Methods and compositions for treating tumor diseases

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.

Description

FIELD OF THE INVENTION[0001]This application provides methods and compositions relating to the treatment of tumor diseases such as Ewing's sarcoma, other sarcomas, tumors comprising EWS-FLI genetic translocations, tumors comprising activating RAS mutations, carcinoid tumors, and other cancers and proliferative diseases.BACKGROUND OF THE INVENTION[0002]Ewing's sarcoma is the most common solid tumor in children and adolescents. The current standard of care comprises aggressive chemotherapy. The side effects of such treatment often include acute toxicity, and can include secondary malignancies, a serious limitation for a young patient population. Moreover, metastatic Ewing's sarcoma is particularly resistant to conventional treatment. Twenty-five percent of Ewing's sarcoma patients have metastases when they are diagnosed; their five year survival rate can be as low as 20%.[0003]Activating RAS mutations are associated with many different types of cancers and are found in well over 50% o...

AI Technical Summary

Benefits of technology

[0022]In one aspect, the present invention provides a method of treating a tumor in a human subject, comprising administering to said subject a therapeutically effective amount of an inhibitor of IGF-1R signalling, wherein 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. In one embodiment, said tumor is selected from the group consisting of: a. a sarcoma tumor, b. a Ewing's sarcoma tumor, c. an adenocarcinoma tumor, d. a pancreatic cancer tumor, e. a carcinoid tumor, f. a thymus tumor, g. an adenoid tumor, h. an adenoid R eye tumor, i. a melanoma tumor, j. a colorectal tumor, k. an ovarian tumor, l. a breast tumor, m. a tumor comprising a cell that has an activating RAS mutation, n. a tumor comprising a cell that has an activating KRAS mutation, o. a tumor comprising a cell that has an activating mutation in codon 12 of KRAS, p. a tumor comprising a cell that has a KRAS G12C mutation, q. a tumor comprising a cell that does not have a missense or a nonsense mutation in the PTEN tumor suppressor, r. a tumor comprising a cell that does not have a reduction of expression of PTEN, relative to a non-tumor tissue sample, detectable by immunohistochemistry using an antibody specific for PTEN, s. a tumor that exhibits a complete loss of PTEN expression in 5% or fewer of tumor cells as assessed by immunohistochemical staining of archival formalin fixed paraffin embedded tumor sections, t. a tumor comprising a cell that has an EWS-FLI genetic translocation, u. a tumor that expresses an EWS-FLI hybrid gene, v. a tumor comprising a cell that has an EWS / ets gene rearrangement, w. a tumor that expresses an EWS / ets hybrid gene, and x. a tumor comprising a cell that has a t(11;22)(q24;q12) chromosomal abnormality. In another embodiment, said subject exhibits said response within six months of said administration of said inhibitor of IGF-1R signaling. In another embodiment, said subject exhibits said response within 90 days of said administration of said inhibitor of IGF-1R signaling. In another embodiment, said subject exhibits said response within 60 days of said administration of said inhibitor of IGF-1R signaling. In another embodiment, said subject exhibits said response within 30 days of said administration of said inhibitor of IGF-1R signaling. In another embodiment, said subject exhibits said response within 14 days of said administration of said inhibitor of IGF-1R signaling. In another embodiment, said subject exhibits said response within 8 days of said administration of said inhibitor of IGF-1R signaling. In another embodiment, said symptom is irregular, labored, or difficult breathing. In another embodiment, said symptom is pain. In another embodiment, said symptom is difficulty sleeping. In another embodiment, said symptom is difficulty eating, drinking, or swallowing. In another embodiment, said inhibitor of IGF-1R signaling is administered to said subject in at least one dose. In another embodiment, said inhibitor of IGF-1R signaling is administered to said subject in at least two doses. In another embodiment, said inhibitor of IGF-1R signaling is administered to said subject in at least three doses. In another embodiment, said inhibitor of IGF-1R signaling is administered to said subject in at least four doses. In another embodiment, said inhibitor of IGF-1R signaling is administered to said subject in intermittent doses at least until said response is achieved. In another embodiment, said response is a complete response according to RECIST criteria. In another embodiment, said inhibitor of IGF-1R signaling is selected from the group consisting of: a. an antibody that specifically binds to the IGF-1 receptor, b. an antibody fragment that specifically binds to the IGF-1 receptor, c. an antibody derivative that specifically binds to the IGF-1 receptor, d. a peptibody that specifically binds to the IGF-1 receptor, e. an Avimer™ that specifically binds to the IGF-1 receptor, f. an IGF-1 receptor siRNA, and g. a small molecule that binds to the IGF-1 receptor. In another embodiment, said antibody is selected from the group consisting of an antibody comprising a combination of a light chain variable domain and a heavy chain variable domain selected from the group of combinations consisting of: L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20, H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29, L30H30, L31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37, L38H38, L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47, L48H48, L49H49, L50H50, L51H51, and L52H52; antibody 1A (DSMZ Deposit No. DSM ACC 2586), antibody 8 (DSMZ Deposit No. DSM ACC 2589), antibody 23 (DSMZ Deposit No. DSM ACC 2588), antibody 18; antibody 2F8, antibody A12, antibody IMC-A12; antibody 7C10, chimaeric antibody C7C10, antibody h7C10, antibody 7H2M, chimaeric antibody *7C10, antibody GM 607, humanized antibody 7C10 version 1, humanized antibody 7C10 version 2, humanized antibody 7C10 version 3, antibody 7H2HM; antibody EM164, resurfaced antibody EM164, humanized antibody EM164, antibody huEM164 v1.0, antibody huEM164 v1.1, antibody huEM164 v1.2, and antibody huEM164 v1.3; antibody CP-751,871, the antibody produced by the hybridoma having the ATCC accession number PTA-2792, the antibody produced by the hybridoma having the ATCC accession number PTA-2788, the antibody produced by the hybridoma having the ATCC accession number PTA-2790, the antibody produced by the hybridoma having the ATCC accession number PTA-2791, the antibody produced by the hybridoma having the ATCC accession number PTA-2789, the antibody produced by the hybridoma having the ATCC accession number PTA-2793; antibody 2.12.1, antibody 2.13.2, antibody 2.14.3, antibody 3.1.1, antibody 4.9.2, and antibody 4.17.3; antibody 19D12, an antibody comprising a heavy chain encoded by a polynucleotide in plasmid 15H12 / 19D12 HCA (γ4), deposited at the ATCC under number PTA-5214, and a light chain encoded by a polynucleotide in plasmid 15H12 / 19D12 LCF (κ), deposited at the ATCC under number PTA-5220; antibody PINT-6A1, antibody PINT-7A2, antibody PINT-7A4, antibody PINT-7A5, antibody PINT-7A6, antibody PINT-8A1, antibody PINT-9A2, antibody PINT-11A1, antibody PINT-11A2, antibody PINT-11A3, antibody PINT-11A4, antibody PINT-11A5, antibody PINT-11A7, antibody PINT-11A12, antibody PINT-12A1, antibody PINT-12A2, antibody PINT-12A3, antibody PINT-12A4, antibody PINT-12A5, antibody M13-C06, antibody M14-G11, antibody M14-C03, antibody M14-B01, antibody M12-E01, and antibody M12-G04, and antibodies produced by hybridomas P2A7.3E11, 20C8.3B8, P1A2.2B11, 20D8.24B11, P1E2.3B12, and P1G10.2B8. In another embodiment, said antibody binds to the IGF-1 receptor L2 domain. In another embodiment, said antibody binds to the IGF-1 receptor FnIII 1 domain. In another embodiment, said antibody binds to the IGF-1 receptor FnIII 1 domain. In another embodiment, said antibody binds to the IGF-1 receptor L1 and FnIII 1 domains. In another embodiment, said antibody competes for binding to IGF-1R with antibody L16 / H16. In another embodiment, said antibody comprises a light chain variable domain that is at least 90% identical to the light chain L16 and a heavy chain variable domain that is at least 90% identical to the heavy chain H16. In another embodiment, said antibody comprises the light chain variable domain of L16 and the heavy chain variable domain of H16. In another embodiment, said inhibitor of IGF-1R signaling is selected from the group consisting of: a. an antibody, or antibody fragment, that specifically binds to IGF-1, b. an antibody, or antibody fragment, that specifically binds to IGF-2, c. an IGF-1 and / or IGF-2 binding protein, d. a soluble, IGF-1 and / or IGF-2 binding fragment of the IGF-1 receptor, e. a soluble, IGF-2 binding fragment of the IGF-2 receptor, f. a small molecule that binds to IGF-1 and / or IGF-2, g. a small molecule that binds to IRS1, h. a small molecule that binds to SHC, GRB2, or SOS1, and i. a small molecule that binds to PI3K or SHP2. In another embodiment, said human subject is a child. In another embodiment, said child is less than 18 years old. In another embodiment, said human subject is an adolescent. In another embodiment, said tumor is a metastatic tumor. In another embodiment, said metastatic tumor is in a bone. In another embodiment, said metastatic tumor is in a lung. In another embodiment, said inhibitor of IGF-1R signalling inhibits IGF-1 receptor signaling at least 10 times more than it inhibits insulin receptor signaling. In another embodiment, said inhibitor of IGF-1R signalling inhibits IGF-1 receptor signaling at least 100 times more than it inhibits insulin receptor signaling. In another embodiment, said inhibitor of IGF-1R signalling inhibits IGF-1 receptor signaling at least 1000 times more than it inhibits insulin receptor signaling. In another embodiment, said method comprises a combination therapy. In another embodiment, said combination therapy comprises administering to said subject a chemotherapeutic agent. In another embodiment, said combination therapy comprises administering to said subject an inhibitor of CD99. In another embodiment, said combination therapy comprises administering to said subject at least one compound selected from the group consisting of adriamycin, cytoxan, ifosfamide, vincristine, topotecan, taxotere, cyclophosphamide, etoposide, actinomycin D, doxorubicin, busulfan, melphalan, cisplatinum, and gemcitabine. In another embodiment, 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 cytoxan, 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. In another embodiment, 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, an anti-vascular agent, bevacizumab, an anti-VEGF antibody, an anti-VEGF receptor antibody, a soluble VEGF receptor fragment, an anti-TWEAK antibody, an anti-TWEAK receptor antibody, a soluble TWEAK receptor fragment, AMG 706, AMG 386, an anti-proliferative 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, a growth hormone secretion inhibitor, an angiopoietin inhibitor, a tumor infiltrating macrophage-inhibiting agent, a c-fms inhibiting agent, an anti-c-fms antibody, an CSF-1 inhibiting agent, an anti-CSF-1 antibody, a soluble c-fms fragment, pegvisomant, gemcitabine, panitumumab, irinothecan, and SN-38. In another embodiment, said method further comprises treating said subject with high-dose chemotherapy and autologous hematopoietic stem cell rescue. In another embodiment, said method further comprises treating said subject with radiation. In another embodiment, said method comprises whole lung irradiation. In another embodiment, said subject receives at least 40 Gy of radiation. In another embodiment, said subject receives between 40 and 60 Gy of radiation. In another embodiment, said subject receives between 40 and 50 Gy of radiation. In another embodiment, said subject receives between 55 and 60 Gy of radiation. In another embodiment, said subject receives no more than 55.8 Gy of radiation. In another embodiment, said subject receives between 45 and 55 Gy of radiation. In another embodiment, said method further comprises surgically removing from said subject at least a portion of said tumor. In another embodiment, said therapeutically effective amount of said inhibitor of IGF-1R signaling has an effect selected from the group consisting of: a. binds to at least 10% of subject's IGF-1 receptors within 24 hours of administration, b. binds to at least 25% of subject's IGF-1 receptors within 24 hours of administration, c. binds to at least 50% of subject's IGF-1 receptors within 24 hours of administration, d. binds to at least 75% of subject's IGF-1 receptors within 24 hours of administration, e. binds to at least 90% of subject's IGF-1 receptors within 24 hours of administration, f. binds to at least 99% of subject's IGF-1 receptors within 24 hours of administration, g. reduces signaling through subject's IGF-1 receptors by at least 10% within 24 hours of administration, h. reduces signaling through subject's IGF-1 receptors by at least 25% within 24 hours of administration, i. reduces signaling through subject's IGF-1 receptors by at least 50% within 24 hours of administration, j. reduces signaling through subject's IGF-1 receptors by at least 75% within 24 hours of administration, k. reduces signaling through subject's IGF-1 receptors by at least 90% within 24 hours of administration, 1. reduces signaling through subject's IGF-1 receptors by at least 99% within 24 hours of administration, m. reduces autophosphorylation of IGF-1 receptor by at least 10% within 24 hours of administration, n. reduces autophosphorylation of IGF-1 receptor by at least 25% within 24 hours of administration, o. reduces autophosphorylation of IGF-1 receptor by at least 50% within 24 hours of administration, p. reduces autophosphorylation of IGF-1 receptor by at least 75% within 24 hours of administration, q. reduces autophosphorylation of IGF-1 receptor by at least 90% within 24 hours of administration, r. reduces autophosphorylation of IGF-1 receptor by at least 99% within 24 hours of administration, s. reduces phosphorylation of IRS-1 by at least 10% within 24 hours of administration, t. reduces phosphorylation of IRS-1 by at least 25% within 24 hours of administration, u. reduces phosphorylation of IRS-1 by at least 50% within 24 hours of administration, v. reduces phosphorylation of IRS-1 by at least 75% within 24 hours of administration, w. reduces phosphorylation of IRS-1 by at least 90% within 24 hours of administration, and x. reduces phosphorylation of IRS-1 by at least 99% within 24 hours of administration.

Problems solved by technology

The side effects of such treatment often include acute toxicity, and can include secondary malignancies, a serious limitation for a young patient population.

Moreover, metastatic Ewing's sarcoma is particularly resistant to conventional treatment.

In spite of intense research efforts, no targeted therapeutic has been found that is effective against tumors containing activating RAS mutations.

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