# US 11,078,288 B2 · Methods and compositions for treating tumor diseases > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,078,288 B2 - Document ID: US11078288B2 - Status: Granted - Kind: B2 - Application number: 15/955,304 - Filed: 2018-04-17 - Published: 2019-02-07 - Granted: 2021-08-03 - Earliest claimed: 2007-03-02 - Assignees: Amgen Inc. - Applicants: Amgen Inc. - Inventors: Pedro J. Beltran; Frank J. Calzone; Gregory Friberg; Christopher Haqq; Anthony W. Tolcher - Web page: https://patentgrep.com/patent/US11078288B2 ## CPC - C07K 16/2863: {against receptors for growth factors, growth regulators} - A61P 35/00: Antineoplastic agents - A61P 35/04: specific for metastasis - A61K 2039/505: {comprising antibodies} - C07K 2317/21: from primates, e.g. man - C07K 2317/55: Fab or Fab' - C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding - C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto - 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) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - 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) ## Abstract The present invention provides, in part, methods for treating a tumor in a human subject comprising inhibiting IGF-1 receptor signaling, methods of determining whether a tumor is more or less likely to respond to such treatment, and compositions for practicing such methods. In particular embodiments, the invention provides fully human, humanized, or chimeric anti-IGF-1R antibodies that bind human IGF-1R, IGF-1R-binding fragments and derivatives of such antibodies, and IGF-1R-binding polypeptides comprising such fragments. Other embodiments provide nucleic acids encoding such antibodies, antibody fragments and derivatives and polypeptides, cells comprising such polynucleotides, methods of making such antibodies, antibody fragments and derivatives and polypeptides, and methods of using such antibodies, antibody fragments and derivatives and polypeptides, including methods of treating or diagnosing subjects having IGF-1R-related disorders or conditions. ## Claims ### Claim 1 A method of treating a Ewing's sarcoma tumor in a human subject, comprising administering to said subject a therapeutically effective amount of an anti-IGF-1R antibody at least until, said subject exhibits at least one of the following responses to said treatment: a. stable disease according to RECIST criteria, b. partial response according to RECIST criteria, c. complete response according to RECIST criteria, d. reduction in metabolic activity in said tumor as assayed by PET, e. elimination of metabolic activity in said tumor as assayed by PET, and f. improvement in a symptom associated with said tumor, wherein said antibody comprises a light chain variable region and a heavy chain variable region, and wherein: a. said light chain variable region comprises the amino acid sequence of SEQ ID NO:32 and said heavy chain variable region comprises the amino acid sequence of SEQ ID NO:136; or b. said light chain variable region comprises: i the CDR 1 sequence of residues 24 through 39 of SEQ ID NO:32; and ii. the CDR 2 sequence of residues 55 through 61 of SEQ ID NO:32; and iii. the CDR 3 sequence of residues 94 through 102 of SEQ ID NO:32; and said heavy chain variable region comprises: i. the CDR 1 sequence of residues 31 through 36 of SEQ ID NO:136; and ii. the CDR 2 sequence of residues 51 through 66 of SEQ ID NO:136; and iii. the CDR 3 sequence of residues 99 through 108 of SEQ ID NO:136; and wherein said antibody binds to the IGF-1 receptor L2 domain. ### Claim 2 (depends on 1) The method of claim 1, wherein said tumor is selected from the group consisting of: a. a tumor comprising a cell that has an EWS-FLI genetic translocation, b. a tumor that expresses an EWS-FLI hybrid gene, c. a tumor comprising a cell that has an EWS/ets gene rearrangement, d. a tumor that expresses an EWS/ets hybrid gene, and e. a tumor comprising a cell that has a t(l 1;22)(q24;ql2) chromosomal abnormality. ### Claim 3 (depends on 1) The method of claim 1, wherein said subject exhibits said response within six months of said administration of said antibody. ### Claim 4 (depends on 1) The method of claim 1, wherein said subject exhibits said response within 90 days of said administration of said antibody. ### Claim 5 (depends on 1) The method of claim 1, wherein said subject exhibits said response within 60 days of said administration of said antibody. ### Claim 6 (depends on 1) The method of claim 1, wherein said subject exhibits said response within 30 days of said administration of said antibody. ### Claim 7 (depends on 1) The method of claim 1, wherein said subject exhibits said response within 14 days of said administration of said antibody. ### Claim 8 (depends on 1) The method of claim 1, wherein said subject exhibits said response within 8 days of said administration of said antibody. ### Claim 9 (depends on 1) The method of claim 1, wherein said human is less than 18 years old. ### Claim 10 (depends on 1) The method of claim 1, wherein said tumor is a metastatic tumor. ### Claim 11 (depends on 1) The method of claim 1, wherein said method comprises a combination therapy. ### Claim 12 (depends on 11) The method of claim 11, wherein said combination therapy comprises administering to said subject a chemotherapeutic agent. ### Claim 13 (depends on 11) The method of claim 11, wherein said combination therapy comprises administering to said subject at least one compound selected from the group consisting of adriamycin, ifosfamide, vincristine, topotecan, docetaxel, cyclophosphamide, etoposide, actinomycin D, doxorubicin, busulfan, melphalan, cisplatinum, and gemcitabine. ### Claim 14 (depends on 11) The method of claim 11, wherein said combination therapy comprises administering to said subject at least one combination of compounds selected from the group of combinations consisting of: a. adriamycin and cyclophosphamide, b. vincristine, actinomycin D, and cyclophosphamide, c. vincristine, actinomycin D, cyclophosphamide, and doxorubicin, d. vincristine, ifosfamide, doxorubicin, and etoposide, e. vincristine, topotecan, and cyclophosphamide, f. ifosfamide and etoposide, g. busulfan and melphalan, h. ifosfamide and vincristine, and i. topotecan and vincristine. ### Claim 15 (depends on 11) The method of claim 11, wherein said combination therapy comprises administering to said subject at least one compound selected from the group consisting of a corticosteroid, an anti-emetic, ondansetron hydrochloride, granisetron hydrochloride, metroclopramide, domperidone, haloperidol, cyclizine, lorazepam, prochlorperazine, dexamethasone, levomepromazine, tropisetron, a cancer vaccine, a GM-CSF inhibiting agent, a GM-CSF DNA vaccine a cell-based vaccine a dendritic cell vaccine a recombinant viral vaccine, a heat shock protein (HSP) vaccine, an allogeneic tumor vaccine, an autologous tumor vaccine, an analgesic, ibuprofen, naproxen, choline magnesium trisalicylate, an oxycodone hydrochloride, an anti-angiogenic agent, bevacizumab, an anti-VEGF antibody, an anti-VEGF receptor antibody, a soluble VEGF receptor, an anti-TWEAK antibody, an anti-TWEAK receptor antibody, a soluble TWEAK receptor, AMG 706, AMG 386, an antiproliferative agent, a farnesyl protein transferase inhibitor, an αvβ3 inhibitor, an αvβ5 inhibitor, a p53 inhibitor, a Kit receptor inhibitor, a ret receptor inhibitor, a PDGFR inhibitor, an angiopoietin inhibitor, an anti-c-fms antibody, an anti-CSF-1 antibody, a soluble c-fms, pegvisomant, gemcitabine, panitumumab, irinotecan, and SN-38. ### Claim 16 (depends on 1) The method of claim 1, further comprising treating said subject with high-dose chemotherapy and autologous hematopoietic stem cell rescue. ### Claim 17 (depends on 1) The method of claim 1, further comprising treating said subject with radiation. ### Claim 18 (depends on 17) The method of claim 17, comprising whole lung irradiation. ### Claim 19 (depends on 1) The method of claim 1, further comprising surgically removing from said subject at least a portion of said tumor. ### Claim 20 (depends on 1) The method of claim 1, wherein said therapeutically effective amount of said antibody has an effect selected from the group consisting of: a. binds to at least 10% of subject's IGF-I receptors within 24 hours of administration, b. binds to at least 25% of subject's IGF-I receptors within 24 hours of administration, c. binds to at least 50% of subject's IGF-I receptors within 24 hours of administration, d. binds to at least 75% of subject's IGF-I receptors within 24 hours of administration, e. binds to at least 90% of subject's IGF-I receptors within 24 hours of administration, f. binds to at least 99% of subject's IGF-I receptors within 24 hours of administration, g. reduces signaling through subject's IGF-I receptors by at least 10% within 24 hours of administration, h. reduces signaling through subject's IGF-I receptors by at least 25% within 24 hours of administration, i. reduces signaling through subject's IGF-I receptors by at least 50% within 24 hours of administration, j. reduces signaling through subject's IGF-I receptors by at least 75% within 24 hours of administration, k. reduces signaling through subject's IGF-I receptors by at least 90% within 24 hours of administration, l. reduces signaling through subject's IGF-I receptors by at least 99% within 24 hours of administration, m. reduces autophosphorylation of IGF-I receptor by at least 10% within 24 hours of administration, n. reduces autophosphorylation of IGF-I receptor by at least 25% within 24 hours of administration, o. reduces autophosphorylation of IGF-I receptor by at least 50% within 24 hours of administration, p. reduces autophosphorylation of IGF-I receptor by at least 75% within 24 hours of administration, q. reduces autophosphorylation of IGF-I receptor by at least 90% within 24 hours of administration, r. reduces autophosphorylation of IGF-I receptor by at least 99% within 24 hours of administration, s. reduces phosphorylation of IRS-I by at least 10% within 24 hours of administration, t. reduces phosphorylation of IRS-I by at least 25% within 24 hours of administration, u. reduces phosphorylation of IRS-I by at least 50% within 24 hours of administration, v. reduces phosphorylation of IRS-I by at least 75% within 24 hours of administration, w. reduces phosphorylation of IRS-I by at least 90% within 24 hours of administration, and x. reduces phosphorylation of IRS-I by at least 99% within 24 hours of administration.