# US 2016/0355597 A1 · Methods of treating cancer using anti-ox40 antibodies > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2016/0355597 A1 - Document ID: US20160355597A1 - Status: Published application - Kind: A1 - Application number: 15/176,100 - Filed: 2016-06-07 - Published: 2016-12-08 - Earliest claimed: 2015-06-08 - Assignees: Genentech, Inc. - Applicants: Genentech, Inc. - Inventors: Ina P. RHEE; Jeong KIM; Mahrukh HUSENI; Eric STEFANICH; Sid SUKUMARAN; Chi-Chung LI - Web page: https://patentgrep.com/patent/US20160355597A1 ## CPC - C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95} - A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)} - A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants - A61P 11/00: Drugs for disorders of the respiratory system - A61P 13/10: of the bladder - A61P 13/12: of the kidneys - A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives - A61P 17/00: Drugs for dermatological disorders - A61P 35/00: Antineoplastic agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575) - A61K 2039/505: {comprising antibodies} - A61K 2039/545: {characterised by the dose, timing or administration schedule} - C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered - C07K 2317/56: variable (Fv) region, i.e. VH and/or VL - C07K 2317/75: Agonist effect on antigen - C12Q 2600/112: Disease subtyping, staging or classification - C12Q 2600/158: Expression markers - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES ## Abstract The invention provides methods of treating or delaying progression of cancer in an individual comprising administering to the individual an anti-human OX40 agonist antibody. In some embodiments, the antibody is administered in a dose selected from about 0.2 mg, about 0.8 mg, about 3.2 mg, about 12 mg, about 40 mg, about 80 mg, about 130 mg, about 160 mg, about 300 mg, about 320 mg, about 400 mg, about 600 mg, and about 1200 mg. ## Claims ### Claim 1 A method of treating or delaying progression of cancer in an individual comprising administering to the individual an anti-human OX40 agonist antibody at a dose selected from the group consisting of about 0.2 mg, about 0.8 mg, about 3.2 mg, about 12 mg, about 40 mg, about 80 mg, about 130 mg, about 160 mg, about 300 mg, about 320 mg, about 400 mg, about 600 mg, and about 1200 mg, wherein 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, and wherein the individual is a human. ### Claim 2 (depends on 1) The method of claim 1, wherein the dose is about 300 mg. ### Claim 3 (depends on 1, 2) The method of claim 1 or claim 2, wherein the dose is administered intravenously. ### Claim 4 (depends on 1, 2, 3) The method of any one of claims 1-3, further comprising repeating the administration of the anti-human OX40 agonist antibody at one or more additional doses, wherein each dose of the one or more additional doses is selected from the group consisting of about 0.2 mg, about 0.8 mg, about 3.2 mg, about 12 mg, about 40 mg, about 80 mg, about 130 mg, about 160 mg, about 300 mg, about 320 mg, about 400 mg, about 600 mg, and about 1200 mg per administration and is administered at an interval of about 2 weeks or about 14 days between each administration. ### Claim 5 (depends on 1, 2, 3) The method of any one of claims 1-3, further comprising repeating the administration of the anti-human OX40 agonist antibody at one or more additional doses, wherein each dose of the one or more additional doses is selected from the group consisting of about 0.2 mg, about 0.8 mg, about 3.2 mg, about 12 mg, about 40 mg, about 80 mg, about 130 mg, about 160 mg, about 300 mg, about 320 mg, about 400 mg, about 600 mg, and about 1200 mg per administration and is administered at an interval of about 3 weeks or about 21 days between each administration. ### Claim 6 (depends on 4, 5) The method of claim 4 or claim 5, wherein 1-10 additional doses of the anti-human OX40 agonist antibody are administered. ### Claim 7 (depends on 4, 5, 6) The method of any one of claims 4-6, wherein each dose of the anti-human OX40 agonist antibody administered to the individual is the same. ### Claim 8 (depends on 4, 5, 6) The method of any one of claims 4-6, wherein each dose of the anti-human OX40 agonist antibody administered to the individual is not the same. ### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8) The method of any one of claims 1-8, wherein each dose of the anti-human OX40 agonist antibody is administered intravenously. ### Claim 10 (depends on 9) The method of claim 9, wherein a first dose of the anti-human OX40 agonist antibody is administered to the individual at a first rate, wherein, after the administration of the first dose, one or more additional doses of the anti-human OX40 agonist antibody are administered to the individual at one or more subsequent rates, and wherein the first rate is slower than the one or more subsequent rates. ### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) The method of any one of claims 1-10, wherein the anti-human OX40 agonist antibody is a humanized antibody. ### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11) The method of any one of claims 1-11, wherein the 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, 183, or 184. ### Claim 13 (depends on 12) The method of claim 12, wherein the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to human OX40. ### Claim 14 (depends on 12, 13) The method of claim 12 or claim 13, wherein a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:56. ### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14) The method of any one of claims 1-14, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 57, 59, 61, 63, 65, 67, or 69. ### Claim 16 (depends on 15) The method of claim 15, wherein the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-human OX40 agonist antibody comprising that sequence retains the ability to bind to human OX40. ### Claim 17 (depends on 15, 16) The method of claim 15 or claim 16, wherein a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 57. ### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17) The method of any one of claims 1-17, wherein the antibody comprises a VH sequence of SEQ ID NO: 56. ### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) The method of any one of claims 1-18, wherein the antibody comprises a VL sequence of SEQ ID NO: 57. ### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19) The method of any one of claims 1-19, wherein the antibody comprises a VH sequence of SEQ ID NO:56 and a VL sequence of SEQ ID NO: 57. ### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) The method of any one of claims 1-20, wherein the antibody is a full length human IgG1 antibody. ### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The method of any one of claims 1-21, wherein the antibody is MOXR0916. ### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22) The method of any one of claims 1-22, wherein the antibody is formulated in a pharmaceutical formulation comprising (a) the antibody at a concentration between about 10 mg/mL and about 100 mg/mL, (b) a polysorbate, wherein the polysorbate concentration is about 0.02% to about 0.06%; (c) a histidine buffer at pH 5.0 to 6.0; and (d) a saccharide, wherein the saccharide concentration is about 120 mM to about 320 mM. ### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23) The method of any one of claims 1-23, wherein the treatment results in a sustained response in the individual after cessation of the treatment. ### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) The method of any one of claims 1-24, wherein the treatment results in a complete response (CR) or partial response (PR) in the individual. ### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25) The method of any one of claims 1-25, wherein the individual is immunotherapy-naïve. ### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26) The method of any one of claims 1-26, wherein the individual has a cancer selected from the group consisting of melanoma, triple-negative breast cancer, ovarian cancer, renal cell cancer, bladder cancer, non-small cell lung cancer, gastric cancer, and colorectal cancer. ### Claim 28 (depends on 27) The method of claim 27, wherein the individual has melanoma, wherein the melanoma has a BRAF V600 mutation, and wherein, prior to the administration of the anti-human OX40 agonist antibody, the individual has been treated with a B-Raf and/or mitogen-activated protein kinase kinase (MEK) kinase inhibitor and exhibited disease progression or intolerance to the B-Raf and/or mitogen-activated protein kinase kinase (MEK) kinase inhibitor treatment. ### Claim 29 (depends on 27) The method of claim 27, wherein the individual has non-small cell lung cancer, wherein the non-small cell lung cancer has a sensitizing epidermal growth factor receptor (EGFR) mutation, and wherein, prior to the administration of the anti-human OX40 agonist antibody, the individual has been treated with an EGFR tyrosine kinase inhibitor and exhibited disease progression or intolerance to the EGFR tyrosine kinase inhibitor treatment. ### Claim 30 (depends on 27) The method of claim 27, wherein the individual has non-small cell lung cancer, wherein the non-small cell lung cancer has an anaplastic lymphoma kinase (ALK) rearrangement, and wherein, prior to the administration of the anti-human OX40 agonist antibody, the individual has been treated with an ALK tyrosine kinase inhibitor and exhibited disease progression or intolerance to the ALK tyrosine kinase inhibitor treatment. ### Claim 31 (depends on 27) The method of claim 27, wherein the individual has renal cell cancer, and wherein the renal cell cancer is refractory to a prior therapy. ### Claim 32 (depends on 31) The method of claim 31, wherein the prior therapy comprises treatment with a VEGF inhibitor, an mTOR inhibitor, or both. ### Claim 33 (depends on 1) The method of claim 1, wherein the anti-human OX40 agonist antibody is MOXR0916, wherein the dose of MOXR0916 is 300 mg, and wherein the cancer is selected from the group consisting of melanoma, triple-negative breast cancer, ovarian cancer, renal cell cancer, bladder cancer, non-small cell lung cancer, gastric cancer, and colorectal cancer. ### Claim 34 (depends on 33) The method of claim 33, further comprising repeating the administration of MOXR0916 at one or more additional doses of 300 mg per administration, administered at an interval of about 3 weeks or about 21 days between each administration. ### Claim 35 (depends on 33, 34) The method of claim 33 or claim 34, wherein MOXR0916 is administered intravenously. ### Claim 36 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35) The method of any one of claims 1-35, further comprising, after administering to the individual the anti-human OX40 agonist antibody, monitoring the responsiveness of the individual to said treatment by: (a) measuring an expression level of one or more marker genes in a sample obtained from the cancer of the individual, wherein the one or more marker genes are selected from the group consisting of CCR5, CD274, IL-7, TNFRSF14, TGFB1, CD40, CD4, PRF1, TNFSF4, CD86, CXCL9, CD3E, LAG3, PDCD1, CCL28, GZMB, IFNg, and IL-2RA; and (b) optionally, classifying the individual as responsive or non-responsive to treatment with the anti-human OX40 agonist antibody based on the expression level of the one or more marker genes in the sample, 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 individual. ### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35) The method of any one of claims 1-35, further comprising, after administering to the individual the anti-human OX40 agonist antibody, monitoring the responsiveness of the individual to said treatment by: (a) measuring an expression level of one or more marker genes in a sample obtained from the cancer of the individual, wherein the one or more marker genes are selected from the group consisting of CD8b, EOMES, GZMA, GZMB, IFNg, and PRF1; and (b) optionally, classifying the individual as responsive or non-responsive to treatment with the anti-human OX40 agonist antibody based on the expression level of the one or more marker genes in the sample, 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 individual. ### Claim 38 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35) The method of any one of claims 1-35, further comprising, after administering to the individual the anti-human OX40 agonist antibody, monitoring the responsiveness of the individual to said treatment by: (a) measuring an expression level of one or more marker genes in a sample obtained from the cancer of the individual, wherein the one or more marker genes are selected from the group consisting of CCL22, IL-2, RORC, IL-8, CTLA4, and FOXP3; and (b) optionally, classifying the individual as responsive or non-responsive to said treatment with the anti-human OX40 agonist antibody based on the expression level of the one or more marker genes in the sample, as compared with a reference, wherein a decreased expression level of the one or more marker genes as compared with the reference indicates a responsive individual. ### Claim 39 A method for determining whether a cancer patient responds to a treatment with an anti-human OX40 agonist antibody, comprising measuring an expression level of one or more marker genes in a sample obtained from the cancer of the individual, wherein the one or more marker genes are selected from the group consisting of CCR5, CD274, IL-7, TNFRSF14, TGFB1, CD40, CD4, PRF1, TNFSF4, CD86, CXCL9, CD3E, LAG3, PDCD1, CCL28, GZMB, IFNg, and IL-2RA, wherein the expression level of the one or more marker genes is compared with a reference, and wherein an increased expression level of the one or more marker genes as compared with the reference indicates that the cancer patient responds to said treatment. ### Claim 40 A method for determining whether a cancer patient responds to a treatment with an anti-human OX40 agonist antibody, comprising measuring an expression level of one or more marker genes in a sample obtained from the cancer of the individual, wherein the one or more marker genes are selected from the group consisting of CD8b, EOMES, GZMA, GZMB, IFNg, and PRF1, wherein the expression level of the one or more marker genes is compared with a reference, and wherein an increased expression level of the one or more marker genes as compared with the reference indicates that the cancer patient responds to said treatment. ### Claim 41 A method for determining whether a cancer patient responds to a treatment with an anti-human OX40 agonist antibody, comprising measuring an expression level of one or more marker genes in a sample obtained from the cancer of the individual, wherein the one or more marker genes are selected from the group consisting of CCL22, IL-2, RORC, IL-8, CTLA4, and FOXP3, wherein the expression level of the one or more marker genes is compared with a reference, and wherein a decreased expression level of the one or more marker genes as compared with the reference indicates that the cancer patient responds to said treatment. ### Claim 42 A kit for treating or delaying progression of cancer in an individual, comprising: (a) a container comprising anti-human OX40 agonist antibody for administration at a dose selected from the group consisting of about 0.2 mg, about 0.8 mg, about 3.2 mg, about 12 mg, about 40 mg, about 80 mg, about 130 mg, about 160 mg, about 300 mg, about 320 mg, about 400 mg, about 600 mg, and about 1200 mg, wherein the antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO:2; an HVR-H2 comprising the amino acid sequence of SEQ ID NO:3; an HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; an HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; an HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and an HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7; and (b) a package insert with instructions for treating or delaying progression of cancer in an individual, wherein the individual is a human.