US20160160290A1 - Methods and biomarkers for predicting efficacy and evaluation of an ox40 agonist treatment - Google Patents

Methods and biomarkers for predicting efficacy and evaluation of an ox40 agonist treatment Download PDF

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US20160160290A1
US20160160290A1 US14/930,597 US201514930597A US2016160290A1 US 20160160290 A1 US20160160290 A1 US 20160160290A1 US 201514930597 A US201514930597 A US 201514930597A US 2016160290 A1 US2016160290 A1 US 2016160290A1
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Mahrukh HUSENI
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Genentech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04M—TELEPHONIC COMMUNICATION
    • H04M3/00—Automatic or semi-automatic exchanges
    • H04M3/42—Systems providing special services or facilities to subscribers
    • H04M3/50—Centralised arrangements for answering calls; Centralised arrangements for recording messages for absent or busy subscribers ; Centralised arrangements for recording messages
    • H04M3/51—Centralised call answering arrangements requiring operator intervention, e.g. call or contact centers for telemarketing
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04M—TELEPHONIC COMMUNICATION
    • H04M2203/00—Aspects of automatic or semi-automatic exchanges
    • H04M2203/40—Aspects of automatic or semi-automatic exchanges related to call centers
    • H04M2203/402—Agent or workforce management
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04M—TELEPHONIC COMMUNICATION
    • H04M3/00—Automatic or semi-automatic exchanges
    • H04M3/42—Systems providing special services or facilities to subscribers
    • H04M3/50—Centralised arrangements for answering calls; Centralised arrangements for recording messages for absent or busy subscribers ; Centralised arrangements for recording messages
    • H04M3/51—Centralised call answering arrangements requiring operator intervention, e.g. call or contact centers for telemarketing
    • H04M3/523—Centralised call answering arrangements requiring operator intervention, e.g. call or contact centers for telemarketing with call distribution or queueing
    • H04M3/5238—Centralised call answering arrangements requiring operator intervention, e.g. call or contact centers for telemarketing with call distribution or queueing with waiting time or load prediction arrangements

Definitions

  • the present disclosure relates to methods of predicting or monitoring responsiveness to treatment with an OX40 agonist, as well as methods of treating cancer related thereto.
  • OX40 (also known as CD34, TNFRSF4 and ACT35) is a member of the tumor necrosis factor receptor superfamily. OX40 is not constitutively expressed on na ⁇ ve T cells, but is induced after engagement of the T cell receptor (TCR). The ligand for OX40, OX40L, is predominantly expressed on antigen presenting cells. OX40 is highly expressed by activated CD4+ T cells, activated CD8+ T cells, memory T cells, and regulatory T cells. OX40 signaling can provide costimulatory signals to CD4 and CD8 T cells, leading to enhanced cell proliferation, survival, effector function and migration. OX40 signaling also enhances memory T cell development and function.
  • Treg Regulatory T cells
  • the present disclosure describes methods and biomarkers for predicting efficacy and evaluation of an OX40 agonist treatment, including methods for predicting responsiveness, monitoring pharmacodynamic activity or responsiveness, and methods of treating or delaying progression of cancer.
  • the present disclosure provides a method for predicting responsiveness of a subject having cancer to an OX40 agonist treatment, comprising: (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein said one or more marker genes are selected from the group consisting of CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R; and (b) classifying the subject as a responsive or non-responsive subject based on the expression level of said one or more marker genes in the sample obtained from the subject, as compared with a reference, wherein an increased expression level of the one or more marker genes as compared with the reference indicates the subject may be responsive to an OX40 agonist treatment.
  • the present disclosure provides a method for treating or delaying progression of cancer in a subject, comprising: (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein said one or more marker genes are selected from the group consisting of CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R; and (b) if the expression level of said one or more marker genes in the sample obtained from the subject is higher than a reference, administering to the subject an effective amount of an OX40 agonist.
  • the present disclosure provides a method for treating or delaying progression of cancer in a subject, comprising administering to the subject an effective amount of an OX40 agonist, wherein a sample comprising leukocytes obtained from the subject has increased expression of one or more marker genes are selected from the group consisting of CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R, as compared with a reference.
  • said one or more marker genes are selected from the group consisting of CD8a, CD8b, IFNg, GZMA, GZMB, PRF1, and PDCA1. In some embodiments, said one or more marker genes are selected from the group consisting of H2-d, CTLA4, CXCL9, PTPRC, IL7R, KLRK1, and CXCL1. In some embodiments, said one or more marker genes are selected from the group consisting of CD64, IDO1, and ITGAM.
  • the present disclosure provides a method for predicting responsiveness of a subject having cancer to an OX40 agonist treatment, comprising: (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein said one or more marker genes are selected from the group consisting of CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1; and (b) classifying the subject as a responsive or non-responsive subject based on the expression level of said one or more marker genes in the sample obtained from the subject, as compared with a reference, wherein a decreased expression level of the one or more marker genes as compared with the reference indicates the subject may be responsive to an OX40 agonist treatment.
  • the present disclosure provides a method for treating or delaying progression of cancer in a subject, comprising: (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein said one or more marker genes are selected from the group consisting of CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1; and (b) if the expression level of said one or more marker genes in the sample obtained from the subject is lower than a reference, administering to the subject an effective amount of an OX40 agonist.
  • the present disclosure provides a method for treating or delaying progression of cancer in a subject, comprising administering to the subject an effective amount of an OX40 agonist, wherein a sample comprising leukocytes obtained from the subject has decreased expression of one or more marker genes are selected from the group consisting of CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1, as compared with a reference.
  • the present disclosure provides a method for monitoring pharmacodynamic activity of an OX40 agonist treatment, comprising: (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein the subject has been treated with an OX40 agonist, and wherein said one or more marker genes are selected from the group consisting of ARG1, CCL2, CCL22, CCL5, CCR5, CD226, CD27, CD274, CD28, CD3E, CD40, CD8A, CD8b, CXCL10, CXCL9, EOMES, FasL, Fcgr1/CD64, FOXP3, GZMA, GZMB, HAVCR2, ICAM1, IDO1, IFNg, IL10, IL12A (TDO2), IL13, IL2, IL7R, ITGAM, KLRK1, LAG3, MAP4K1, MS4A1, PDCD1, PDCD1LG2, PRF1, PTPRC, TNF, TNFRSF14
  • the present disclosure provides a method for monitoring responsiveness of a subject to an OX40 agonist treatment, comprising: (a) measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, wherein the subject has been treated with an OX40 agonist, and wherein said one or more marker genes are selected from the group consisting of BTLA, CD4, CD69, CD80, CD83, CD86, CSF2, CTLA4, CXCR3, Fcgr2b/CD32, Fcgr3/CD16, H2-aa, H2-d, H2-k, ICOS, IL10, PDCA1, and TNFRSF18; and (b) classifying the subject as responsive or non-responsive to said treatment based on the expression level of said one or more marker genes in the sample obtained from the subject, as compared with a reference, wherein an increased expression level of the one or more marker genes as compared with the reference indicates a responsive subject.
  • said one or more marker genes are selected from the group consisting of BT
  • the sample comprising leukocytes is from a tumor sample obtained from the subject. In some embodiments, the sample comprising leukocytes is from a peripheral blood sample obtained from the subject. In some embodiments, the expression level of said one or more marker genes is normalized to the expression level of a reference gene in the sample. In some embodiments, the reference gene is a housekeeping gene. In some embodiments, the expression level of said one or more marker genes is mRNA expression level. In some embodiments, the mRNA expression level is measured by an assay selected from the group consisting of quantitative PCR, semi-quantitative PCR, nucleotide microarray, RNA-seq, in situ hybridization, and Northern blotting.
  • the expression level of said one or more marker genes is protein expression level.
  • the protein expression level is measured by Western blotting, peptide microarray, immunohistochemistry, flow cytometry, or mass spectrometry.
  • the cancer is selected from the group consisting of colorectal cancer, non-small cell lung cancer, renal cell carcinoma, bladder cancer, ovarian cancer, glioblastoma, neuroblastoma, melanoma, breast carcinoma, gastric cancer, and hepatocellular carcinoma.
  • the breast carcinoma is triple-negative breast carcinoma.
  • the OX40 agonist is an agonist anti-human OX40 antibody.
  • the antibody is a monoclonal antibody.
  • the antibody is a humanized or human antibody. In some embodiments, the antibody comprises an IgG1 Fc region. In some embodiments, the antibody comprises an IgG4 Fc region. In some embodiments, the antibody comprises an Fc region comprising a mutation that decreases binding to an Fc receptor.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, 8 or 9; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, 10, 11, 12, 13, or 14; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4, 15 or 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7, 22, 23, 24, 25, 26, 27 or 28.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:26.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:27.
  • the antibody is MEDI6469 or MEDI0562.
  • the OX40 agonist comprises one or more extracellular domains of OX40L.
  • the OX40 agonist is MEDI6383.
  • FIGS. 1A & 1B show the effects of anti-OX40 treatment on T cell function.
  • the graphs depict T cell proliferation ( FIG. 1A ) and IFN ⁇ production ( FIG. 1B ) in response to activation with anti-CD3 and anti-OX40 treatment.
  • FIG. 2 shows the effect of anti-OX40 treatment on Treg activity in an in vitro Treg suppression assay, as compared to control treatment.
  • FIGS. 3A-3C show the effect of anti-OX40 treatment on tumor volume in syngeneic mouse tumor models. Results from the EMT6 breast ( FIG. 3A ), Cloudman melanoma ( FIG. 3B ), and CT26 CRC ( FIG. 3C ) tumor models are shown.
  • FIGS. 4A-4C show the effect of anti-OX40 treatment on tumor volume in syngeneic mouse tumor models. Results from the MC38 CRC ( FIG. 4A ), 51Blim10 CRC ( FIG. 4B ), and JC breast ( FIG. 4C ) tumor models are shown.
  • FIG. 5 provides a heat-map of gene expression in mouse tumor models (as labeled) prior to anti-OX40 treatment.
  • FIGS. 6A & 6B demonstrate a dose-dependent effect of anti-OX40 treatment on peripheral blood cells in EMT6 tumor-bearing mice. Shown are the percentages of Tregs ( FIG. 6A ) and CD8 T cells ( FIG. 6B ) in peripheral blood following treatment with the labeled concentration of anti-OX40 antibody.
  • FIGS. 7A & 7B show the effect of anti-OX40 treatment on numbers of Treg ( FIG. 7A ) and CD8 ( FIG. 7B ) cell infiltrates in EMT6 tumors, compared to control treatment.
  • FIGS. 8A & 8B show the effect of anti-OX40 treatment on numbers of Treg ( FIG. 8A ) and CD8 ( FIG. 8B ) cell infiltrates in JC tumors, compared to control treatment.
  • FIGS. 9A-9D show genes that are upregulated following anti-OX40 treatment, compared to control treatment, in both EMT6 and JC tumor models. Shown are relative expression levels of IFNg ( FIG. 9A ), granzyme A ( FIG. 9B ), perforin ( FIG. 9C ), and TNFa ( FIG. 9D ).
  • FIGS. 10A-10D show genes that are upregulated following anti-OX40 treatment, compared to control treatment, in an EMT6 tumor model. Shown are relative expression levels of H2-aa ( FIG. 10A ), CD86 ( FIG. 10B ), ICOS ( FIG. 10C ), and CXCR3 ( FIG. 10D ).
  • references to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
  • disfunction in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation.
  • disfunctional also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., gamma interferon) and/or target cell killing.
  • T-cell effector functions such as proliferation, cytokine production (e.g., gamma interferon) and/or target cell killing.
  • “Enhancing T cell function” means to induce, cause or stimulate an effector or memory T cell to have a renewed, sustained or amplified biological function.
  • Examples of enhancing T-cell function include: increased secretion of ⁇ -interferon from CD8 + effector T cells, increased secretion of ⁇ -interferon from CD4+ memory and/or effector T-cells, increased proliferation of CD4+ effector and/or memory T cells, increased proliferation of CD8+ effector T-cells, increased antigen responsiveness (e.g., clearance), relative to such levels before the intervention.
  • the level of enhancement is at least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner of measuring this enhancement is known to one of ordinary skill in the art.
  • Tumor immunity refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance.
  • Immunogenicity refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response.
  • acceptor human framework for the purposes herein is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below.
  • An acceptor human framework “derived from” a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less.
  • the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.
  • Bind refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).
  • binding affinity refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described in the following.
  • An “agonist antibody,” as used herein, is an antibody which activates a biological activity of the antigen it binds.
  • an “anti-angiogenic agent” refers to a compound which blocks, or interferes with to some degree, the development of blood vessels.
  • An anti-angiogenic agent may, for instance, be a small molecule or antibody that binds to a growth factor or growth factor receptor involved in promoting angiogenesis.
  • an anti-angiogenic agent is an antibody that binds to vascular endothelial growth factor (VEGF), such as bevacizumab (AVASTIN).
  • VEGF vascular endothelial growth factor
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • FcRs Fc receptors
  • cytotoxic cells e.g. NK cells, neutrophils, and macrophages
  • NK cells express Fc ⁇ RIII only, whereas monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev.
  • ADCC activity of a molecule of interest an in vitro ADCC assay, such as that described in U.S. Pat. No. 5,500,362 or 5,821,337 or U.S. Pat. No. 6,737,056 (Presta), may be performed.
  • Useful effector cells for such assays include PBMC and NK cells.
  • ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. PNAS ( USA ) 95:652-656 (1998).
  • An exemplary assay for assessing ADCC activity is provided in the examples herein.
  • anti-OX40 antibody and “an antibody that binds to OX40” refer to an antibody that is capable of binding OX40 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting OX40.
  • the extent of binding of an anti-OX40 antibody to an unrelated, non-OX40 protein is less than about 10% of the binding of the antibody to OX40 as measured, e.g., by a radioimmunoassay (RIA).
  • RIA radioimmunoassay
  • an antibody that binds to OX40 has a dissociation constant (Kd) of ⁇ 1 ⁇ M, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g. 10 ⁇ 8 M or less, e.g. from 10 ⁇ 8 M to 10 ⁇ 13 M, e.g., from 10 ⁇ 9 M to 10 ⁇ 13 M).
  • Kd dissociation constant
  • an anti-OX40 antibody binds to an epitope of OX40 that is conserved among OX40 from different species.
  • the term “binds”, “specifically binds to” or is “specific for” refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules.
  • an antibody that binds to or specifically binds to a target is an antibody that binds this target with greater affinity, avidity, more readily, and/or with greater duration than it binds to other targets.
  • the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, e.g., by a radioimmunoassay (RIA).
  • an antibody that specifically binds to a target has a dissociation constant (Kd) of ⁇ 1 ⁇ M, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, or ⁇ 0.1 nM.
  • Kd dissociation constant
  • an antibody specifically binds to an epitope on a protein that is conserved among the protein from different species.
  • specific binding can include, but does not require exclusive binding.
  • antibody herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.
  • antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
  • antibody fragments include but are not limited to Fv, Fab, Fab′, Fab′-SH, F(ab′) 2 ; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments.
  • an “antibody that binds to the same epitope” as a reference antibody refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more.
  • An exemplary competition assay is provided herein.
  • binding domain refers to the region of a polypeptide that binds to another molecule.
  • the binding domain can comprise a portion of a polypeptide chain thereof (e.g. the alpha chain thereof) which is responsible for binding an Fc region.
  • One useful binding domain is the extracellular domain of an FcR alpha chain.
  • a polypeptide with a variant IgG Fc with “altered” FcR, ADCC or phagocytosis activity is one which has either enhanced or diminished FcR binding activity (e.g, Fc ⁇ R) and/or ADCC activity and/or phagocytosis activity compared to a parent polypeptide or to a polypeptide comprising a native sequence Fc region.
  • OX40 refers to any native OX40 from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g., mice and rats), unless otherwise indicated.
  • the term encompasses “full-length,” unprocessed OX40 as well as any form of OX40 that results from processing in the cell.
  • the term also encompasses naturally occurring variants of OX40, e.g., splice variants or allelic variants.
  • the amino acid sequence of an exemplary human OX40 is shown in SEQ ID NO:1.
  • OX40 activation refers to activation, of the OX40 receptor. Generally, OX40 activation results in signal transduction.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • cancers include, but not limited to, squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer and gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanomas, nodular melan
  • cancers that are amenable to treatment by the antibodies of the invention include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkins lymphoma (NHL), renal cell cancer, prostate cancer, liver cancer, pancreatic cancer, soft-tissue sarcoma, kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer, mesothelioma, and multiple myeloma.
  • the cancer is selected from: non-small cell lung cancer, glioblastoma, neuroblastoma, melanoma, breast carcinoma (e.g.
  • the cancer is selected from: non-small cell lung cancer, colorectal cancer, glioblastoma and breast carcinoma (e.g. triple-negative breast cancer), including metastatic forms of those cancers.
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer cancer
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  • cell proliferative disorder and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation.
  • the cell proliferative disorder is cancer.
  • chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
  • the “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • “Complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass), which are bound to their cognate antigen.
  • C1q the first component of the complement system
  • a CDC assay e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), may be performed.
  • Polypeptide variants with altered Fc region amino acid sequences polypeptides with a variant Fc region
  • increased or decreased C1q binding capability are described, e.g., in U.S. Pat. No. 6,194,551 B1 and WO 1999/51642. See also, e.g., Idusogie et al. J. Immunol. 164: 4178-4184 (2000).
  • cytostatic agent refers to a compound or composition which arrests growth of a cell either in vitro or in vivo.
  • a cytostatic agent may be one which significantly reduces the percentage of cells in S phase.
  • Further examples of cytostatic agents include agents that block cell cycle progression by inducing G0/G1 arrest or M-phase arrest.
  • the humanized anti-Her2 antibody trastuzumab (HERCEPTIN®) is an example of a cytostatic agent that induces G0/G1 arrest.
  • Classical M-phase blockers include the vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin.
  • Certain agents that arrest G1 also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C.
  • Taxanes are anticancer drugs both derived from the yew tree.
  • Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analogue of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization, which results in the inhibition of mitosis in cells.
  • cytotoxic agent refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction.
  • Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal
  • a “depleting anti-OX40 antibody,” is an anti-OX40 antibody that kills or depletes OX40-expressing cells. Depletion of OX40 expressing cells can be achieved by various mechanisms, such as antibody-dependent cell-mediated cytotoxicity and/or phagocytosis. Depletion of OX40-expressing cells may be assayed in vitro, and exemplary methods for in vitro ADCC and phagocytosis assays are provided herein.
  • the OX40-expressing cell is a human CD4+ effector T cell.
  • the OX40-expressing cell is a transgenic BT474 cell that expresses human OX40.
  • “Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation.
  • an “effective amount” of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • Fc receptor or “FcR” describes a receptor that binds to the Fc region of an antibody.
  • an FcR is a native human FcR.
  • an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and alternatively spliced forms of those receptors.
  • Fc ⁇ RII receptors include Fc ⁇ RIIA (an “activating receptor”) and Fc ⁇ RIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
  • Activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain.
  • Inhibiting receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain.
  • ITAM immunoreceptor tyrosine-based activation motif
  • ITIM immunoreceptor tyrosine-based inhibition motif
  • FcR Fc receptor
  • FcRn neonatal receptor
  • Methods of measuring binding to FcRn are known (see, e.g., Ghetie and Ward., Immunol.
  • Binding to human FcRn in vivo and serum half life of human FcRn high affinity binding polypeptides can be assayed, e.g., in transgenic mice or transfected human cell lines expressing human FcRn, or in primates to which the polypeptides with a variant Fc region are administered.
  • WO 2000/42072 (Presta) describes antibody variants with improved or diminished binding to FcRs. See also, e.g., Shields et al. J. Biol. Chem. 9(2):6591-6604 (2001).
  • Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region.
  • the term includes native sequence Fc regions and variant Fc regions.
  • a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain.
  • the C-terminal lysine (Lys447) of the Fc region may or may not be present.
  • numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991.
  • a “functional Fc region” possesses an “effector function” of a native sequence Fc region.
  • effector functions include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor; BCR), etc.
  • Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays as disclosed, for example, in definitions herein.
  • Human effector cells refer to leukocytes that express one or more FcRs and perform effector functions. In certain embodiments, the cells express at least Fc ⁇ RIII and perform ADCC effector function(s). Examples of human leukocytes which mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells, and neutrophils.
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • monocytes cytotoxic T cells
  • neutrophils neutrophils.
  • the effector cells may be isolated from a native source, e.g., from blood.
  • “Framework” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues.
  • the FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.
  • full length antibody “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.
  • host cell refers to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells.
  • Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.
  • a “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • a “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences.
  • the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences.
  • the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest , Fifth Edition, NIH Publication 91-3242, Bethesda Md. (1991), vols. 1-3.
  • the subgroup is subgroup kappa I as in Kabat et al., supra.
  • the subgroup is subgroup III as in Kabat et al., supra.
  • a “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs.
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody.
  • a humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody.
  • a “humanized form” of an antibody, e.g., a non-human antibody refers to an antibody that has undergone humanization.
  • hypervariable region refers to each of the regions of an antibody variable domain which are hypervariable in sequence (“complementarity determining regions” or “CDRs”) and/or form structurally defined loops (“hypervariable loops”) and/or contain the antigen-contacting residues (“antigen contacts”).
  • CDRs complementarity determining regions
  • hypervariable loops form structurally defined loops
  • antigen contacts antigen contacts
  • antibodies comprise six HVRs: three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3).
  • Exemplary HVRs herein include:
  • HVR residues and other residues in the variable domain are numbered herein according to Kabat et al., supra.
  • an “immunoconjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.
  • mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats).
  • domesticated animals e.g., cows, sheep, cats, dogs, and horses
  • primates e.g., humans and non-human primates such as monkeys
  • rabbits e.g., mice and rats
  • rodents e.g., mice and rats.
  • the individual or subject is a human.
  • “Promoting cell growth or proliferation” means increasing a cell's growth or proliferation by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%.
  • an “isolated” antibody is one which has been separated from a component of its natural environment.
  • an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC).
  • electrophoretic e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis
  • chromatographic e.g., ion exchange or reverse phase HPLC
  • nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment.
  • An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.
  • isolated nucleic acid encoding an anti-OX40 antibody refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts.
  • polyclonal antibody preparations typically include different antibodies directed against different determinants (epitopes)
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
  • naked antibody refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel.
  • the naked antibody may be present in a pharmaceutical formulation.
  • “Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures.
  • native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain.
  • the light chain of an antibody may be assigned to one of two types, called kappa ( ⁇ ) and lambda ( ⁇ ), based on the amino acid sequence of its constant domain.
  • a “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature.
  • Native sequence human Fc regions include a native sequence human IgG1 Fc region (non-A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof.
  • package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.
  • Percent (%) amino acid sequence identity with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • a “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • antibodies of the invention are used to delay development of a disease or to slow the progression of a disease.
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
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  • variable region refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen.
  • the variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs).
  • FRs conserved framework regions
  • HVRs hypervariable regions
  • antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).
  • a “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s).
  • the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide.
  • the variant Fc region herein will preferably possess at least about 80% homology with a native sequence Fc region and/or with an Fc region of a parent polypeptide, and most preferably at least about 90% homology therewith, more preferably at least about 95% homology therewith.
  • vector refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked.
  • the term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced.
  • Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”
  • VH subgroup III consensus framework comprises the consensus sequence obtained from the amino acid sequences in variable heavy subgroup III of Kabat et al.
  • the VH subgroup III consensus framework amino acid sequence comprises at least a portion or all of each of the following sequences:
  • VL subgroup I consensus framework comprises the consensus sequence obtained from the amino acid sequences in variable light kappa subgroup I of Kabat et al.
  • the VH subgroup I consensus framework amino acid sequence comprises at least a portion or all of each of the following sequences:
  • cytotoxic agent refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction.
  • Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
  • radioactive isotopes e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu
  • chemotherapeutic agents e.g., At211, I131, I125, Y90, Re186
  • Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signalling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.
  • the cytotoxic agent is selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signalling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism.
  • the cytotoxic agent is a taxane.
  • the taxane is paclitaxel or docetaxel.
  • the cytotoxic agent is a platinum agent. In one embodiment the cytotoxic agent is an antagonist of EGFR. In one embodiment the antagonist of EGFR is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib). In one embodiment the cytotoxic agent is a RAF inhibitor. In one embodiment, the RAF inhibitor is a BRAF and/or CRAF inhibitor. In one embodiment the RAF inhibitor is vemurafenib. In one embodiment the cytotoxic agent is a PI3K inhibitor.
  • “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer.
  • chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirol
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, es
  • Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (let
  • Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab
  • Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizum
  • Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.”
  • EGFR inhibitors refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity
  • Examples of such agents include antibodies and small molecules that bind to EGFR.
  • antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No.
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH).
  • EGFR antagonists include small molecules such as compounds described in U.S. Pat. Nos.
  • EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033,2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperid
  • Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted
  • Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin,
  • Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective
  • celecoxib or etoricoxib proteosome inhibitor
  • CCI-779 tipifarnib (R11577); orafenib, ABT510
  • Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®)
  • pixantrone farnesyltransferase inhibitors
  • SCH 6636 farnesyltransferase inhibitors
  • pharmaceutically acceptable salts, acids or derivatives of any of the above as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone
  • FOLFOX an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.
  • Chemotherapeutic agents also include non-steroidal anti-inflammatory drugswith analgesic, antipyretic and anti-inflammatory effects.
  • NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase.
  • Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumirac
  • NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • cytokine is a generic term for proteins released by one cell population that act on another cell as intercellular mediators.
  • cytokines are lymphokines, monokines; interleukins (ILs) such as IL-1, IL-1a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, IL-15; a tumor necrosis factor such as TNF- ⁇ or TNF- ⁇ ; and other polypeptide factors including LIF and kit ligand (KL) and gamma interferon.
  • cytokine includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native-sequence cytokines, including synthetically produced small-molecule entities and pharmaceutically acceptable derivatives and salts thereof.
  • PD-1 axis binding antagonist is a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partner, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis—with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, target cell killing).
  • a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.
  • PD-1 binding antagonists is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1, PD-L2.
  • the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its binding partners.
  • the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2.
  • PD-1 binding antagonists include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2.
  • a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • the PD-1 binding antagonist is an anti-PD-1 antibody.
  • a PD-1 binding antagonist is MDX-1 106 described herein.
  • a PD-1 binding antagonist is Merck 3745 described herein.
  • a PD-1 binding antagonist is CT-011 described herein.
  • PD-L1 binding antagonists is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1, B7-1.
  • a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners.
  • the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1.
  • the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1, B7-1.
  • a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • a PD-L1 binding antagonist is an anti-PD-L1 antibody.
  • an anti-PD-L1 antibody is YW243.55.S70 described herein.
  • an anti-PD-L1 antibody is MDX-1 105 described herein.
  • an anti-PD-L1 antibody is MPDL3280A described herein.
  • PD-L2 binding antagonists is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1.
  • a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partners.
  • the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1.
  • the PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1.
  • a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • a PD-L2 binding antagonist is an immunoadhesin.
  • phagocytosis means the internalization of cells or particulate matter by cells.
  • the phagocytic cells or phagocytes are macrophages or neutrophils.
  • the cells are cells that express human OX40.
  • Methods for assaying phagocytosis are known in the art and include use of microscopy to detect the presence of cells internalized within another cells.
  • phagocytosis is detected using FACS, e.g., by detecting presence of a detectably labeled cell within another cell (which may be detectably labeled, e.g., with a different label than the first cell).
  • the phrase “does not possess substantial activity” or “substantially no activity” with respect to an antibody, as used herein, means the antibody does not exhibit an activity that is above background level (in some embodiments, that is above background level that is statistically significant).
  • the phrase “little to no activity” with respect to an antibody, as used herein, means the antibody does not display a biologically meaningful amount of a function.
  • the function can be measured or detected according to any assay or technique known in the art, including, e.g., those described herein.
  • antibody function is stimulation of effector T cell proliferation and/or cytokine secretion.
  • biomarker refers generally to a molecule, including a gene, mRNA, protein, carbohydrate structure, or glycolipid, the expression of which in or on a tissue or cell or secreted can be detected by known methods (or methods disclosed herein) and is predictive or can be used to predict (or aid prediction) for a cell, tissue, or patient's responsiveness to treatment regimes.
  • a biomarker may refer to a gene or protein, e.g., the level of expression of the gene or protein detected in one or more cells.
  • a biomarker may refer to a cell type of interest, e.g., the number of a cell type of interest detected in one or more samples.
  • tissue sample is meant a collection of cells or fluids obtained from a cancer patient.
  • the source of the tissue or cell sample may be solid tissue as from a fresh, frozen and/or preserved organ or tissue sample or biopsy or aspirate; blood or any blood constituents; bodily fluids such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject.
  • the tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like.
  • tumor samples herein include, but are not limited to, tumor biopsy, fine needle aspirate, bronchiolar lavage, pleural fluid, sputum, urine, a surgical specimen, circulating tumor cells, serum, plasma, circulating plasma proteins, ascitic fluid, primary cell cultures or cell lines derived from tumors or exhibiting tumor-like properties, as well as preserved tumor samples, such as formalin-fixed, paraffin-embedded tumor samples or frozen tumor samples.
  • phrases “based on expression of” when used herein means that information about expression level or presence or absence of expression (e.g., presence or absence or prevalence of (e.g., percentage of cells displaying) of the one or more biomarkers herein (e.g., presence or absence of or amount or prevalence of FcR-expressing cells, or e.g., presence or absence or amount or prevalence of human effector cells) is used to inform a treatment decision, information provided on a package insert, or marketing/promotional guidance etc.
  • information about expression level or presence or absence of expression e.g., presence or absence or prevalence of (e.g., percentage of cells displaying) of the one or more biomarkers herein (e.g., presence or absence of or amount or prevalence of FcR-expressing cells, or e.g., presence or absence or amount or prevalence of human effector cells) is used to inform a treatment decision, information provided on a package insert, or marketing/promotional guidance etc.
  • a cancer or biological sample which “has human effector cells” is one which, in a diagnostic test, has human effector cells present in the sample (e.g., infiltrating human effector cells).
  • a cancer or biological sample which “has FcR-expressing cells” is one which, in a diagnostic test, has FcR-expressing present in the sample (e.g., infiltrating FcR-expressing cells).
  • FcR is Fc ⁇ R.
  • FcR is an activating Fc ⁇ R.
  • the phrase “recommending a treatment” as used herein refers to using the information or data generated relating to the level or presence of c-met in a sample of a patient to identify the patient as suitably treated or not suitably treated with a therapy.
  • the therapy may comprise c-met antibody (e.g., onartuzumab).
  • the therapy may comprise VEGF antagonist (e.g., bevacizumab).
  • the therapy may comprise anti-human OX40 agonist antibody.
  • the information or data may be in any form, written, oral or electronic.
  • using the information or data generated includes communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof.
  • communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof are performed by a computing device, analyzer unit or combination thereof. In some further embodiments, communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, dispensing, or combinations thereof are performed by an individual (e.g., a laboratory or medical professional).
  • the information or data includes a comparison of the amount or prevalence of FcR expressing cells to a reference level. In some embodiments, the information or data includes a comparison of the amount or prevalence of human effector cells to a reference level.
  • the information or data includes an indication that human effector cells or FcR-expressing cells are present or absent in the sample. In some embodiments, the information or data includes an indication that FcR-expressing cells and/or human effector cells are present in a particular percentage of cells (e.g., high prevalence). In some embodiments, the information or data includes an indication that the patient is suitably treated or not suitably treated with a therapy comprising anti-human OX40 agonist antibody.
  • detection includes any means of detecting, including direct and indirect detection.
  • the “amount” or “level” of a biomarker associated with an increased clinical benefit to an individual is a detectable level in a biological sample. These can be measured by methods known to one skilled in the art and also disclosed herein. The expression level or amount of biomarker assessed can be used to determine the response to the treatment.
  • “Elevated expression,” “elevated expression levels,” or “elevated levels” refers to an increased expression or increased levels of a biomarker in an individual relative to a control, such as an individual or individuals who are not suffering from the disease or disorder (e.g., cancer), a tumor with a known responsiveness to a treatment (e.g., with an OX40 agonist), an internal control (e.g., housekeeping biomarker), or a reference number (e.g., a set threshold amount, such as a threshold based on clinical outcome data).
  • a control such as an individual or individuals who are not suffering from the disease or disorder (e.g., cancer), a tumor with a known responsiveness to a treatment (e.g., with an OX40 agonist), an internal control (e.g., housekeeping biomarker), or a reference number (e.g., a set threshold amount, such as a threshold based on clinical outcome data).
  • Reduced expression refers to a decrease expression or decreased levels of a biomarker in an individual relative to a control, such as an individual or individuals who are not suffering from the disease or disorder (e.g., cancer), a tumor with a known responsiveness to a treatment (e.g., with an OX40 agonist), an internal control (e.g., housekeeping biomarker), or a reference number (e.g., a set threshold amount, such as a threshold based on clinical outcome data). In some embodiments, reduced expression is little or no expression.
  • a control such as an individual or individuals who are not suffering from the disease or disorder (e.g., cancer), a tumor with a known responsiveness to a treatment (e.g., with an OX40 agonist), an internal control (e.g., housekeeping biomarker), or a reference number (e.g., a set threshold amount, such as a threshold based on clinical outcome data).
  • reduced expression is little or no expression.
  • housekeeping gene or “housekeeping biomarker” as used herein may refer to any gene or genes thought to be constitutively expressed in a cell in normal and/or pathological states. Such a gene may be used, for example, as a reference, since its expression is detectable at a consistent amount across different physiological conditions.
  • a housekeeping gene may encode a protein required for basic cellular function and/or maintenance.
  • diagnosis is used herein to refer to the identification or classification of a molecular or pathological state, disease or condition (e.g., cancer).
  • diagnosis may refer to identification of a particular type of cancer.
  • Diagnosis may also refer to the classification of a particular subtype of cancer, e.g., by histopathological criteria, or by molecular features (e.g., a subtype characterized by expression of one or a combination of biomarkers (e.g., particular genes or proteins encoded by said genes)).
  • a method of aiding diagnosis of a disease or condition can comprise measuring certain biomarkers in a biological sample from an individual.
  • sample refers to a composition that is obtained or derived from a subject and/or individual of interest that contains a cellular and/or other molecular entity that is to be characterized and/or identified, for example based on physical, biochemical, chemical and/or physiological characteristics.
  • disease sample and variations thereof refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and/or molecular entity that is to be characterized.
  • Samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, perspiration, mucus, tumor lysates, and tissue culture medium, tissue extracts such as homogenized tissue, tumor tissue, cellular extracts, and combinations thereof.
  • tissue sample or “cell sample” is meant a collection of similar cells obtained from a tissue of a subject or individual.
  • the source of the tissue or cell sample may be solid tissue as from a fresh, frozen and/or preserved organ, tissue sample, biopsy, and/or aspirate; blood or any blood constituents such as plasma; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject.
  • the tissue sample may also be primary or cultured cells or cell lines.
  • the tissue or cell sample is obtained from a disease tissue/organ.
  • the tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like.
  • a “section” of a tissue sample is meant a single part or piece of a tissue sample, e.g. a thin slice of tissue or cells cut from a tissue sample. It is understood that multiple sections of tissue samples may be taken and subjected to analysis according to the present invention, provided that it is understood that the present invention comprises a method whereby the same section of tissue sample is analyzed at both morphological and molecular levels, or is analyzed with respect to protein or nucleic acid.
  • correlate or “correlating” is meant comparing, in any way, the performance and/or results of a first analysis or protocol with the performance and/or results of a second analysis or protocol. For example, one may use the results of a first analysis or protocol in carrying out a second protocols and/or one may use the results of a first analysis or protocol to determine whether a second analysis or protocol should be performed. With respect to the embodiment of polypeptide analysis or protocol, one may use the results of the polypeptide expression analysis or protocol to determine whether a specific therapeutic regimen should be performed. With respect to the embodiment of polynucleotide analysis or protocol, one may use the results of the polynucleotide expression analysis or protocol to determine whether a specific therapeutic regimen should be performed.
  • “Individual response” or “response” can be assessed using any endpoint indicating a benefit to the individual, including, without limitation, (1) inhibition, to some extent, of disease progression (e.g., cancer progression), including slowing down and complete arrest; (2) a reduction in tumor size; (3) inhibition (i.e., reduction, slowing down or complete stopping) of cancer cell infiltration into adjacent peripheral organs and/or tissues; (4) inhibition (i.e. reduction, slowing down or complete stopping) of metastasis; (5) relief, to some extent, of one or more symptoms associated with the disease or disorder (e.g., cancer); (6) increase or extend in the length of survival, including overall survival and progression free survival; and/or (9) decreased mortality at a given point of time following treatment.
  • disease progression e.g., cancer progression
  • a reduction in tumor size i.e., reduction, slowing down or complete stopping
  • inhibition i.e. reduction, slowing down or complete stopping
  • metastasis i.e. reduction, slow
  • an “effective response” of a patient or a patient's “responsiveness” to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a patient at risk for, or suffering from, a disease or disorder, such as cancer.
  • a disease or disorder such as cancer.
  • such benefit includes any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.
  • extending survival is meant increasing overall or progression free survival in a treated patient relative to an untreated patient (i.e. relative to a patient not treated with the medicament), or relative to a patient who does not express a biomarker at the designated level, and/or relative to a patient treated with an approved anti-tumor agent.
  • An objective response refers to a measurable response, including complete response (CR) or partial response (PR).
  • a subject having cancer to an OX40 agonist treatment provides methods for predicting responsiveness of a subject having cancer to an OX40 agonist treatment. These methods are based in part on the discovery described herein that the expression level of specific biomarkers correlates with responsiveness to OX40 agonist treatment. For example, an increased expression level of genes such as CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R correlates with responsiveness to OX40 agonist treatment. Additionally, a decreased expression level of genes such as CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1 was also found to correlate with responsiveness to OX40 agonist treatment.
  • genes such as CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF
  • RNA samples obtained from the subject, where the subject has been treated with an OX40 agonist, and where the one or more marker genes are selected from ARG1, CCL2, CCL22, CCL5, CCR5, CD226, CD27, CD274, CD28, CD3E, CD40, CD8A, CD8b, CXCL10, CXCL9, EOMES, FasL, Fcgr1/CD64, FOXP3, GZMA, GZMB, HAVCR2, ICAM1, IDO1, IFNg, IL10, IL12A (TDO2), IL13, IL2, IL7R, ITGAM, KLRK1, LAG3, MAP4K1, MS4A1, PDCD1, PDCD1LG2, PRF1, PTPRC, TNF, TNFRSF14, TNFRSF9, and TNFSF4; and determining the treatment
  • Yet further provided herein are methods monitoring responsiveness of a subject to an OX40 agonist treatment by measuring the expression level of one or more marker genes in a sample containing leukocytes obtained from the subject, where the subject has been treated with an OX40 agonist, and where the one or more marker genes are selected from BTLA, CD4, CD69, CD80, CD83, CD86, CSF2, CTLA4, CXCR3, Fcgr2b/CD32, Fcgr3/CD16, H2-aa, H2-d, H2-k, ICOS, IL10, PDCA1, and TNFRSF18; and classifying the subject as responsive or non-responsive to said treatment based on the expression level of said one or more marker genes in the sample obtained from the subject, as compared with a reference, wherein an increased expression level of the one or more marker genes as compared with the reference indicates a responsive subject.
  • These methods are based in part on the discovery described herein that the expression level of specific biomarkers is upregulated upon OX40 agonist treatment specifically
  • an OX40 agonist is an isolated antibody that binds to human OX40.
  • Antibodies suitable for use in the methods of the invention include antibodies that bind to human OX40. Descriptions of anti-OX40 antibodies (e.g., anti-human OX40 agonist antibodies) may be found in US PG Pub. No. US2015/0307617 and International Publication No. WO/2015/153513, which are each incorporated by reference herein in their entirety.
  • the anti-human OX40 agonist antibody binds human OX40 with an affinity of less than or equal to about 0.45 nM. In some embodiments, the anti-human OX40 antibody binds human OX40 with an affinity of less than or equal to about 0.4 nM. In some embodiments, the anti-human OX40 antibody binds human OX40 with an affinity of less than or equal to about 0.5 nM. In some embodiments, the binding affinity is determined using radioimmunoassay.
  • the anti-human OX40 agonist antibody binds human OX40 and cynomolgus OX40. In some embodiments, binding is determined using a FACS assay. In some embodiments, binding to human OX40 has an EC50 of about 0.2 ug/ml. In some embodiments, binding to human OX40 has an EC50 of about 0.3 ug/ml or lower. In some embodiments, binding to cynomolgus OX40 has an EC50 of about 1.5 ug/ml. In some embodiments, binding to cynomolgus OX40 has an EC50 of about 1.4 ug/ml.
  • the anti-human OX40 agonist antibody does not bind to rat OX40 or mouse OX40.
  • the anti-human OX40 agonist antibody is a depleting anti-human OX40 antibody (e.g., depletes cells that express human OX40).
  • the human OX40 expressing cells are CD4+ effector T cells.
  • the human OX40 expressing cells are Treg cells.
  • depleting is by ADCC and/or phagocytosis.
  • the antibody mediates ADCC by binding Fc ⁇ R expressed by a human effector cell and activating the human effector cell function.
  • the antibody mediates phagocytosis by binding Fc ⁇ R expressed by a human effector cell and activating the human effector cell function.
  • Exemplary human effector cells include, e.g., macrophage, natural killer (NK) cells, monocytes, neutrophils.
  • the human effector cell is macrophage.
  • the human effector cell is NK cells.
  • depletion is not by apoptosis.
  • the anti-human OX40 agonist antibody has a functional Fc region.
  • effector function of a functional Fc region is ADCC.
  • effector function of a functional Fc region is phagocytosis.
  • effector function of a functional Fc region is ADCC and phagocytosis.
  • the Fc region is human IgG1. In some embodiments, the Fc region is human IgG4.
  • the anti-human OX40 agonist antibody does not induce apoptosis in OX40-expressing cells (e.g., Treg).
  • apoptosis is assayed using an antibody concentration of 30 ug/ml, e.g., by determining whether apoptosis has occurred using annexin V and proprodium iodide stained Treg.
  • the anti-human OX40 agonist antibody enhances CD4+ effector T cell function, for example, by increasing CD4+ effector T cell proliferation and/or increasing gamma interferon production by the CD4+ effector T cell (for example, as compared to proliferation and/or cytokine production prior to treatment with anti-human OX40 agonist antibody).
  • the cytokine is gamma interferon.
  • the anti-human OX40 agonist antibody increases number of intratumoral (infiltrating) CD4+ effector T cells (e.g., total number of CD4+ effector T cells, or e.g., percentage of CD4+ cells in CD45+ cells), e.g., as compared to number of intratumoral (infiltrating) CD4+ T cells prior to treatment with anti-human OX40 agonist antibody.
  • the anti-human OX40 agonist antibody increases number of intratumoral (infiltrating) CD4+ effector T cells that express gamma interferon (e.g., total gamma interferon expressing CD4+ cells, or e.g., percentage of gamma interferon expressing CD4+ cells in total CD4+ cells), e.g., as compared to number of intratumoral (infiltrating) CD4+ T cells that express gamma interferon prior to treatment with anti-human OX40 agonist antibody.
  • gamma interferon e.g., total gamma interferon expressing CD4+ cells, or e.g., percentage of gamma interferon expressing CD4+ cells in total CD4+ cells
  • the anti-human OX40 agonist antibody increases number of intratumoral (infiltrating) CD8+ effector T cells (e.g., total number of CD8+ effector T cells, or e.g., percentage of CD8+ in CD45+ cells), e.g., as compared to number of intratumoral (infiltrating) CD8+ T effector cells prior to treatment with anti-human OX40 agonist antibody.
  • the anti-human OX40 agonist antibody increases number of intratumoral (infiltrating) CD8+ effector T cells that express gamma interferon (e.g., percentage of CD8+ cells that express gamma interferon in total CD8+ cells), e.g., compared to number of intratumoral (infiltrating) CD8+ T cells that express gamma interferon prior to treatment with anti-human OX40 agonist antibody.
  • the anti-human OX40 agonist antibody enhances memory T cell function, for example by increasing memory T cell proliferation and/or increasing cytokine production by the memory cell.
  • the cytokine is gamma interferon.
  • the anti-human OX40 agonist antibody inhibits Treg function, for example, by decreasing Treg suppression of effector T cell function (e.g., effector T cell proliferation and/or effector T cell cytokine secretion).
  • the effector T cell is a CD4+ effector T cell.
  • the anti-human OX40 agonist antibody reduces the number of intratumoral (infiltrating) Treg (e.g., total number of Treg or e.g., percentage of Fox3p+ cells in CD4+ cells).
  • the anti-human OX40 agonist antibody is engineered to increase effector function (e.g., compared to effector function in a wild-type IgG1).
  • the antibody has increased binding to a Fc ⁇ receptor.
  • the antibody lacks fucose attached (directly or indirectly) to the Fc region.
  • the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%.
  • the Fc region comprises bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc.
  • the antibody comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).
  • the anti-human OX40 agonist antibody increases OX40 signal transduction in a target cell that expresses OX40.
  • OX40 signal transduction is detected by monitoring NFkB downstream signaling.
  • the anti-human OX40 agonist antibody is stable after treatment at 40 C for two weeks.
  • the anti-human OX40 agonist antibody binds human effector cells, e.g., binds Fc ⁇ R (e.g., an activating Fc ⁇ R) expressed by human effector cells.
  • the human effector cell performs (is capable of performing) ADCC effector function.
  • the human effector cell performs (is capable of performing) phagocytosis effector function.
  • the anti-human OX40 agonist antibody comprising a variant IgG1 Fc polypeptide comprising a mutation that eliminates binding to human effector cells has diminished activity (e.g., CD4+ effector T cell function, e.g., proliferation), relative to anti-human OX40 agonist antibody comprising native sequence IgG1 Fc portion.
  • the anti-human OX40 agonist antibody comprising a variant IgG1 Fc polypeptide comprising a mutation that eliminates binding to human effector cells does not possess substantial activity (e.g., CD4+ effector T cell function, e.g., proliferation).
  • antibody cross-linking is required for anti-human OX40 agonist antibody function.
  • function is stimulation of CD4+ effector T cell proliferation.
  • antibody cross-linking is determined by providing anti-human OX40 agonist antibody adhered on a solid surface (e.g., a cell culture plate).
  • antibody cross-linking is determined by introducing a mutation in the antibody's IgG1 Fc portion (e.g., a DANA mutation) and testing function of the mutant antibody.
  • the anti-human OX40 agonist antibody competes for binding to human OX40 with OX40L. In some embodiments, addition of OX40L does not enhance anti-human OX40 antibody function in an in vitro assay.
  • the anti-human OX40 agonist antibodies include any one, any combination, or all of the following properties: (1) binds human OX40 with an affinity of less than or equal to about 0.45 nM, in some embodiments, binds human OX40 with an affinity of less than or equal to about 0.4 nM, in some embodiments, binds human OX40 with an affinity of less than or equal to about 0.5 nM, in some embodiments, the binding affinity is determined using radioimmunoassay; (2) binds human OX40 and cynomolgus OX40, in some embodiments, binding is determined using a FACS assay, (3) binds human OX40 with an EC50 of about 0.2 ug/ml, in some embodiments, binds to human OX40 has an EC50 of about 0.3 ug/ml or lower, in some embodiments, binds to cynomolgus OX40 with an EC50 of about 1.5 ug/ml
  • the effector T cell is a CD4+ effector T cell, (10) increases OX40 signal transduction in a target cell that expresses OX40 (in some embodiments, OX40 signal transduction is detected by monitoring NFkB downstream signaling), (11) is stable after treatment at 40 C for two weeks, (12) binds human effector cells, e.g., binds Fc ⁇ R expressed by human effector cells, (13) anti-human OX40 agonist antibody comprising a variant IgG1 Fc polypeptide comprising a mutation that eliminates binding to human effector cells (e.g., N297G) has diminished activity (e.g., CD4+ effector T cell function, e.g., proliferation), relative to anti-human OX40 agonist antibody comprising native sequence IgG1 Fc portion, in some embodiment, the anti-human OX40 agonist antibody comprising a variant IgG1 Fc polypeptide comprising a mutation that eliminates binding to human effector cells (e.g.
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • HVR-H1 comprising the amino acid sequence of SEQ ID NO:2
  • HVR-H2 comprising the amino acid sequence of SEQ ID NO:3
  • HVR-H3 comprising the amino acid sequence of SEQ ID NO:4
  • HVR-L1 comprising the amino acid sequence of SEQ ID NO:5
  • HVR-L2
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:4.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:4 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:4, HVR-L3 comprising the amino acid sequence of SEQ ID NO:7, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:3.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4.
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • an anti-human OX40 agonist antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:4; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • the invention provides an anti-human OX40 agonist antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7.
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26.
  • HVR-H1 comprising the amino acid sequence of SEQ ID NO:2
  • HVR-H2 comprising the amino acid sequence of SEQ ID NO:3
  • HVR-H3 comprising the amino acid sequence of SEQ ID NO:4
  • HVR-L1 comprising the amino acid sequence of SEQ ID NO:5
  • HVR-L2
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:4 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:26.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:4, HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:3.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:4; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26.
  • the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:26.
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:27.
  • HVR-H1 comprising the amino acid sequence of SEQ ID NO:2
  • HVR-H2 comprising the amino acid sequence of SEQ ID NO:3
  • HVR-H3 comprising the amino acid sequence of SEQ ID NO:4
  • HVR-L1 comprising the amino acid sequence of SEQ ID NO:5
  • HVR-L2
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:4 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:27.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:4, HVR-L3 comprising the amino acid sequence of SEQ ID NO:27, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:3.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:4; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:27.
  • the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:27.
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, 8 or 9; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, 10, 11, 12, 13 or 14; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4, 15, or 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7, 22, 23, 24, 25, 26, 27, or 28.
  • HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, 8 or 9
  • HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, 10, 11, 12, 13 or 14
  • HVR-H3 comprising the amino acid sequence of SEQ ID
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 2, 8 or 9; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3, 10, 11, 12, 13 or 14; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 4, 15, or 19.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 4, 15, or 19.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:4, 15, or 19 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 7, 22, 23, 24, 25, 26, 27, or 28.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 4, 15, or 19, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 7, 22, 23, 24, 25, 26, 27, or 28, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3, 10, 11, 12, 13 or 14.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 2, 8 or 9; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3, 10, 11, 12, 13 or 14; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 4, 15, or 19.
  • the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 7, 22, 23, 24, 25, 26, 27, or 28.
  • the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 7, 22, 23, 24, 25, 26, 27, or 28.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 2, 8 or 9, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3, 10, 11, 12, 13 or 14, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 4, 15, or 19; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 7, 22, 23, 24, 25, 26, 27, or 28.
  • the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 2, 8 or 9; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3, 10, 11, 12, 13 or 14; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 4, 15, or 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 7, 22, 23, 24, 25, 26, 27, or 28.
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:172; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:173; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:174; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:175.
  • HVR-H1 comprising the amino acid sequence of SEQ ID NO:172
  • HVR-H2 comprising the amino acid sequence of SEQ ID NO:173
  • HVR-H3 comprising the amino acid sequence of SEQ ID NO:174
  • HVR-L1 comprising the amino acid sequence of SEQ ID NO:5
  • HVR-H2 is not DMYPDAAAASYNQKFRE (SEQ ID NO:222).
  • HVR-H3 is not APRWAAAA (SEQ ID NO:223).
  • HVR-L3 is not QAAAAAAAT (SEQ ID NO:224).
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:172; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:173; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:174.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:174.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:174 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:175.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:174, HVR-L3 comprising the amino acid sequence of SEQ ID NO:175, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:173.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:172; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:173; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:174.
  • HVR-H2 is not DMYPDAAAASYNQKFRE (SEQ ID NO:222).
  • HVR-H3 is not APRWAAAA (SEQ ID NO:223).
  • HVR-L3 is not QAAAAAAAT (SEQ ID NO:224).
  • the invention provides an antibody comprising (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:175.
  • HVR-L3 is not QAAAAAAAT (SEQ ID NO:224).
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:172, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:173, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:174; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:175.
  • the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:172; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:173; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:174; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:175.
  • HVR-H2 is not DMYPDAAAASYNQKFRE (SEQ ID NO:222).
  • HVR-H3 is not APRWAAAA (SEQ ID NO:223).
  • HVR-L3 is not QAAAAAAAT (SEQ ID NO:224).
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42.
  • HVR-H1 comprising the amino acid sequence of SEQ ID NO:29
  • HVR-H2 comprising the amino acid sequence of SEQ ID NO:30
  • HVR-H3 comprising the amino acid sequence of SEQ ID NO:33
  • HVR-L1 comprising the amino acid sequence of SEQ ID NO:37
  • HVR-L2
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:33.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:33 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:42.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:33, HVR-L3 comprising the amino acid sequence of SEQ ID NO:42, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:30.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33.
  • the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42.
  • the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:33; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42.
  • the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:40; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42.
  • HVR-H1 comprising the amino acid sequence of SEQ ID NO:29
  • HVR-H2 comprising the amino acid sequence of SEQ ID NO:30
  • HVR-H3 comprising the amino acid sequence of SEQ ID NO:33
  • HVR-L1 comprising the amino acid sequence of SEQ ID NO:37
  • HVR-L2
  • the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:40; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42.
  • the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:40; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:33; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:40, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42.
  • the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:40; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, 31, or 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, 40 or 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42, 43, or 44.
  • HVR-H1 comprising the amino acid sequence of SEQ ID NO:29
  • HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, 31, or 32
  • HVR-H3 comprising the amino acid sequence of SEQ ID NO:33
  • HVR-L1 comprising the
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30, 31, or 32; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:33 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, 43, or 44.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:33, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, 43, or 44, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39, 40 or 41.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, 31, or 32; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33.
  • the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39, 40 or 41; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, 43, or 44.
  • the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39, 40 or 41; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, 43, or 44.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30, 31, or 32, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:33; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39, 40 or 41, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, 43, or 44.
  • the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30, 31, or 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39, 40 or 41; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 42, 43, or 44.
  • the invention provides an anti-human OX40 agonist antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:175; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:177; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:178.
  • HVR-H1 comprising the amino acid sequence of SEQ ID NO:29
  • HVR-H2 comprising the amino acid sequence of SEQ ID NO:175
  • HVR-H3 comprising the amino acid sequence of SEQ ID NO:33
  • HVR-L1 comprising the amino acid sequence of SEQ ID NO:37
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:175; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:33 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:177.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:33, HVR-L3 comprising the amino acid sequence of SEQ ID NO:178, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:176.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33.
  • the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:177; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:177.
  • the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:177; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:178.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:33; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:177, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:178.
  • the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:177; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:178.
  • an anti-OX40 agonist antibody is humanized.
  • an anti-OX40 antibody comprises HVRs as in any of the above embodiments or for any of the embodiments in FIG. 11 , and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.
  • an anti-OX40 antibody comprises HVRs as in any of the above embodiments, and further comprises a VH and/or VL comprising an FR sequence shown in FIG. 11 .
  • an anti-human OX40 agonist antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 108, 114 or 116.
  • VH heavy chain variable domain
  • a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to OX40.
  • a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 108, 114 or 116.
  • substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs).
  • the anti-human OX40 agonist antibody comprises the VH sequence in SEQ ID NO: SEQ ID NO:56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 108, 114 or 116, including post-translational modifications of that sequence.
  • the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4.
  • an anti-human OX40 agonist antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 109, 115 or 117.
  • VL light chain variable domain
  • a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to OX40.
  • a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 109, 115 or 117.
  • the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs).
  • the anti-human OX40 agonist antibody comprises the VL sequence in SEQ ID NO: 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 109, 115 or 117, including post-translational modifications of that sequence.
  • the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • an anti-human OX40 agonist antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:56.
  • VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to OX40.
  • the anti-human OX40 agonist antibody comprises the VH sequence in SEQ ID NO:56, including post-translational modifications of that sequence.
  • the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4.
  • an anti-human OX40 agonist antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:57.
  • VL light chain variable domain
  • a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to OX40.
  • the anti-human OX40 agonist antibody comprises the VL sequence in SEQ ID NO: 57, including post-translational modifications of that sequence.
  • the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • an anti-human OX40 agonist antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:94.
  • VH heavy chain variable domain
  • a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to OX40.
  • the anti-human OX40 agonist antibody comprises the VH sequence in SEQ ID NO:94, including post-translational modifications of that sequence.
  • the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4.
  • an anti-human OX40 agonist antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:95.
  • VL light chain variable domain
  • a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to OX40.
  • the anti-human OX40 agonist antibody comprises the VL sequence in SEQ ID NO:95, including post-translational modifications of that sequence.
  • the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26.
  • an anti-human OX40 agonist antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:96.
  • VH heavy chain variable domain
  • a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to OX40.
  • the anti-human OX40 agonist antibody comprises the VH sequence in SEQ ID NO:96, including post-translational modifications of that sequence.
  • the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4.
  • an anti-human OX40 agonist antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:97.
  • VL light chain variable domain
  • a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to OX40.
  • the anti-human OX40 agonist antibody comprises the VL sequence in SEQ ID NO:97, including post-translational modifications of that sequence.
  • the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:27.
  • an anti-human OX40 agonist antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148.
  • VH heavy chain variable domain
  • a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to OX40.
  • a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148.
  • the anti-human OX40 agonist antibody comprises the VH sequence in SEQ ID NO: SEQ ID NO: 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, including post-translational modifications of that sequence.
  • the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 29, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33.
  • an anti-human OX40 agonist antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149.
  • VL light chain variable domain
  • a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to OX40.
  • a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149.
  • the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs).
  • the anti-human OX40 agonist antibody comprises the VL sequence in SEQ ID NO: 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, including post-translational modifications of that sequence.
  • the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:56 and SEQ ID NO:57, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:58 and SEQ ID NO:59, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:60 and SEQ ID NO:61, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:62 and SEQ ID NO:63, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:64 and SEQ ID NO:65, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:66 and SEQ ID NO:67, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:68 and SEQ ID NO:69, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:70 and SEQ ID NO:71, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:72 and SEQ ID NO:73, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:74 and SEQ ID NO:75, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:76 and SEQ ID NO:77, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:78 and SEQ ID NO:79, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:80 and SEQ ID NO:81, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:82 and SEQ ID NO:83, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:84 and SEQ ID NO:85, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:86 and SEQ ID NO:87, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:88 and SEQ ID NO:89, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:90 and SEQ ID NO:91, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:92 and SEQ ID NO:93, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:94 and SEQ ID NO:95, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:96 and SEQ ID NO:97, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:98 and SEQ ID NO:99, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:100 and SEQ ID NO:101, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:108 and SEQ ID NO:109, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:114 and SEQ ID NO:115, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:116 and SEQ ID NO:117, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:118 and SEQ ID NO:119, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:120 and SEQ ID NO:121, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:122 and SEQ ID NO:123, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:124 and SEQ ID NO:125, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:126 and SEQ ID NO:127, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:128 and SEQ ID NO:129, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:130 and SEQ ID NO:131, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:132 and SEQ ID NO:133, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:134 and SEQ ID NO:135, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:136 and SEQ ID NO:137, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:138 and SEQ ID NO:139, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:140 and SEQ ID NO:141, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:142 and SEQ ID NO:143, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:144 and SEQ ID NO:145, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:146 and SEQ ID NO:147, respectively, including post-translational modifications of those sequences.
  • an anti-human OX40 agonist antibody comprising a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above.
  • the OX40 agonist antibody is MEDI6469. In some embodiments, the OX40 agonist antibody is MEDI0562.
  • the invention provides an antibody that binds to the same epitope as an anti-human OX40 antibody provided herein.
  • the antibody is an anti-human OX40 agonist antibody.
  • an anti-OX40 antibody is a monoclonal antibody, including a chimeric, humanized or human antibody.
  • an anti-OX40 antibody is an antibody fragment, e.g., a Fv, Fab, Fab′, scFv, diabody, or F(ab′)2 fragment.
  • the antibody is a full length antibody, e.g., an intact IgG1 antibody or other antibody class or isotype as defined herein. In some embodiments, the antibody is a full length intact IgG4 antibody.
  • CON1 (1A7) QX 1 X 2 X 3 X 4 X 5 X 6 X 7 T, wherein X 1 is A 175 HVR-L3 or Q, X 2 is A or G, X 3 is A or H, X 4 is A or T, X 5 is A or L, X 6 is A or P, and X 7 is A or P.
  • CON2 (3C8) VINPGSGDX 1 YYSEKFKG, wherein X 1 is 176 HVR-H2 T, A or Q.
  • CON2 (3C8) HGTNLEX 1 wherein X 1 is S, E, 177 HVR-L2 or Q.
  • X 1 is V or 178 HVR-L3 A
  • X 2 is H or A
  • X 3 is Y or A.
  • 1A7 V L DIQMTQTTSSLSASLGDRVTISCRASQDISNY 179 LNWYQQKPDGTVKLLIYYTSRLRSGVPSRFSG SGSGKDYFLTISNLEQEDVAAYFCQQGHTLPP TFGGGTKLEIK 1A7 V H EVQLQQSGPELVKPGASVKISCKASGYTFTDS 180 YMSWVKQSHGKTLEWIGDMYPDNGDSSYNQKF REKVTLTVDKSSTTAYMEFRSLTSEDSAVYYC VLAPRWYFSVWGTGTTVTVSS 3C8 V L DILMTQSPSSMSVSLGDTVSITCHASQDISSY 181 IVWLQQKPGKSFRGLIYHGTNLEDGIPSRFSG SGS
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in U.S. Pat. No. 7,550,140. In some embodiments, the agonist anti-human OX40 antibody comprises a heavy chain comprising the sequence of
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody 008 as described in U.S. Pat. No. 7,550,140. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody 008 as described in U.S. Pat. No. 7,550,140.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in U.S. Pat. No. 7,550,140.
  • the agonist anti-human OX40 antibody comprises the sequence of MAEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYTMNWVRQAPGKGLEWVSAISGSG GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRYSQVHYALDYWG QGTLVTVLEGTGGSGGTGSGTSELDIQMTQSPDSLPVTPGEPASISCRSSQSLLHSNGY NYLDWYLQKAGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQ QYYNHPTTFGQGTKLEIKRAA (SEQ ID NO:185).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody SC02008 as described in U.S. Pat. No. 7,550,140.
  • the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody SC02008 as described in U.S. Pat. No. 7,550,140.
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in U.S. Pat. No. 7,550,140.
  • the agonist anti-human OX40 antibody comprises a heavy chain comprising the sequence of EVQLVESGGGLVHPGGSLRLSCAGSGFTFSSYAMHWVRQAPGKGLEWVSAIGTGGGTY YADSVMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYDNVMGLYWFDYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody 023 as described in U.S. Pat. No. 7,550,140. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody 023 as described in U.S. Pat. No. 7,550,140.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in U.S. Pat. No. 7,960,515.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSSTID YADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCARESGWYLFDYWGQGTLVTV SS (SEQ ID NO:188) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPPTFGGGTKVEIK (SEQ ID NO:189).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody 11D4 as described in U.S. Pat. No. 7,960,515.
  • the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody 11D4 as described in U.S. Pat. No. 7,960,515.
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in U.S. Pat. No. 7,960,515.
  • the agonist anti-human OX40 antibody comprises a heavy chain comprising the sequence of EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSI GYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDQSTADYYFYYGMDVW GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPC PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSN
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody 18D8 as described in U.S. Pat. No. 7,960,515.
  • the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody 18D8 as described in U.S. Pat. No. 7,960,515.
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2012/027328.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGSELKKPGASVKVSCKASGYTFTDYSMHWVRQAPGQGLKWMGWINTETG EPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCANPYYDYVSYYAMDYWGQ GTTVTVSS (SEQ ID NO:192) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLIYSASYLYTGVP SRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYSTPRTFGQGTKLEIK (SEQ ID NO:193).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody hu106-222 as described in WO2012/027328. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody hu106-222 as described in WO2012/027328.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2012/027328.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of EVQLVESGGGLVQPGGSLRLSCAASEYEFPSHDMSWVRQAPGKGLELVAAINSDGGST YYPDTMERRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHYDDYYAWFAYWGQGT MVTVSS (SEQ ID NO:194) and/or a light chain variable region comprising the sequence of EIVLTQSPATLSLSPGERATLSCRASKSVSTSGYSYMHWYQQKPGQAPRLLIYLASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRELPLTFGGGTKVEIK (SEQ ID NO:195).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody Hu119-122 as described in WO2012/027328. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody Hu119-122 as described in WO2012/027328.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2013/028231.
  • the agonist anti-human OX40 antibody comprises a heavy chain comprising the sequence of MYLGLNYVFIVFLLNGVQSEVKLEESGGGLVQPGGSMKLSCAASGFTFSDAWMDWVR QSPEKGLEWVaEIRSKANNHATYYAESVNGRFTISRDDSKSSVYLQMNSLRAEDTGIYY CTWGEVFYFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYITCNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
  • the anti-human OX40 agonist antibody comprises a heavy chain variable region comprising the sequence of MYLGLNYVFIVFLLNGVQSEVKLEESGGGLVQPGGSMKLSCAASGFTFSDAWMDWVRQSPEKG LEWVAEIRSKANNHATYYAESVNGRFTISRDDSKSSVYLQMNSLRAEDTGIYYCTWGEVFYFDY WGQGTTLTVSS (SEQ ID NO:198) and/or a light chain variable region comprising the sequence of MRPSIQFLGLLLFWLHGAQCDIQMTQSPSSLSASLGGKVTITCKSSQDINKYIAWYQHKPGKGPR LLIHYTSTLQPGIPSRFSGSGSGRDYSFSISNLEPEDIATYYCLQYDNLLTFGAGTKLELK (SEQ ID NO:199).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody Mab CH 119-43-1 as described in WO2013/028231.
  • the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody Mab CH 119-43-1 as described in WO2013/028231.
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2013038191.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYINPYNDG TKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCANYYGSSLSMDYWGQGTSV TVSS (SEQ ID NO:200) and/or a light chain variable region comprising the sequence of DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLHSGVPS RFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFGGGTKLEIKR (SEQ ID NO:201).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 20E5 as described in WO2013038191. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 20E5 as described in WO2013038191.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2013038191.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of EVQLQQSGPELVKPGASVKISCKTSGYTFKDYTMHWVKQSHGKSLEWIGGIYPNNGGS TYNQNFKDKATLTVDKSSSTAYMEFRSLTSEDSAVYYCARMGYHGPHLDFDVWGAGT TVTVSP (SEQ ID NO:202) and/or a light chain variable region comprising the sequence of DIVMTQSHKFMSTSLGDRVSITCKASQDVGAAVaWYQQKPGQSPKLLIYWASTRHTGV PDRFTGGGSGTDFTLTISNVQSEDLTDYFCQQYINYPLTFGGGTKLEIKR (SEQ ID NO:203).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 12H3 as described in WO2013038191. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 12H3 as described in WO2013038191.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWMGYINPYND GTKYNEKFKGRVTITSDTSASTAYMELSSLRSEDTAVYYCANYYGSSLSMDYWGQGTL VTVSS (SEQ ID NO:204) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLHSGVPS RFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKR (SEQ ID NO:205).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 20E5 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 20E5 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWMGYINPYND GTKYNEKFKGRVTITSDTSASTAYMELSSLRSEDTAVYYCANYYGSSLSMDYWGQGTL VTVSS (SEQ ID NO:204) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAVKLLIYYTSRLHSGVPS RFSGSGSGTDYTLTISSLQPEDFATYFCQQGNTLPWTFGQGTKVEIKR (SEQ ID NO:206).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 20E5 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 20E5 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWIGYINPYNDG TKYNEKFKGRATITSDTSASTAYMELSSLRSEDTAVYYCANYYGSSLSMDYWGQGTLV TVSS (SEQ ID NO:207) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLHSGVPS RFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKR (SEQ ID NO:205).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 20E5 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 20E5 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWIGYINPYNDG TKYNEKFKGRATITSDTSASTAYMELSSLRSEDTAVYYCANYYGSSLSMDYWGQGTLV TVSS (SEQ ID NO:207) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAVKLLIYYTSRLHSGVPS RFSGSGSGTDYTLTISSLQPEDFATYFCQQGNTLPWTFGQGTKVEIKR (SEQ ID NO:206).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 20E5 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 20E5 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWIGYINPYNDG TKYNEKFKGRATLTSDKSASTAYMELSSLRSEDTAVYYCANYYGSSLSMDYWGQGTL VTVSS (SEQ ID NO:208) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLHSGVPS RFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKR (SEQ ID NO:205).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 20E5 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 20E5 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWIGYINPYNDG TKYNEKFKGRATLTSDKSASTAYMELSSLRSEDTAVYYCANYYGSSLSMDYWGQGTL VTVSS (SEQ ID NO:208) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAVKLLIYYTSRLHSGVPS RFSGSGSGTDYTLTISSLQPEDFATYFCQQGNTLPWTFGQGTKVEIKR (SEQ ID NO:206).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 20E5 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 20E5 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWMGGIYPNNG GSTYNQNFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQ GTTVTVSS (SEQ ID NO:209) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCKASQDVGAAVaWYQQKPGKAPKLLIYWASTRHTGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQYINYPLTFGGGTKVEIKR (SEQ ID NO:210).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone clone 12H3 as described in WO2014148895A1.
  • the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 12H3 as described in WO2014148895A1.
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWMGGIYPNNG GSTYNQNFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQ GTTVTVSS (SEQ ID NO:209) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCKASQDVGAAVaWYQQKPGKAPKLLIYWASTRHTGVP DRFSGGGSGTDFTLTISSLQPEDFATYYCQYINYPLTFGGGTKVEIKR (SEQ ID NO:211).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 12H3 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 12H3 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGG STYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQG TTVTVSS (SEQ ID NO:212) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCKASQDVGAAVaWYQQKPGKAPKLLIYWASTRHTGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQYINYPLTFGGGTKVEIKR (SEQ ID NO:210).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 12H3 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 12H3 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGG STYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQG TTVTVSS (SEQ ID NO:212) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCKASQDVGAAVaWYQQKPGKAPKLLIYWASTRHTGVP DRFSGGGSGTDFTLTISSLQPEDFATYYCQYINYPLTFGGGTKVEIKR (SEQ ID NO:211).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 12H3 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 12H3 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGG STYNQNFKDRATLTVDKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQG TTVTVSS (SEQ ID NO:213) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCKASQDVGAAVaWYQQKPGKAPKLLIYWASTRHTGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQYINYPLTFGGGTKVEIKR (SEQ ID NO:210).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 12H3 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 12H3 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is an anti-OX40 antibody described in WO2014148895A1.
  • the agonist anti-human OX40 antibody comprises a heavy chain variable region comprising the sequence of QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGG STYNQNFKDRATLTVDKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQG TTVTVSS (SEQ ID NO:213) and/or a light chain variable region comprising the sequence of DIQMTQSPSSLSASVGDRVTITCKASQDVGAAVaWYQQKPGKAPKLLIYWASTRHTGVP DRFSGGGSGTDFTLTISSLQPEDFATYYCQYINYPLTFGGGTKVEIKR (SEQ ID NO:211).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody clone 12H3 as described in WO2014148895A1. In some embodiments, the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody clone 12H3 as described in WO2014148895A1.
  • HVR hypervariable region
  • the agonist anti-human OX40 antibody is L106 BD (Pharmingen Product #340420).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody L106 (BD Pharmingen Product #340420).
  • the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody L106 (BD Pharmingen Product #340420).
  • the agonist anti-human OX40 antibody is ACT35 (Santa Cruz Biotechnology, Catalog #20073).
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody ACT35 (Santa Cruz Biotechnology, Catalog #20073).
  • the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody ACT35 (Santa Cruz Biotechnology, Catalog #20073).
  • the agonist anti-human OX40 antibody is MEDI6469.
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody MEDI6469.
  • the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody MEDI6469.
  • the agonist anti-human OX40 antibody is MEDI0562.
  • the antibody comprises at least one, two, three, four, five or six hypervariable region (HVR) sequences of antibody MEDI0562.
  • the antibody comprises a heavy chain variable region sequence and/or a light chain variable region sequence of antibody MEDI0562.
  • OX40 agonists useful for the methods described herein are in no way intended to be limited to antibodies. Non-antibody OX40 agonists are contemplated and well known in the art.
  • OX40L (also known as CD134L) serves as a ligand for OX40.
  • agonists that present part or all of OX40L may serve as OX40 agonists.
  • an OX40 agonist may include one or more extracellular domains of OX40L. Examples of extracellular domains of OX40L may include OX40-binding domains.
  • an OX40 agonist may be a soluble form of OX40L that includes one or more extracellular domains of OX40L but lacks other, insoluble domains of the protein, e.g., transmembrane domains.
  • an OX40 agonist is a soluble protein that includes one or more extracellular domains of OX40L able to bind OX40L.
  • an OX40 agonist may be linked to another protein domain, e.g., to increase its effectiveness, half-life, or other desired characteristics.
  • an OX40 agonist may include one or more extracellular domains of OX40L linked to an immunoglobulin Fc domain.
  • an OX40 agonist may be any one of the OX40 agonists described in U.S. Pat. No. 7,696,175.
  • an OX40 agonist may be an oligomeric or multimeric molecule.
  • an OX40 agonist may contain one or more domains (e.g., a leucine zipper domain) that allows proteins to oligomerize.
  • an OX40 agonist may include one or more extracellular domains of OX40L linked to one or more leucine zipper domains.
  • an OX40 agonist may be any one of the OX40 agonists described in European Patent No. EP0672141 B1.
  • an OX40 agonist may be a trimeric OX40L fusion protein.
  • an OX40 agonist may include one or more extracellular domains of OX40L linked to an immunoglobulin Fc domain and a trimerization domain (including without limitation an isoleucine zipper domain).
  • an OX40 agonist may be any one of the OX40 agonists described in International Publication No. WO2006/121810. In some embodiments, the OX40 agonist is MEDI6383.
  • an anti-OX40 agonist and/or antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.
  • an antibody provided herein has a dissociation constant (Kd) of ⁇ 1 ⁇ M, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g. 10-8 M or less, e.g. from 10-8 M to 10-13 M, e.g., from 10-9 M to 10-13 M).
  • Kd dissociation constant
  • Kd is measured by a radiolabeled antigen binding assay (RIA).
  • RIA radiolabeled antigen binding assay
  • an RIA is performed with the Fab version of an antibody of interest and its antigen.
  • solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of (1251)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881(1999)).
  • MICROTITER® multi-well plates (Thermo Scientific) are coated overnight with 5 ⁇ g/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23° C.).
  • a non-adsorbent plate (Nunc #269620)
  • 100 pM or 26 pM [125I]-antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res.
  • the Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. When the plates have dried, 150 ⁇ l/well of scintillant (MICROSCINT-20 TM; Packard) is added, and the plates are counted on a TOPCOUNTTM gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.
  • Kd is measured using a BIACORE® surface plasmon resonance assay.
  • a BIACORE®-2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.) is performed at 25° C. with immobilized antigen CM5 chips at ⁇ 10 response units (RU).
  • CM5 chips ⁇ 10 response units
  • carboxymethylated dextran biosensor chips CM5, BIACORE, Inc.
  • EDC N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 ⁇ g/ml ( ⁇ 0.2 ⁇ M) before injection at a flow rate of 5 ⁇ l/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20TM) surfactant (PBST) at 25° C. at a flow rate of approximately 25 ⁇ l/min.
  • TWEEN-20TM polysorbate 20
  • association rates (kon) and dissociation rates (koff) are calculated using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams.
  • a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2 in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophometer (Aviv Instruments) or a 8000-series SLM-AMINCOTM spectrophotometer (ThermoSpectronic) with a stirred cuvette.
  • a spectrometer such as a stop-flow equipped spectrophometer (Aviv Instruments) or a 8000-series SLM-AMINCOTM spectrophotometer (ThermoSpectronic) with a stirred cuvette.
  • an antibody provided herein is an antibody fragment.
  • Antibody fragments include, but are not limited to, Fab, Fab′, Fab′-SH, F(ab′)2, Fv, and scFv fragments, and other fragments described below.
  • Fab fragment antigen
  • Fab′ fragment antigen binding domain
  • Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).
  • Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody.
  • a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, e.g., U.S. Pat. No. 6,248,516 B1).
  • Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g. E. coli or phage), as described herein.
  • recombinant host cells e.g. E. coli or phage
  • an antibody provided herein is a chimeric antibody.
  • Certain chimeric antibodies are described, e.g., in U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).
  • a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region.
  • a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
  • a chimeric antibody is a humanized antibody.
  • a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody.
  • a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences.
  • HVRs e.g., CDRs, (or portions thereof) are derived from a non-human antibody
  • FRs or portions thereof
  • a humanized antibody optionally will also comprise at least a portion of a human constant region.
  • some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.
  • a non-human antibody e.g., the antibody from which the HVR residues are derived
  • Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci.
  • an antibody provided herein is a human antibody.
  • Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).
  • Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge.
  • Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal's chromosomes.
  • the endogenous immunoglobulin loci have generally been inactivated.
  • Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006).
  • Additional methods include those described, for example, in U.S. Pat. No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas).
  • Human hybridoma technology Trioma technology
  • Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).
  • Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.
  • Antibodies of the invention may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, N. J., 2001) and further described, e.g., in the McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol.
  • repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994).
  • Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments.
  • scFv single-chain Fv
  • Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas.
  • naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al., EMBO J, 12: 725-734 (1993).
  • naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992).
  • Patent publications describing human antibody phage libraries include, for example: U.S. Pat. No. 5,750,373, and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.
  • Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.
  • an antibody provided herein is a multispecific antibody, e.g. a bispecific antibody.
  • Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites.
  • one of the binding specificities is for OX40 and the other is for any other antigen.
  • bispecific antibodies may bind to two different epitopes of OX40.
  • Bispecific antibodies may also be used to localize cytotoxic agents to cells which express OX40.
  • Bispecific antibodies can be prepared as full length antibodies or antibody fragments.
  • Multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/08829, and Traunecker et al., EMBO J. 10: 3655 (1991)), and “knob-in-hole” engineering (see, e.g., U.S. Pat. No. 5,731,168). Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009/089004A1); cross-linking two or more antibodies or fragments (see, e.g., U.S. Pat. No.
  • the antibody or fragment herein also includes a “Dual Acting FAb” or “DAF” comprising an antigen binding site that binds to OX40 as well as another, different antigen (see, US 2008/0069820, for example).
  • DAF Double Acting FAb
  • amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody.
  • Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.
  • antibody variants having one or more amino acid substitutions are provided.
  • Sites of interest for substitutional mutagenesis include the HVRs and FRs.
  • Conservative substitutions are shown in Table A under the heading of “preferred substitutions.” More substantial changes are provided in Table A under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes.
  • Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.
  • Amino acids may be grouped according to common side-chain properties:
  • Non-conservative substitutions will entail exchanging a member of one of these classes for another class.
  • substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g. a humanized or human antibody).
  • a parent antibody e.g. a humanized or human antibody
  • the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and/or will have substantially retained certain biological properties of the parent antibody.
  • An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g. binding affinity).
  • Alterations may be made in HVRs, e.g., to improve antibody affinity. Such alterations may be made in HVR “hotspots,” i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or residues that contact antigen, with the resulting variant VH or VL being tested for binding affinity.
  • HVR “hotspots,” i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)
  • residues that contact antigen with the resulting variant VH or VL being tested for binding affinity.
  • Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al.
  • affinity maturation diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis).
  • a secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity.
  • Another method to introduce diversity involves HVR-directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.
  • substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen.
  • conservative alterations e.g., conservative substitutions as provided herein
  • Such alterations may, for example, be outside of antigen contacting residues in the HVRs.
  • each HVR either is unaltered, or contains no more than one, two or three amino acid substitutions.
  • a useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081-1085.
  • a residue or group of target residues e.g., charged residues such as arg, asp, his, lys, and glu
  • a neutral or negatively charged amino acid e.g., alanine or polyalanine
  • Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions.
  • a crystal structure of an antigen-antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution.
  • Variants may be screened to determine whether they contain the desired properties.
  • Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.
  • terminal insertions include an antibody with an N-terminal methionyl residue.
  • Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g. for ADEPT) or a polypeptide which increases the serum half-life of the antibody.
  • an antibody provided herein is altered to increase or decrease the extent to which the antibody is glycosylated.
  • Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.
  • the carbohydrate attached thereto may be altered.
  • Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997).
  • the oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure.
  • modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibody variants with certain improved properties.
  • antibody variants having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region.
  • the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%.
  • the amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example.
  • Asn297 refers to the asparagine residue located at about position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located about ⁇ 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd).
  • Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng.
  • Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially at Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003/085107).
  • Antibodies variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided.
  • Such antibody variants may have improved CDC function.
  • Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).
  • one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant.
  • the Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions.
  • the invention contemplates an antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half life of the antibody in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious.
  • In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities.
  • Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks Fc ⁇ R binding (hence likely lacking ADCC activity), but retains FcRn binding ability.
  • NK cells express Fc(RIII only, whereas monocytes express Fc(RI, Fc(RII and Fc(RIII.
  • FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991).
  • Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Pat. No. 5,500,362 (see, e.g. Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc.
  • non-radioactive assays methods may be employed (see, for example, ACTITM non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, Calif.; and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, Wis.).
  • Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
  • ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998).
  • C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402.
  • a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J. Immunol.
  • FcRn binding and in vivo clearance/half life determinations can also be performed using methods known in the art (see, e.g., Petkova, S. B. et al., Int'l. Immunol. 18(12):1759-1769 (2006)).
  • an antibody includes an Fc region with a mutation that decreases binding to an Fc receptor.
  • Antibodies with reduced effector function include without limitation those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Pat. No. 6,737,056).
  • Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (U.S. Pat. No. 7,332,581).
  • an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).
  • alterations are made in the Fc region that result in altered (i.e., either improved or diminished) C1q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).
  • CDC Complement Dependent Cytotoxicity
  • Antibodies with increased half lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus are described in US2005/0014934A1 (Hinton et al.). Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn.
  • Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (U.S. Pat. No. 7,371,826).
  • cysteine engineered antibodies e.g., “thioMAbs”
  • one or more residues of an antibody are substituted with cysteine residues.
  • the substituted residues occur at accessible sites of the antibody.
  • reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein.
  • any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region.
  • Cysteine engineered antibodies may be generated as described, e.g., in U.S. Pat. No. 7,521,541.
  • an antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available.
  • the moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers.
  • water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., g
  • Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water.
  • the polymer may be of any molecular weight, and may be branched or unbranched.
  • the number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.
  • conjugates of an antibody and nonproteinaceous moiety that may be selectively heated by exposure to radiation are provided.
  • the nonproteinaceous moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)).
  • the radiation may be of any wavelength, and includes, but is not limited to, wavelengths that do not harm ordinary cells, but which heat the nonproteinaceous moiety to a temperature at which cells proximal to the antibody-nonproteinaceous moiety are killed.
  • Antibodies may be produced using recombinant methods and compositions, e.g., as described in U.S. Pat. No. 4,816,567.
  • isolated nucleic acid encoding an anti-OX40 antibody described herein is provided.
  • Such nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody).
  • one or more vectors e.g., expression vectors
  • a host cell comprising such nucleic acid is provided.
  • a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody.
  • the host cell is eukaryotic, e.g. a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., Y0, NS0, Sp20 cell).
  • a method of making an anti-OX40 antibody comprises culturing a host cell comprising a nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).
  • nucleic acid encoding an antibody is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell.
  • nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).
  • Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.
  • antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed.
  • For expression of antibody fragments and polypeptides in bacteria see, e.g., U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa, N. J., 2003), pp. 245-254, describing expression of antibody fragments in E. coli .)
  • the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.
  • eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).
  • Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.
  • Plant cell cultures can also be utilized as hosts. See, e.g., U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIESTM technology for producing antibodies in transgenic plants).
  • Vertebrate cells may also be used as hosts.
  • mammalian cell lines that are adapted to grow in suspension may be useful.
  • Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod.
  • monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells.
  • Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Natl. Acad. Sci.
  • Anti-OX40 antibodies provided herein may be identified, screened for, or characterized for their physical/chemical properties and/or biological activities by various assays known in the art.
  • an antibody of the invention is tested for its antigen binding activity, e.g., by known methods such as ELISA, Western blot, etc.
  • OX40 binding may be determined using methods known in the art and exemplary methods are disclosed herein.
  • binding is measured using radioimmunoassay.
  • An exemplary radioimmunassay is exemplified in the Examples.
  • OX40 antibody is iodinated, and competition reaction mixtures are prepared containing a fixed concentration of iodinated antibody and decreasing concentrations of serially diluted, unlabeled OZ X40 antibody.
  • Cells expressing OX40 e.g., BT474 cells stably transfected with human OX40 are added to the reaction mixture.
  • OX40 antibody is washed to separate the free iodinated OX40 antibody from the OX40 antibody bound to the cells.
  • Level of bound iodinated OX40 antibody is determined, e.g., by counting radioactivity associated with cells, and binding affinity determined using standard methods.
  • ability of OX40 antibody to bind to surface-expressed OX40 is assessed using flow cytometry.
  • Peripheral white blood cells are obtained (e.g., from human, cynomolgus monkey, rat or mouse) and cells are blocked with serum. Labeled OX40 antibody is added in serial dilutions, and T cells are also stained to identify T cell subsets (using methods known in the art).
  • OX40 binding may be analyzed using surface plasmon resonance.
  • An exemplary surface plasmon resonance method is exemplified in the Examples.
  • competition assays may be used to identify an antibody that competes with any of the anti-OX40 antibodies disclosed herein for binding to OX40.
  • a competing antibody binds to the same epitope (e.g., a linear or a conformational epitope) that is bound by any of the anti-OX40 antibodies disclosed herein.
  • epitope e.g., a linear or a conformational epitope
  • Detailed exemplary methods for mapping an epitope to which an antibody binds are provided in Morris (1996) “Epitope Mapping Protocols,” in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, N.J.).
  • a competition assay is exemplified in the Examples.
  • immobilized OX40 is incubated in a solution comprising a first labeled antibody that binds to OX40 (e.g., mab 1A7.gr.1, mab 3C8.gr5) and a second unlabeled antibody that is being tested for its ability to compete with the first antibody for binding to OX40.
  • the second antibody may be present in a hybridoma supernatant.
  • immobilized OX40 is incubated in a solution comprising the first labeled antibody but not the second unlabeled antibody. After incubation under conditions permissive for binding of the first antibody to OX40, excess unbound antibody is removed, and the amount of label associated with immobilized OX40 is measured.
  • assays are provided for identifying anti-OX40 antibodies thereof having biological activity.
  • Biological activity may include, e.g., binding OX40 (e.g., binding human and/or cynomolgus OX40), increasing OX40-mediated signal transduction (e.g., increasing NFkB-mediated transcription), depleting cells that express human OX40 (e.g., T cells), depleting cells that express human OX40 by ADCC and/or phagocytosis, enhancing T effector cell function (e.g., CD4+ effector T cell), e.g., by increasing effector T cell proliferation and/or increasing cytokine production (e.g., gamma interferon) by effector T cells, enhancing memory T cell function (e.g., CD4+ memory T cell), e.g., by increasing memory T cell proliferation and/or increasing cytokine production by memory T cells (e.g., gamma interferon), inhibiting regulatory T cell function
  • an antibody of the invention is tested for such biological activity.
  • T cell costimulation may be assayed using methods known in the art and exemplary methods are disclosed herein.
  • T cells e.g., memory or effector T cells
  • peripheral white blood cells e.g., isolated from human whole blood using Ficoll gradient centrifugation.
  • Memory T cells e.g., CD4+ memory T cells
  • effector T cells e.g. CD4+ Teff cells
  • PBMC peripheral white blood cells
  • the Miltenyi CD4+ memory T cell isolation kit or Miltenyi na ⁇ ve CD4+ T cell isolation kit may be used.
  • Isolated T cells are cultured in the presence of antigen presenting cells (e.g., irradiated L cells that express CD32 and CD80), and activated by addition of anti-CD3 antibody in the presence or absence of OX40 agonist antibody.
  • Antigen presenting cells e.g., irradiated L cells that express CD32 and CD80
  • Effect of agonist OX40 antibody of T cell proliferation may be measured using methods well known in the art. For example, the CellTiter Glo kit (Promega) may be used, and results read on a Multilabel Reader (Perkin Elmer). Effect of agonist OX40 antibody on T cell function may also be determined by analysis of cytokines produced by the T cell.
  • production of interferon gamma by CD4+ T cells is determined, e.g., by measurement of interferon gamma in cell culture supernatant. Methods for measuring interferon gamma are well-known in the art.
  • Treg cell function may be assayed using methods known in the art and exemplary methods are disclosed herein.
  • T cells are isolated from human whole blood using methods known in the art (e.g., isolating memory T cells or na ⁇ ve T cells).
  • Purified CD4+na ⁇ ve T cells are labeled (e.g., with CFSE) and purified Treg cells are labeled with a different reagent.
  • Irradiated antigen presenting cells e.g., L cells expressing CD32 and CD80 are co-cultured with the labeled purified na ⁇ ve CD4+ T cells and purified Tregs.
  • the co-cultures are activated using anti-CD3 antibody and tested in the presence or absence of agonist OX40 antibody.
  • a suitable time e.g., 6 days of coculture
  • level of CD4+na ⁇ ve T cell proliferation is tracked by dye dilution in reduced label staining (e.g., reduced CFSE label staining) using FACS analysis.
  • OX40 signaling may be assayed using methods well known in the art and exemplary methods are disclosed herein.
  • transgenic cells are generated that express human OX40 and a reporter gene comprising the NFkB promoter fused to a reporter gene (e.g., beta luciferase).
  • a reporter gene e.g., beta luciferase
  • Addition of OX40 agonist antibody to the cells results in increased NFkB transcription, which is detected using an assay for the reporter gene.
  • Phagocytosis may be assayed, e.g., by using monocyte-derived macrophages, or U937 cells (a human histiocytic lymphoma cells line with the morphology and characteristics of mature macrophages). OX40 expressing cells are added to the monocyte-derived macrophages or U937 cells in the presence or absence of anti-OX40 agonist antibody.
  • the percentage of phagocytosis is determined by examining percentage of cells that double stain for markers of 1) the macrophage or U937 cell and 2) the OX40 expressing cell, and dividing this by the total number of cells that show markers of the OX40 expressing cell (e.g., GFP). Analysis may be done by flow cytometry. In another embodiment, analysis may be done by fluorescent microscopy analysis.
  • ADCC may be assayed, e.g., using methods well known in the art. Exemplary methods are described in the definition section and an exemplary assay is disclosed in the Examples.
  • level of OX40 is characterized on an OX40 expressing cell that is used for testing in an ADCC assay.
  • the cell may be stained with a detectably labeled anti-OX40 antibody (e.g., PE labeled), then level of fluorescence determined using flow cytometry, and results presented as median fluorescence intensity (MFI).
  • MFI median fluorescence intensity
  • ADCC may be analyzed by CellTiter Glo assay kit and cell viability/cytotoxicity may be determined by chemioluminescence.
  • the binding affinities of various antibodies to Fc ⁇ RIA, Fc ⁇ RIIA, Fc ⁇ RIIB, and two allotypes of Fc ⁇ RIIIA may be measured in ELISA-based ligand-binding assays using the respective recombinant Fc ⁇ receptors.
  • Purified human Fc ⁇ receptors are expressed as fusion proteins containing the extracellular domain of the receptor ⁇ chain linked to a Gly/6 ⁇ His/glutathione S-transferase (GST) polypeptide tag at the C-terminus.
  • GST Gly/6 ⁇ His/glutathione S-transferase
  • Fc ⁇ RIIA CD32A
  • Fc ⁇ RIIB CD32B
  • the two allotypes of Fc ⁇ RIIIA CD16
  • F-158 and V-158 antibodies may be tested as multimers by cross-linking with a F(ab′)2 fragment of goat anti-human kappa chain (ICN Biomedical; Irvine, Calif.) at an approximate molar ratio of 1:3 antibody:cross-linking F(ab′)2. Plates are coated with an anti-GST antibody (Genentech) and blocked with bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • Fc ⁇ receptors are added to the plate at 25 ng/well and incubated at room temperature for 1 hour. After the plates are washed, serial dilutions of test antibodies are added as multimeric complexes and the plates were incubated at room temperature for 2 hours.
  • PBS phosphate-buffered saline
  • ELx405TM plate washer Biotek Instruments; Winooski, Vt.
  • HRP horseradish peroxidase
  • TMB tetramethylbenzidine
  • the plates are incubated at room temperature for 5-20 minutes, depending on the Fc ⁇ receptors tested, to allow color development.
  • the reaction is terminated with 1 M H3PO4 and absorbance at 450 nm was measured with a microplate reader (SpectraMax®190, Molecular Devices; Sunnyvale, Calif.).
  • Dose-response binding curves are generated by plotting the mean absorbance values from the duplicates of antibody dilutions against the concentrations of the antibody. Values for the effective concentration of the antibody at which 50% of the maximum response from binding to the Fc ⁇ receptor is detected (EC50) were determined after fitting the binding curve with a four-parameter equation using SoftMax Pro (Molecular Devices).
  • PI uptake assay can be performed in the absence of complement and immune effector cells.
  • OX40 expressing cells are incubated with medium alone or medium containing of the appropriate monoclonal antibody at e.g., about 10 ⁇ g/ml.
  • the cells are incubated for a time period (e.g., 1 or 3 days). Following each treatment, cells are washed and aliquoted.
  • cells are aliquoted into 35 mm strainer-capped 12 ⁇ 75 tubes (1 ml per tube, 3 tubes per treatment group) for removal of cell clumps. Tubes then receive PI (10 ⁇ g/ml). Samples may be analyzed using a FACSCANTM flow cytometer and FACSCONVERTTM CellQuest software (Becton Dickinson).
  • Cells for use in any of the above in vitro assays include cells or cell lines that naturally express OX40 or that have been engineered to express OX40. Such cells include activated T cells, Treg cells and activated memory T cells that naturally express OX40. Such cells also include cell lines that express OX40 and cell lines that do not normally express OX40 but have been transfected with nucleic acid encoding OX40. Exemplary cell lines provided herein for use in any of the above in vitro assays include transgenic BT474 cells (a human breast cancer cell line) that express human OX40
  • any of the above assays may be carried out using anti-OX40 antibody and an additional therapeutic agent.
  • the invention also provides immunoconjugates comprising an anti-OX40 antibody herein conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.
  • cytotoxic agents such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.
  • an immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Pat. Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Pat. Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Pat. Nos.
  • ADC antibody-drug conjugate
  • drugs including but not limited to a maytansinoid (see U.S. Pat. Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and
  • an immunoconjugate comprises an antibody as described herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa ), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.
  • an enzymatically active toxin or fragment thereof including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain
  • an immunoconjugate comprises an antibody as described herein conjugated to a radioactive atom to form a radioconjugate.
  • a radioactive atom to form a radioconjugate.
  • radioactive isotopes are available for the production of radioconjugates. Examples include At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu.
  • the radioconjugate When used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or I123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.
  • NMR nuclear magnetic resonance
  • Conjugates of an antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5
  • a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987).
  • Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026.
  • the linker may be a “cleavable linker” facilitating release of a cytotoxic drug in the cell.
  • an acid-labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker or disulfide-containing linker (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Pat. No. 5,208,020) may be used.
  • the immunuoconjugates or ADCs herein expressly contemplate, but are not limited to such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, Ill., U.S.A).
  • cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC
  • the methods include measuring the expression level of one or more marker genes in a sample containing leukocytes obtained from the subject, where the one or more marker genes are selected from CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R; and classifying the subject as a responsive or non-responsive subject based on the expression level of the one or more marker genes in the sample obtained from the subject, as compared with a reference, where an increased expression level of the one or more marker genes as compared with the reference indicates the subject may be responsive to an OX40 agonist treatment, or where a decreased expression level of the one or more marker genes as compared with the reference indicates the
  • the one or more marker genes may be selected from CD8a, CD8b, IFNg, GZMA, GZMB, PRF1, and PDCA1. In some embodiments, the one or more marker genes may be selected from H2-d, CTLA4, CXCL9, PTPRC, IL7R, KLRK1, and CXCL1. In some embodiments, the one or more marker genes may be selected from CD64, IDO1, and ITGAM.
  • the methods include measuring the expression level of one or more marker genes in a sample containing leukocytes obtained from the subject, where the one or more marker genes are selected from CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1; and classifying the subject as a responsive or non-responsive subject based on the expression level of the one or more marker genes in the sample obtained from the subject, as compared with a reference, wherein a decreased expression level of the one or more marker genes as compared with the reference indicates the subject may be responsive to an OX40 agonist treatment, or wherein an increased expression level of the one or more marker genes as compared with the reference indicates the subject may not be responsive to an OX40 agonist treatment.
  • expression level may refer to mRNA expression level.
  • mRNA expression level may be measured by many methods. Such methods may quantify the copies of a specific mRNA present in a sample by measuring the amount of hybridization to an mRNA-specific probe. Other methods may amplify mRNA, or cDNA generated from mRNA, and quantify the amount of amplicon generated to extrapolate how much mRNA was present in a sample. Yet other methods may involve next-generation sequencing of part or all of mRNA transcripts, or cDNA generated from mRNA, then quantifying the number of sequences detected that correspond to particular gene(s). In some embodiments, mRNA expression level is measured by quantitative PCR, semi-quantitative PCR, nucleotide microarray, RNA-seq, in situ hybridization, and/or Northern blotting.
  • expression level may refer to protein expression level.
  • Protein expression level may be measured by many methods. Such methods may quantify proteins present in a sample by using a probe that specifically binds to a particular protein, such as an antibody, then detecting the amount of specific binding in a sample. Other methods may fragment proteins into short peptides, then detect these peptides and quantify how many peptides correspond to particular protein(s).
  • protein expression level is measured by Western blotting, peptide microarray, immunohistochemistry, flow cytometry, and/or mass spectrometry.
  • a murine homolog may be listed by the name of a murine homolog.
  • the expression level of a human homolog of one or more marker genes described herein may be measured in a human sample. Methods for determining a human homolog of a murine gene are known in the art.
  • a homolog may be functionally determined, i.e., by performing a similar cellular function.
  • a homolog may be determined by sequence homology, e.g., by using a program such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or ALIGN-2 software as described herein.
  • the marker gene may be one or more of the marker genes provided in Table 3 below.
  • Table 3 provides a list of genes whose expression level was discovered as described herein to be useful for predicting responsiveness to an OX40 agonist treatment.
  • positive predictors are those genes that, when expressed at an increased level, predict responsiveness to an OX40 agonist treatment.
  • Negative predictors are those genes that, when expressed at a decreased level, predict responsiveness to an OX40 agonist treatment.
  • Exemplary gene/protein names or aliases, as well as an exemplary accession number corresponding to a human protein homolog, are also provided.
  • expression level of an mRNA or protein may be normalized to the expression level of a reference gene. Normalizing the expression level of a particular gene to a reference is thought to enhance reproducibility across samples by factoring differences in sample size and/or mRNA/protein extraction. In these examples, expression level relative to the reference is measured. In some embodiments, multiple reference genes may be used, either singly or in aggregate (e.g., by averaging). In other embodiments, expression level of an mRNA or protein may refer to absolute expression level.
  • a reference gene may be a housekeeping gene.
  • a housekeeping gene is thought to be constitutively expressed in a cell in normal and/or pathological states, such as a gene encoding a protein required for basic cellular function and/or maintenance.
  • Housekeeping genes are typically used as a reference to ensure they will be expressed at a detectable and/or reproducible level across multiple samples. Exemplary housekeeping genes and further description of the use of such genes as a reference may be found, for example, in de Kok, J. B., et al. (2005) Lab Invest. 85(1):154-9.
  • the expression level of one or more marker genes described herein is compared to a reference.
  • the reference is the average, mean, or median level of expression of the corresponding marker gene in a sample comprising leukocytes from subjects that have cancer.
  • the reference is the average, mean, or median level of expression of the corresponding marker gene in samples comprising leukocytes from other subjects having cancer who are not responsive to the OX40 agonist treatment after receiving treatment.
  • a set of samples obtained from cancers having a shared characteristic e.g., the same cancer type and/or stage, or exposure to a common treatment such as an OX40 agonist
  • This set may be used to derive a reference, e.g., a reference number, to which a subject's sample may be compared.
  • responsiveness to treatment may refer to any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.
  • responsiveness may refer to improvement of one or more factors according to the published set of RECIST or Immune-Related Response Criteria guidelines for determining the status of a tumor in a cancer patient, i.e., responding, stabilizing, or progressing.
  • a responsive subject may refer to a subject whose cancer(s) show improvement, e.g., according to one or more factors based on RECIST or Immune-Related Response criteria.
  • a non-responsive subject may refer to a subject whose cancer(s) do not show improvement, e.g., according to one or more factors based on RECIST or Immune-Related Response criteria.
  • responsiveness may include immune activation.
  • responsiveness may include treatment efficacy.
  • responsiveness may include immune activation and treatment efficacy.
  • responsiveness may refer to improvement of one of more factors according to immune-related response criteria (irRC). See, e.g., Wolchok et al., Clin Can Res 2009; 15:7412-20.
  • new lesions are added into the defined tumor burden and followed, e.g., for radiological progression at a subsequent assessment.
  • presence of non-target lesions are included in assessment of complete response and not included in assessment of radiological progression.
  • radiological progression may be determined only on the basis of measurable disease and/or may be confirmed by a consecutive assessment ⁇ 4 weeks from the date first documented.
  • tumor may refer to a physical mass containing a plurality of cancer cells, e.g., cells showing the characteristics of any of the cancers described herein.
  • examples of tumors may include primary tumors of any of the above types of cancer or metastatic tumors at a second site derived from any of the above types of cancer.
  • a tumor may contain cancer cells as well as tumor stroma.
  • a sample may include leukocytes.
  • the sample may be a tumor sample.
  • a tumor sample may include cancer cells, lymphocytes, leukocytes, stroma, blood vessels, connective tissue, basal lamina, and any other cell type in association with the tumor.
  • the sample is a tumor tissue sample containing tumor-infiltrating leukocytes. As used herein, any leukocyte associated with a tumor may be considered a tumor-infiltrating leukocyte.
  • tumor-infiltrating leukocytes include without limitation T lymphocytes (such as CD8+ T lymphocytes and/or CD4+ T lymphocytes), B lymphocytes, or other bone marrow-lineage cells including granulocytes (neutrophils, eosinophils, basophils), monocytes, macrophages, dendritic cells (i.e., interdigitating dendritic cells), histiocytes, and natural killer cells.
  • a tumor-infiltrating leukocyte may be associated with cancer cells of a tumor.
  • a tumor-infiltrating leukocyte may be associated with tumor stroma.
  • the tumor samples are enriched for tumor area by macrodissection.
  • the sample may be processed to separate or isolate one or more cell types (e.g., leukocytes). In some embodiments, the sample may be used without separating or isolating cell types.
  • a tumor sample may be obtained from a subject by any method known in the art, including without limitation a biopsy, endoscopy, or surgical procedure. In some embodiments, a tumor sample may be prepared by methods such as freezing, fixation (e.g., by using formalin or a similar fixative), and/or embedding in paraffin wax. In some embodiments, a tumor sample may be sectioned. In some embodiments, a fresh tumor sample (i.e., one that has not been prepared by the methods described above) may be used. In some embodiments, a sample may be prepared by incubation in a solution to preserve mRNA and/or protein integrity. A tumor sample containing leukocytes may be assayed by any technique described herein for measuring marker gene expression level.
  • the sample may be a peripheral blood sample.
  • a peripheral blood sample may include white blood cells, PBMCs, and the like. Any technique known in the art for isolating leukocytes from a peripheral blood sample may be used. For example, a blood sample may be drawn, red blood cells may be lysed, and a white blood cell pellet may be isolated and used for the sample. In another example, density gradient separation may be used to separate leukocytes (e.g., PBMCs) from red blood cells. Isolated leukocytes from a peripheral blood sample may be assayed by any technique described herein for measuring marker gene expression level.
  • RNA samples comprising leukocytes obtained from the subject, where the subject has been treated with an OX40 agonist, and where the one or more marker genes are selected from ARG1, CCL2, CCL22, CCL5, CCR5, CD226, CD27, CD274, CD28, CD3E, CD40, CD8A, CD8b, CXCL10, CXCL9, EOMES, FasL, Fcgr1/CD64, FOXP3, GZMA, GZMB, HAVCR2, ICAM1, IDO1, IFNg, IL10, IL12A (TDO2), IL13, IL2, IL7R, ITGAM, KLRK1, LAG3, MAP4K1, MS4A1, PDCD1, PDCD1LG2, PRF1, PTPRC, TNF, TNFRSF14, TNFRSF9, and TNFSF4; and determining the treatment
  • marker genes e.g., ARG1, CCL2, CCL22, CCL5, CCR5, CD226, CD27, CD274, CD28, CD3E, CD40, CD8A, CD8b, CXCL10, CXCL9, EOMES, FasL, Fcgr1/CD64, FOXP3, GZMA, GZMB, HAVCR2, ICAM1, IDO1, IFNg, IL10, IL12A (TDO2), IL13, IL2, IL7R, ITGAM, KLRK1, LAG3, MAP4K1, MS4A1, PDCD1, PDCD1LG2, PRF1, PTPRC, TNF, TNFRSF14, TNFRSF9, and/or TNFSF4) is upregulated following treatment with an OX40 agonist in tumors that are responsive to such treatment and tumors that are non-responsive to such treatment.
  • Expression level of a marker gene may be measured by one or more methods as described here
  • PD activity may refer to an effect of a treatment (e.g., an OX40 agonist treatment) to the subject.
  • An example of a PD activity may include modulation of the expression level of one or more genes.
  • monitoring PD activity such as by measuring expression of a gene marker, may be advantageous during a clinical trial examining an OX40 agonist.
  • Monitoring PD activity may be used, for example, to monitor response to treatment, toxicity, and the like.
  • the expression level of one or more marker genes may be compared to a reference which may include a sample from a subject not receiving a treatment (e.g., an OX40 agonist treatment).
  • a reference may include a sample from the same subject before receiving a treatment (e.g., an OX40 agonist treatment).
  • a reference may include a reference value from one or more samples of other subjects receiving a treatment (e.g., an OX40 agonist treatment). For example, a population of patients may be treated, and a mean, average, or median value for expression level of one or more genes may be generated from the population as a whole.
  • a set of samples obtained from cancers having a shared characteristic may be studied from a population, such as with a clinical outcome study.
  • This set may be used to derive a reference, e.g., a reference number, to which a subject's sample may be compared. Any of the references described herein may be used as a reference for monitoring PD activity.
  • the one or more marker genes are selected from CD3, CD8, IFNg, GZMA, GZMB, PRF1, TNFa, PDCD1, and CD274.
  • the marker gene may be one or more of the marker genes provided in Table 4 below. Table 4 provides a list of genes whose expression level was discovered as described herein to be upregulated in response OX40 agonist treatment (e.g., as a marker of PD activity). Exemplary gene/protein names or aliases, as well as an exemplary accession number corresponding to a human protein homolog, are provided.
  • kits for monitoring responsiveness of a subject to an OX40 agonist treatment by measuring the expression level of one or more marker genes in a sample comprising leukocytes obtained from the subject, where the subject has been treated with an OX40 agonist, and where the one or more marker genes are selected from BTLA, CD4, CD69, CD80, CD83, CD86, CSF2, CTLA4, CXCR3, Fcgr2b/CD32, Fcgr3/CD16, H2-aa, H2-d, H2-k, ICOS, IL10, PDCA1, and TNFRSF18; and classifying the subject as responsive or non-responsive to the treatment based on the expression level of the one or more marker genes in the sample obtained from the subject, as compared with a reference, where an increased expression level of the one or more marker genes as compared with the reference indicates a responsive subject.
  • a reference for monitoring responsiveness may include a sample from a subject not receiving a treatment (e.g., an OX40 agonist treatment). In some embodiments, a reference for monitoring responsiveness may include a sample from the same subject before receiving a treatment (e.g., an OX40 agonist treatment). In some embodiments, a reference for monitoring responsiveness may include a reference value from one or more samples of other patients receiving a treatment (e.g., an OX40 agonist treatment). For example, a population of patients may be treated, and a mean, average, or median value for expression level of one or more genes may be generated from the population as a whole.
  • a set of samples obtained from cancers having a shared characteristic may be studied from a population, such as with a clinical outcome study.
  • This set may be used to derive a reference, e.g., a reference number, to which a subject's sample may be compared. Any of the references described herein may be used as a reference for monitoring PD activity.
  • the one or more marker genes are selected from CD80, CD86, ICOS, H2-aa, and CXCR3.
  • the marker gene may be one or more of the marker genes provided in Table 5 below. Table 5 provides a list of genes whose expression level was discovered as described herein to be upregulated in response OX40 agonist treatment in tumors that are responsive to such treatment (e.g., as a marker of responsiveness). Exemplary gene/protein names or aliases, as well as an exemplary accession number corresponding to a human protein homolog, are provided.
  • tumor may refer to a physical mass containing a plurality of cancer cells, e.g., cells showing the characteristics of any of the cancers described herein.
  • examples of tumors may include primary tumors of any of the above types of cancer or metastatic tumors at a second site derived from any of the above types of cancer.
  • a tumor may contain cancer cells as well as tumor stroma.
  • a sample may include leukocytes.
  • the sample may be a tumor sample.
  • a tumor sample may include cancer cells, lymphocytes, leukocytes, stroma, blood vessels, connective tissue, basal lamina, and any other cell type in association with the tumor.
  • the sample is a tumor tissue sample containing tumor-infiltrating leukocytes.
  • leukocyte associated with a tumor may be considered a tumor-infiltrating leukocyte.
  • tumor-infiltrating leukocytes include without limitation T lymphocytes (such as CD8+ T lymphocytes and/or CD4+ T lymphocytes), B lymphocytes, or other bone marrow-lineage cells including granulocytes (neutrophils, eosinophils, basophils), monocytes, macrophages, dendritic cells (i.e., interdigitating dendritic cells), histiocytes, and natural killer cells.
  • a tumor-infiltrating leukocyte may be associated with cancer cells of a tumor.
  • a tumor-infiltrating leukocyte may be associated with tumor stroma.
  • the sample may be processed to separate or isolate one or more cell types (e.g., leukocytes). In some embodiments, the sample may be used without separating or isolating cell types.
  • a tumor sample may be obtained from a subject by any method known in the art, including without limitation a biopsy, endoscopy, or surgical procedure. In some embodiments, a tumor sample may be prepared by methods such as freezing, fixation (e.g., by using formalin or a similar fixative), and/or embedding in paraffin wax. In some embodiments, a tumor sample may be sectioned. In some embodiments, a fresh tumor sample (i.e., one that has not been prepared by the methods described above) may be used.
  • a sample may be prepared by incubation in a solution to preserve mRNA and/or protein integrity.
  • a tumor sample containing leukocytes may be assayed by any technique described herein for measuring marker gene expression level.
  • the tumor samples are enriched for tumor area by macrodissection.
  • the sample may be a peripheral blood sample.
  • a peripheral blood sample may include white blood cells, PBMCs, and the like. Any technique known in the art for isolating leukocytes from a peripheral blood sample may be used. For example, a blood sample may be drawn, red blood cells may be lysed, and a white blood cell pellet may be isolated and used for the sample. In another example, density gradient separation may be used to separate leukocytes (e.g., PBMCs) from red blood cells.
  • a fresh peripheral blood sample i.e., one that has not been prepared by the methods described above may be used.
  • a peripheral blood sample may be prepared by incubation in a solution to preserve mRNA and/or protein integrity.
  • responsiveness to treatment may refer to any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.
  • responsiveness may refer to improvement of one or more factors according to the published set of RECIST guidelines for determining the status of a tumor in a cancer patient, i.e., responding, stabilizing, or progressing.
  • a responsive subject may refer to a subject whose cancer(s) show improvement, e.g., according to one or more factors based on RECIST criteria.
  • a non-responsive subject may refer to a subject whose cancer(s) do not show improvement, e.g., according to one or more factors based on RECIST criteria.
  • responsiveness may refer to improvement of one of more factors according to immune-related response criteria2(irRC). See, e.g., Wolchok et al., Clin Can Res 2009; 15:7412-20.
  • new lesions are added into the defined tumor burden and followed, e.g., for radiological progression at a subsequent assessment.
  • presence of non-target lesions are included in assessment of complete response and not included in assessment of radiological progression.
  • radiological progression may be determined only on the basis of measurable disease and/or may be confirmed by a consecutive assessment ⁇ 4 weeks from the date first documented.
  • responsiveness may include immune activation. In some embodiments, responsiveness may include treatment efficacy. In some embodiments, responsiveness may include immune activation and treatment efficacy.
  • kits for treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of an OX40 agonist.
  • the methods of this disclosure may find use, inter alia, in treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer or T cell dysfunctional disorders.
  • a variety of cancers may be treated, or their progression may be delayed, by these methods.
  • kits for treating or delaying progression of cancer in a subject by measuring the expression level of one or more marker genes in a sample containing leukocytes obtained from the subject, where the one or more marker genes are selected from CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R; and if the expression level of said one or more marker genes in the sample obtained from the subject is higher than a reference, administering to the subject an effective amount of an OX40 agonist.
  • kits for treating or delaying progression of cancer in a subject including administering to the subject an effective amount of an OX40 agonist, where a sample containing leukocytes obtained from the subject has increased expression of one or more marker genes are selected from CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R, as compared with a reference.
  • Th1 markers e.g., CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and/or IL7R
  • Yet further provided herein are methods for treating or delaying progression of cancer in a subject by measuring the expression level of one or more marker genes in a sample containing leukocytes obtained from the subject, where the one or more marker genes are selected from CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1; and if the expression level of said one or more marker genes in the sample obtained from the subject is lower than a reference, administering to the subject an effective amount of an OX40 agonist.
  • a sample containing leukocytes obtained from the subject has decreased expression of one or more marker genes are selected from CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1, as compared with a reference.
  • OX40 agonist an OX40 agonist
  • a sample containing leukocytes obtained from the subject has decreased expression of one or more marker genes are selected from CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1, as compared with a reference.
  • the OX40 agonist is administered to a subject wherein a sample containing leukocytes from the subject have been detected for increased expression of one or more marker genes selected from the group consisting of CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R, and/or decreased expression of one or more marker selected from the group consisting of CSF2, CCL22, EPCAM, GATA3, IL13, and VTCN1.
  • one or more marker genes selected from the group consisting of CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, and IL7R, and/or decreased expression of one or more marker selected from the group consisting of CSF2, CCL
  • a sample or cell that expresses a protein of interest may be one in which mRNA encoding the protein, or the protein, including fragments thereof, is determined to be present in the sample or cell.
  • a sample, cell, tumor, or cancer which has increased expression of one or more markers (such as CD8a, CD8b, H2-d, CTLA4, CD64, CXCL9, IFNg, IDO1, GZMA, GZMB, PRF1, PDCA1, KLRK1, PTPRC, CXCL1, ITGAM, IL7R) in a type of cancer may be one in which the level of one or more marker expression may be considered increased to a skilled person for that type of cancer.
  • such increase may be at least about 0.5 fold, at least about 1 fold, at least about 2 fold, or at least about 5 fold relative to the levels in a population of samples, cells, tumors, or cancers of the same cancer type.
  • a sample, cell, tumor, or cancer which has decreased expression of one or more markers (such as CSF2, CCL22, EPCAM, GATA3, IL13, and/or VTCN1) in a type of cancer may be one in which the level of one or more marker expression may be considered decreased to a skilled person for that type of cancer. For example, such decrease may be at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% decrease relative to the levels in a population of samples, cells, tumors, or cancers of the same cancer type.
  • a cancer to be treated by the methods of the present disclosure includes, but is not limited to, squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer and gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lent
  • the cancer is colorectal cancer.
  • the cancer is selected from non-small cell lung cancer, renal cell carcinoma, ovarian cancer, bladder cancer, glioblastoma, neuroblastoma, melanoma, breast carcinoma, gastric cancer, and hepatocellular carcinoma.
  • the cancer is triple-negative breast carcinoma.
  • the cancer may be an early stage cancer or a late stage cancer.
  • the cancer may be a primary tumor.
  • the cancer may be a metastatic tumor at a second site derived from any of the above types of cancer.
  • examples of cancer further include, but are not limited to, B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), B-cell proliferative disorders, and Meigs' syndrome.
  • B-cell lymphoma including low grade/follicular non-Hodg
  • More specific examples include, but are not limited to, relapsed or refractory NHL, front line low grade NHL, Stage III/IV NHL, chemotherapy resistant NHL, precursor B lymphoblastic leukemia and/or lymphoma, small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia and/or prolymphocytic leukemia and/or small lymphocytic lymphoma, B-cell prolymphocytic lymphoma, immunocytoma and/or lymphoplasmacytic lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, splenic marginal zone lymphoma, extranodal marginal zone—MALT lymphoma, nodal marginal zone lymphoma, hairy cell leukemia, plasmacytoma and/or plasma cell myeloma, low grade/follicular lymphoma, intermediate grade/follicular NHL, mantle cell lymphoma, follicle center lymphoma (folli
  • examples of cancer further include, but are not limited to, B-cell proliferative disorders, which further include, but are not limited to, lymphomas (e.g., B-Cell Non-Hodgkin's lymphomas (NHL)) and lymphocytic leukemias.
  • lymphomas e.g., B-Cell Non-Hodgkin's lymphomas (NHL)
  • NHL lymphocytic leukemias.
  • lymphomas and lymphocytic leukemias include e.g.
  • follicular lymphomas b) Small Non-Cleaved Cell Lymphomas/Burkitt's lymphoma (including endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma and Non-Burkitt's lymphoma), c) marginal zone lymphomas (including extranodal marginal zone B-cell lymphoma (Mucosa-associated lymphatic tissue lymphomas, MALT), nodal marginal zone B-cell lymphoma and splenic marginal zone lymphoma), d) Mantle cell lymphoma (MCL), e) Large Cell Lymphoma (including B-cell diffuse large cell lymphoma (DLCL), Diffuse Mixed Cell Lymphoma, Immunoblastic Lymphoma, Primary Mediastinal B-Cell Lymphoma, Angiocentric Lymphoma-Pulmonary B-Cell Lymphoma), f) hairy cell leukemia, g) lympho
  • the cancer is a B-cell proliferative disorder.
  • the B-cell proliferative disorder is lymphoma, non-Hodgkins lymphoma (NHL), aggressive NHL, relapsed aggressive NHL, relapsed indolent NHL, refractory NHL, refractory indolent NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, leukemia, hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL), or mantle cell lymphoma.
  • NHL such as indolent NHL and/or aggressive NHL.
  • the B-cell proliferative disorder is indolent follicular lymphoma or diffuse large B-cell lymphoma.
  • the subject has cancer or is at risk of developing cancer.
  • the treatment results in a sustained response in the subject after cessation of the treatment.
  • the subject has cancer that may be at early stage or late stage.
  • the subject is a human.
  • the subject is a mammal, such as domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats).
  • a method for treating or delaying progression of cancer in a subject comprising administering to the subject an effective amount of an OX40 agonist, and further comprising administering an additional therapy.
  • the additional therapy may be radiation therapy, surgery (e.g., lumpectomy and a mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing.
  • the additional therapy may be in the form of adjuvant or neoadjuvant therapy.
  • the additional therapy is the administration of small molecule enzymatic inhibitor or anti-metastatic agent.
  • the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence and/or severity of side effects of treatment, such as anti-nausea agents, etc.).
  • the additional therapy is radiation therapy.
  • the additional therapy is surgery.
  • the additional therapy is a combination of radiation therapy and surgery.
  • the additional therapy is gamma irradiation.
  • the additional therapy is therapy targeting PI3K/AKT/mTOR pathway, HSP90 inhibitor, tubulin inhibitor, apoptosis inhibitor, and/or chemopreventative agent.
  • the additional therapy may be one or more of the chemotherapeutic agents described hereabove.
  • combination therapies noted above encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, in which case, administration of the OX40 agonist of the invention can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent or agents.
  • administration of the OX40 agonist and administration of an additional therapeutic agent occur within about one month, or within about one, two or three weeks, or within about one, two, three, four, five, or six days, of each other.
  • OX40 agonists of the invention can also be used in combination with radiation therapy.
  • an anti-human OX40 agonist may be administered in conjunction with a chemotherapy or chemotherapeutic agent. In some embodiments, an anti-human OX40 agonist may be administered in conjunction with a radiation therapy or radiotherapeutic agent. In some embodiments, an anti-human OX40 agonist may be administered in conjunction with a targeted therapy or targeted therapeutic agent. In some embodiments, an anti-human OX40 agonist may be administered in conjunction with an immunotherapy or immunotherapeutic agent, for example a monoclonal antibody.
  • an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with in combination with a PD-1 axis binding antagonist.
  • a PD-1 axis binding antagonist includes but is not limited to a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.
  • Alternative names for “PD-1” include CD279 and SLEB2.
  • Alternative names for “PD-L1” include B7-H 1, B7-4, CD274, and B7-H.
  • Alternative names for “PD-L2” include B7-DC, Btdc, and CD273.
  • PD-1, PD-L1, and PD-L2 are human PD-1, PD-L1 and PD-L2.
  • the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand binding partners.
  • the PD-1 ligand binding partners are PD-L1 and/or PD-L2.
  • a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners.
  • PD-L1 binding partners are PD-1 and/or B7-1.
  • the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partners.
  • a PD-L2 binding partner is PD-1.
  • the antagonist may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.
  • the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody).
  • the anti-PD-1 antibody is selected from the group consisting of MDX-1 106, Merck 3475 and CT-011.
  • the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
  • the PD-1 binding antagonist is AMP-224.
  • the PD-L1 binding antagonist is an anti-PD-L1 antibody.
  • the anti-PD-L1 binding antagonist is selected from the group consisting of YW243.55.S70, MPDL3280A (atezolizumab), MEDI4736 (durvalumab), MDX-1105, and MSB0010718C (avelumab).
  • MDX-1 105 also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007/005874.
  • Antibody YW243.55.S70 (heavy and light chain variable region sequences shown in SEQ ID Nos. 20 and 21, respectively) is an anti-PD-L1 described in WO 2010/077634 A1.
  • MDX-1 106 also known as MDX-1 106-04, ONO-4538 or BMS-936558, is an anti-PD-1 antibody described in WO2006/121168.
  • Merck 3745 also known as MK-3475, SCH-900475, pembrolizumab, and KEYTRUDA®, is an anti-PD-1 antibody described in WO2009/114335.
  • CT-011 also known as hBAT, hBAT-1, and pidilizumab
  • AMP-224 also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in WO2010/027827 and WO2011/066342.
  • the anti-PD-1 antibody is MDX-1 106.
  • Alternative names for “MDX-1106” include MDX-1 106-04, ONO-4538, BMS-936558, Nivolumab, or OPDIVO®.
  • the anti-PD-1 antibody is Nivolumab (CAS Registry Number: 946414-94-4).
  • the anti-PD-1 antibody is selected from the group consisting of MDX-1106 (nivolumab, OPDIVO®), Merck 3475 (MK-3475, pembrolizumab, KEYTRUDA®), CT-011 (Pidilizumab), MEDI-0680 (AMP-514), PDR001, REGN2810, BGB-108, and BGB-A317.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an antagonist directed against CTLA-4 also known as CD152
  • a blocking antibody e.g., a blocking antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • ipilimumab also known as MDX-010, MDX-101, or Yervoy®
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • tremelimumab also known as ticilimumab or CP-675,206.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an antagonist directed against B7-H3 also known as CD276
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • MGA271 e.g., MAA271
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an antagonist directed against a TGF beta e.g., metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), or LY2157299.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • a treatment comprising adoptive transfer of a T cell e.g., a cytotoxic T cell or CTL
  • a chimeric antigen receptor CAR
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • a treatment comprising a HERCREEM protocol see, e.g., ClinicalTrials.gov Identifier NCT00889954.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an agonist directed against CD137 also known as TNFRSF9, 4-1BB, or ILA
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • urelumab also known as BMS-663513
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an activating antibody e.g., an activating antibody.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an agonist directed against OX40 also known as CD134
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • a different anti-OX40 antibody e.g., AgonOX
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an agonist directed against CD27 e.g., an activating antibody.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • CDX-1127 e.g., an OX40 agonist (e.g., an anti-human OX40 agonist antibody)
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • IDO indoleamine-2,3-dioxygenase
  • with the IDO antagonist is 1-methyl-D-tryptophan (also known as 1-D-MT).
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an antibody-drug conjugate comprises mertansine or monomethyl auristatin E (MMAE).
  • MMAE monomethyl auristatin E
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist may be administered in conjunction with and anti-NaPi2b antibody-MMAE conjugate (also known as DNIB0600A or RG7599).
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • trastuzumab emtansine also known as T-DM1, ado-trastuzumab emtansine, or KADCYLA®, Genentech
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • DMUC5754A DMUC5754A
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an antibody-drug conjugate targeting the endothelin B receptor e.g., an antibody directed against EDNBR conjugated with MMAE.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an angiogenesis inhibitor e.g., an OX40 agonist (e.g., an anti-human OX40 agonist antibody)
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an antibody directed against a VEGF e.g., VEGF-A
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • bevacizumab also known as AVASTIN®, Genentech.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an antibody directed against angiopoietin 2 also known as Ang2
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • MEDI3617 an antibody directed against MEDI3617.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an agent targeting CSF-1R also known as M-CSFR or CD115
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • anti-CSF-1R also known as IMC-CS4
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an interferon for example interferon alpha or interferon gamma.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • Roferon-A also known as recombinant Interferon alpha-2a
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • GM-CSF also known as recombinant human granulocyte macrophage colony stimulating factor, rhu GM-CSF, sargramostim, or Leukine®
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • IL-2 also known as aldesleukin or Proleukin®
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • IL-12 also known as aldesleukin or Proleukin®
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an antibody targeting CD20 is obinutuzumab (also known as GA101 or Gazyva®) or rituximab.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an antibody targeting GITR is TRX518.
  • an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with a cancer vaccine.
  • the cancer vaccine is a peptide cancer vaccine, which in some embodiments is a personalized peptide vaccine.
  • the peptide cancer vaccine is a multivalent long peptide, a multi-peptide, a peptide cocktail, a hybrid peptide, or a peptide-pulsed dendritic cell vaccine (see, e.g., Yamada et al., Cancer Sci, 104:14-21, 2013).
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an adjuvant e.g., an OX40 agonist (e.g., an anti-human OX40 agonist antibody)
  • a treatment comprising a TLR agonist e.g., Poly-ICLC (also known as Hiltonol®), LPS, MPL, or CpG ODN.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • TNF tumor necrosis factor
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • HMGB1 e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an IL-4 antagonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an HVEM antagonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an ICOS agonist e.g., by administration of ICOS-L, or an agonistic antibody directed against ICOS.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with a treatment targeting CXCL9.
  • an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with a treatment targeting CXCL10.
  • an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with a treatment targeting CCL5.
  • an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with an LFA-1 or ICAM1 agonist.
  • an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with a Selectin agonist.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • a targeted therapy e.g., an OX40 agonist (e.g., an anti-human OX40 agonist antibody)
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • vemurafenib also known as Zelboraf®
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • dabrafenib also known as Tafinlar®
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • erlotinib also known as Tarceva®
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an inhibitor of a MEK such as MEK1 (also known as MAP2K1) or MEK2 (also known as MAP2K2).
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • cobimetinib also known as GDC-0973 or XL-518.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • trametinib also known as Mekinist®
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an inhibitor of K-Ras e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • onartuzumab also known as MetMAb
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist may be administered in conjunction with an inhibitor of Alk.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • AF802 also known as CH5424802 or alectinib
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • PI3K phosphatidylinositol 3-kinase
  • an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with BKM120.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • idelalisib also known as GS-1101 or CAL-101
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • perifosine also known as KRX-0401
  • an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with an inhibitor of an Akt.
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • MK2206 e.g., an anti-human OX40 agonist antibody
  • GSK690693 e.g., an anti-human OX40 agonist antibody
  • GDC-0941 e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • sirolimus also known as rapamycin
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • temsirolimus also known as CCI-779 or Torisel®
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • everolimus also known as RAD001
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • ridaforolimus also known as AP-23573, MK-8669, or deforolimus
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • OSI-027 e.g., an OX40 agonist (e.g., an anti-human OX40 agonist antibody)
  • AZD8055 e.g., an anti-human OX40 agonist antibody
  • INK128 e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • a dual PI3K/mTOR inhibitor e.g., an OX40 agonist (e.g., an anti-human OX40 agonist antibody)
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • XL765 e.g., an anti-human OX40 agonist antibody
  • GDC-0980 e.g., an anti-human OX40 agonist antibody
  • an OX40 agonist e.g., an anti-human OX40 agonist antibody
  • BEZ235 also known as NVP-BEZ235
  • an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with BGT226. In some embodiments, an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with GSK2126458. In some embodiments, an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with PF-04691502. In some embodiments, an OX40 agonist (e.g., an anti-human OX40 agonist antibody) may be administered in conjunction with PF-05212384 (also known as PKI-587).
  • PF-05212384 also known as PKI-587.
  • An OX40 agonist of the invention can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, e.g. by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic.
  • Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.
  • OX40 agonists of the invention would be formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the antibody need not be, but is optionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosages and with administration routes as described herein, or about from 1 to 99% of the dosages described herein, or in any dosage and by any route that is empirically/clinically determined to be appropriate.
  • an OX40 agonist of the invention when used alone or in combination with one or more other additional therapeutic agents, will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician.
  • the antibody is suitably administered to the patient at one time or over a series of treatments.
  • about 1 ⁇ g/kg to 40 mg/kg of antibody can be an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion.
  • One typical daily dosage might range from about 1 ⁇ g/kg to 100 mg/kg or more, depending on the factors mentioned above.
  • the treatment would generally be sustained until a desired suppression of disease symptoms occurs.
  • Such doses may be administered intermittently, e.g. every week or every three weeks (e.g. such that the patient receives from about two to about twenty, or e.g. about six doses of the antibody).
  • An initial higher loading dose, followed by one or more lower doses may be administered.
  • other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.
  • the cancer has elevated levels of T cell infiltration.
  • T cell infiltration of a cancer may refer to the presence of T cells, such as tumor-infiltrating lymphocytes (TILs), within or otherwise associated with the cancer tissue. It is known in the art that T cell infiltration may be associated with improved clinical outcome in certain cancers (see, e.g., Zhang et al., N. Engl. J. Med. 348(3):203-213 (2003)).
  • the TILs may be OX40+.
  • the TILs may be CD4+OX40+Foxp3+ Treg or CD4+OX40+Foxp3-Teff cells.
  • kits or articles of manufacture are also provided by the invention.
  • Such kits may comprise at least one reagent specific for detecting expression level of a marker gene described herein (e.g., genes described in Tables 3-5), and may further include instructions for carrying out a method described herein.
  • the invention provides compositions and kits comprising primers and primer pairs, which allow the specific amplification of the polynucleotides of the marker genes or of any specific parts thereof, and probes that selectively or specifically hybridize to nucleic acid molecules described herein or to any part thereof.
  • Probes may be labeled with a detectable marker, such as, for example, a radioisotope, fluorescent compound, bioluminescent compound, a chemiluminescent compound, metal chelator or enzyme.
  • Such probes and primers can be used to detect the presence of polynucleotides, such as the polynucleotides corresponding to genes listed in Tables 3-5, in a sample and as a means for detecting cell expressing proteins encoded by the polynucleotides.
  • polynucleotides such as the polynucleotides corresponding to genes listed in Tables 3-5
  • primers and probes may be prepared based on the sequences provided herein and used effectively to amplify, clone and/or determine the presence and/or levels of mRNAs.
  • the kits may further comprise a surface or substrate (such as a microarray) for capture probes for detecting of amplified nucleic acids.
  • the kits comprise at least one pair of primers and a probe specific for detecting one marker gene expression level using qRT-PCR.
  • the reagents for detecting the protein expression level of a marker gene may comprise an antibody that specifically binds to the protein encoded by the marker gene.
  • kits further comprise an OX40 agonist (e.g., an anti-OX40 agonist antibody).
  • the kits may further comprise instructions to administering an OX40 agonist if the patient is identified as responsive to the OX40 agonist treatment.
  • kits may further comprise a carrier means being compartmentalized to receive in close confinement one or more container means such as vials, tubes, and the like, each of the container means comprising one of the separate elements to be used in the method.
  • container means such as vials, tubes, and the like
  • each of the container means comprising one of the separate elements to be used in the method.
  • one of the container means may comprise a probe that is or can be detectably labeled.
  • probe may be an antibody or polynucleotide specific for a marker gene.
  • the kit may also have containers containing nucleotide(s) for amplification of the target nucleic acid sequence and/or a container comprising a reporter-means, such as a biotin-binding protein, such as avidin or streptavidin, bound to a reporter molecule, such as an enzymatic, florescent, or radioisotope label.
  • a reporter-means such as a biotin-binding protein, such as avidin or streptavidin
  • the kit of the invention will typically comprise the container described above and one or more other containers comprising materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • a label may be present on the container to indicate that the composition is used for a specific therapy or non-therapeutic application, and may also indicate directions for either in vivo or in vitro use, such as those described above.
  • the kit can further comprise a set of instructions and materials for preparing a tissue or cell sample and preparing nucleic acids (such as mRNA) from the sample.
  • nucleic acids such as mRNA
  • OX40 Agonist Treatment Modulates T Cell Activities and Anti-Tumor Activity
  • OX40 is known to be a co-stimulatory molecule expressed on activated CD4 T cells (Teff) and T regulatory (Treg) cells. Ligation of OX40 in the presence of TCR stimulation is known to enhance T effector cell function via dual mechanism of potentiating activation of Teff cells and inhibiting Treg cells.
  • Enhancement of anti-tumor immunity by OX40 agonist treatment is a promising therapeutic approach to treat cancer. Therefore, in vitro and in vivo preclinical studies were conducted to characterize co-stimulatory activity, evaluate anti-tumor efficacy, and identify predictive and pharmacodynamic (PD) biomarkers of OX40 agonists.
  • PD pharmacodynamic
  • CD4 + T cells were isolated from PBMCs from healthy donors via magnetic enrichment (Miltenyi). Sorted CD4 + were stimulated with PHA to induce OX40 expression, followed by resting in the presence of IL-2, and subsequently restimulated with a fixed concentration of anti-CD3 and variable anti-OX40 (anti-human OX40 mAb) concentrations in platebound form. T cell proliferation was measured by quantitation of ATP levels (Promega), and supernatant IFN-gamma levels were assessed by ELISA.
  • Tregs and na ⁇ ve T cells were isolated from healthy donors via FACS and magnetic purification, respectively. Suppression assay cultures were comprised of Tregs and CFSE labeled na ⁇ ve CD4 + cells (2 Treg:1 naive), irradiated CD80 + CD32 + L cells as APCs, anti-CD3, and anti-human OX40 mAb. Suppression of na ⁇ ve T cell proliferation was quantified via FACS.
  • Syngeneic tumor cells were inoculated either subcutaneously (CT26, 51Blim10) or orthotopically (EMT6, JC) in C57/B16 or BalbC mice.
  • CCT26, 51Blim10 subcutaneously
  • EMT6, JC orthotopically
  • tumors were harvested when they reached a volume of 150-250 mm 3 .
  • mice were treated with 10 mg/kg of either control Ab or murine anti-mouse OX40 mAb 2 ⁇ /wk for 3 weeks. Tumors and peripheral blood were harvested on day 2, day 9, and day 16 post first dose.
  • Tumor tissues were cut into small pieces, incubated with collagenase and DNAse (Roche), and single cell suspensions were prepared using a gentle MACS Dissociator (Miltenyi) per manufacturer's protocol. Phenotyping of tumor infiltrating lymphocytes (TILs) was performed with commercial antibodies against CD45, CD3, CD4, CD8, CD25, (all BD Biosciences) and Foxp3 (eBiosciences) per manufacturers' instructions. The Live/Dead Fixable Near-IR Dead Cell Stain Kit (Life Technologies) protocol was used to exclude dead cells from analysis. Stained cells were analyzed on a BD FACSCanto flow cytometer.
  • OX40 is known to be highly expressed on Teff and Treg cells in mouse and human tumors. As such, modulating OX40 activity may provide a means to modulate T cell function in cancer, i.e., for cancer immunotherapy. Therefore, the effect of OX40 agonist treatment on T cell function in vitro was examined.
  • FIGS. 1A & 1B demonstrate that T cell proliferation ( FIG. 1A ) and IFN ⁇ production ( FIG. 1B ) were both enhanced by treatment with anti-OX40, as compared to a control treatment.
  • OX40 agonist treatment was next analyzed in several syngeneic mouse tumor models to examine whether OX40 agonism has an effect on tumor growth in vivo.
  • Mice were inoculated with various syngeneic tumor cell types to develop tumors, and once these tumors reached a threshold size, mice were treated with murine anti-mouse OX40 mAb or control antibody, as described above.
  • anti-OX40 agonist treatment caused a dramatic reduction and durable regression in several tumor models, including EMT6 breast ( FIG. 3A ), Cloudman melanoma ( FIG. 3B ), and CT26 colorectal cancer (CRC) ( FIG. 3C ) tumor models.
  • EMT6 breast FIG. 3A
  • Cloudman melanoma FIG. 3B
  • CT26 colorectal cancer FIG. 3C
  • other mouse tumor models showed less responsiveness to treatment, such as the MC38 CRC ( FIG. 4A ), 51Blim10 CRC ( FIG. 4B ), and JC breast ( FIG. 4C ) tumor models.
  • These results demonstrate differential anti-tumor activity of OX40 agonist treatment in mouse tumor models.
  • OX40 agonist treatment led to anti-tumor activity, including durable tumor regression, in several tumor models.
  • higher expression of certain immune activation and Th1 markers may be associated with better responsiveness in EMT6 and CT26 tumors.
  • higher expression of CD8, IFNg, GZMB, PRF1, and PDCA1 may be associated with better responsiveness to anti-OX40 treatment.
  • higher expression of CXCL9, PTPRC, IL7R, KLRK1, and CXCL1 may also be associated with better responsiveness to anti-OX40 treatment.
  • CCL2, GATA3, IL13, VTCN1, and CSF2 may be associated with poor responsiveness to an anti-OX40 treatment, but lower expression of these genes may be associated with better responsiveness to an anti-OX40 treatment.
  • Genes that are differentially expressed between responsive and non-responsive tumor types are listed below in Table 7. As shown in Table 7, genes that were found to correlate with better responsiveness when expressed at a higher level are classified as positive predictors, whereas genes that were found to correlate with poor responsiveness when expressed at a higher level are classified as negative predictors. These negative predictors may correlate with better responsiveness when expressed at a lower level in a tumor.
  • FIGS. 6A & 6B show the dose-dependent effects of anti-OX40 treatment on peripheral blood cells in the EMT6 tumor model.
  • Anti-OX40 treatment using murine anti-mouse OX40 mAb led to a dose-dependent reduction in peripheral Treg cells ( FIG. 6A ) and a dose-dependent increase in peripheral CD8 T cell proliferation ( FIG. 6B ).
  • T cell sub-populations in tumors were also analyzed.
  • Anti-OX40 treatment caused a reduction in Treg cells in the EMT6 breast tumor model, which showed better responsiveness to the anti-OX40 treatment ( FIG. 7A ).
  • the anti-OX40 treatment induced a sustained increase in CD8 tumor infiltrate in the EMT6 model ( FIG. 7B ).
  • the anti-OX40 antibody also led to a reduction in Treg cells in JC tumors ( FIG. 8A ).
  • CD8 T cells in JC tumors showed a more slight increase than in EMT6 cells ( FIG. 8B ).
  • FIGS. 9A-9D Gene expression of specific markers of immune activation was also examined in these tumor models. As shown in FIGS. 9A-9D , expression of several gene markers was associated with pharmacodynamic (PD) activity in both tumor models, with slightly increased activity in the EMT6 model compared to the JC model. These gene markers included IFNg ( FIG. 9A ), granzyme A ( FIG. 9B ), perforin ( FIG. 9C ), and TNFa ( FIG. 9D ). Table 8 lists the markers for PD activity identified in these experiments.
  • FIGS. 10A-10D Other genes associated with antigen presentation, co-stimulation, and IFNg response were differentially upregulated in EMT6 tumors ( FIGS. 10A-10D ). These gene markers included H2-aa ( FIG. 10A ), CD86 ( FIG. 10B ), ICOS ( FIG. 10C ), and CXCR3 ( FIG. 10D ). Table 9 lists the markers for responsiveness to OX40 agonist treatment identified in these experiments.

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SG11201703521UA (en) 2017-05-30
CA2966507A1 (fr) 2016-05-12
EP3215637A1 (fr) 2017-09-13
KR20170074246A (ko) 2017-06-29
AU2015343339A1 (en) 2017-06-15
AR102518A1 (es) 2017-03-08
HK1243738A1 (zh) 2018-07-20
RU2017119231A3 (fr) 2019-06-07
JP2017536842A (ja) 2017-12-14
BR112017009159A2 (pt) 2018-03-06
CN107109484A (zh) 2017-08-29
CN114381521A (zh) 2022-04-22
US20180195133A1 (en) 2018-07-12
MX2017005751A (es) 2018-04-10
IL251969A0 (en) 2017-06-29
US10718031B1 (en) 2020-07-21
WO2016073380A1 (fr) 2016-05-12
EP3215637B1 (fr) 2019-07-03
CN107109484B (zh) 2021-12-14

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