYQQKP PGKAVKLLIYYTSRLHSGVPSRFSGSGS DGTVKLLIYYTSRLHSGVPSRFSGSGS GTDYSLTISN LEQEDIATYFCQQGNTLPWTFGGGTKLEIKR (SEQ ID GTDYTLTISSLQPEDFATYFCQQGNTLP NO:201). In some embodiments, the antibody comprises at WTFGQGTKVEIKR (SEQ ID NO:206). In some embodi least one, two, three, four, five, or six hyperVariable region ments, the antibody comprises at least one, two, three, four, (HVR) sequences of antibody clone 20E.5as described in WO five, or six hypervariable region (HVR) sequences of anti 2013/038191. In some embodiments, the antibody comprises body clone 20E5 as described in WO 2014/148895A1. In a heavy chain variable region sequence and/or a light chain Some embodiments, the antibody comprises a heavy chain variable region sequence of antibody clone 20E.5as described variable region sequence and/or a light chain variable region in WO 2013/0381.91. sequence of antibody clone 20E5 as described in WO 2014/ 0532. In some embodiments, the OX40 agonistantibody is 148895A1. an anti-human OX40 agonist antibody described in WO 0535 In some embodiments the OX40 agonistantibody is 2013/038191. In some embodiments, the anti-human OX40 an anti-human OX40 agonist antibody described in WO agonist antibody comprises a heavy chain variable region 2014/148895A1. In some embodiments, the anti-human comprising the sequence of EVOLOQSGPELVKPGAS OX40 agonist antibody comprises a heavy chain variable US 2015/0307617 A1 Oct. 29, 2015 60 region comprising the sequence of QVOLVOSGAEVKKP region comprising the sequence of QVOLVOSGAEVKKP GASVKVSCKASGYTFTSYVMH GASVKVSCKASGYTFTSYVMH WVRQAPGQRLEWIGYINPYNDGTKYNEK WVRQAPGQRLEWIGYINPYNDGTKYNEK FKGRATITSDTSASTAYMELSSLRSED FKGRATILTSDKSASTAYMELSSLRSED TAVYYCANYYGSSLSMDYWGQGTLVTVSS (SEQ ID TAVYYCANYYGSSLSMDYWGQGTLVTVSS (SEQ ID NO:207) and/or a light chain variable region comprising the NO:208) and/or a light chain variable region comprising the Sequence of DIQMTQSPSSLSASVGDRVTIT Sequence of DIQMTQSPSSLSASVGDRVTIT CRASQDISNYLNWYQQKPGKAP CRASQDISNYLNWYQQK KLLIYYTSRLHSGVPSRFSGSGS GTDYTLTISSLQPED PGKAVKLLIYYTSRLHSGVPSRFSGSGS FATYYCQQGNTLPWTFGQGTKVEIKR (SEQ ID GTDYTLTISSLQPEDFATYFCQQGNTLP NO:205). In some embodiments, the antibody comprises at WTFGQGTKVEIKR (SEQ ID NO:206). In some embodi least one, two, three, four, five, or six hyperVariable region ments, the antibody comprises at least one, two, three, four, (HVR) sequences of antibody clone 20E.5as described in WO five, or six hypervariable region (HVR) sequences of anti 2014/148895A1. In some embodiments, the antibody com body clone 20E5 as described in WO 2014/148895A1. In prises a heavy chain variable region sequence and/or a light Some embodiments, the antibody comprises a heavy chain chain variable region sequence of antibody clone 20E5 as variable region sequence and/or a light chain variable region described in WO 2014/148895A1. sequence of antibody clone 20E5 as described in WO 2014/ 0536. In some embodiments, the OX40 agonistantibody is 148895A1. an anti-human OX40 agonist antibody described in WO 0539. In some embodiments, the OX40 agonistantibody is 2014/148895A1. In some embodiments, the anti-human an anti-human OX40 agonist antibody described in WO OX40 agonist antibody comprises a heavy chain variable 2014/148895A1. In some embodiments, the anti-human region comprising the sequence of QVOLVOSGAEVKKP OX40 agonist antibody comprises a heavy chain variable GASVKVSCKASGYTFTSYVMH region comprising the sequence of QVOLVOSGAE WVRQAPGQRLEWIGYINPYNDGTKYNEK VKKPGSSVKVSCKASGYTFKDYTMH FKGRATITSDTSASTAYMELSSLRSED WVRQAPGQGLEWMGGIYPNNGGSTYNQ TAVYYCANYYGSSLSMDYWGQGTLVTVSS (SEQ ID NFKDRVTITADKSTSTAYMELSSLRSED NO:207) and/or a light chain variable region comprising the TAVYYCARMGYHGPHLDFDVWGQGTTVTVSS (SEQ Sequence of DIQMTQSPSSLSASVGDRVTIT ID NO:209) and/or a light chain variable region comprising CRASQDISNYLNWYQQK the sequence of DIQMTQSPSSLSASVGDRVTITCK PGKAVKLLIYYTSRLHSGVPSRFSGSGS ASQDVGAAVAWYQQKPGKAPKLLIY GTDYTLTISSLQPEDFATYFCQQGNTLP WASTRHTGVPSRFSGS GSGTDFTLTISSLQPEDFA WTFGQGTKVEIKR (SEQ ID NO:206). In some embodi TYYCQQYINYPLTFGGGTKVEIKR (SEQID NO:210). In ments, the antibody comprises at least one, two, three, four, Some embodiments, the antibody comprises at least one, two, five, or six hypervariable region (HVR) sequences of anti three, four, five, or six hypervariable region (HVR) sequences body clone 20E5 as described in WO 2014/148895A1. In of antibody clone 12H3 as described in WO 2014/148895A1. Some embodiments, the antibody comprises a heavy chain In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region variable region sequence and/or a light chain variable region sequence of antibody clone 20E5 as described in WO 2014/ sequence of antibody clone 12H3 as described in WO 2014/ 148895A1. 148895A1. 0537. In some embodiments, the OX40 agonistantibody is 0540. In some embodiments, the OX40 agonistantibody is an anti-human OX40 agonist antibody described in WO an anti-human OX40 agonist antibody described in WO 2014/148895A1. In some embodiments, the anti-human 2014/148895A1. In some embodiments, the anti-human OX40 agonist antibody comprises a heavy chain variable OX40 agonist antibody comprises a heavy chain variable region comprising the sequence of QVOLVOSGAEVKKP region comprising the sequence of QVOLVOSGAE GASVKVSCKASGYTFTSYVMH VKKPGSSVKVSCKASGYTFKDYTMH WVRQAPGQRLEWIGYINPYNDGTKYNEK WVRQAPGQGLEWMGGIYPNNGGSTYNQ FKGRATILTSDKSASTAYMELSSLRSED NFKDRVTITADKSTSTAYMELSSLRSED TAVYYCANYYGSSLSMDYWGQGTLVTVSS (SEQ ID TAVYYCARMGYHGPHLDFDVWGQGTTVTVSS (SEQ NO:208) and/or a light chain variable region comprising the ID NO:209) and/or a light chain variable region comprising Sequence of DIQMTQSPSSLSASVGDRVTIT the sequence of DIQMTQSPSSLSASVGDRVTITCK CRASQDISNYLNWYQQKPGKAP ASQDVGAAVAWYQQKPGKAPKLLIY KLLIYYTSRLHSGVPSRFSGSGS GTDYTLTISSLQPED WASTRHTGVPDRFSGG GSGTDFTLTISSLQPEDFA FATYYCQQGNTLPWTFGQGTKVEIKR (SEQ ID TYYCQQYINYPLTFGGGTKVEIKR (SEQID NO:211). In NO:205). In some embodiments, the antibody comprises at Some embodiments, the antibody comprises at least one, two, least one, two, three, four, five, or six hyperVariable region three, four, five, or six hypervariable region (HVR) sequences (HVR) sequences of antibody clone 20E.5as described in WO of antibody clone 12H3 as described in WO 2014/148895A1. 2014/148895A1. In some embodiments, the antibody com In some embodiments, the antibody comprises a heavy chain prises a heavy chain variable region sequence and/or a light variable region sequence and/or a light chain variable region chain variable region sequence of antibody clone 20E5 as sequence of antibody clone 12H3 as described in WO 2014/ described in WO 2014/148895A1. 148895A1. 0538. In some embodiments, the OX40 agonistantibody is 0541. In some embodiments, the OX40 agonistantibody is an anti-human OX40 agonist antibody described in WO an anti-human OX40 agonist antibody described in WO 2014/148895A1. In some embodiments, the anti-human 2014/148895A1. In some embodiments, the anti-human OX40 agonist antibody comprises a heavy chain variable OX40 agonist antibody comprises a heavy chain variable