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.

1 . 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.   
     
     
         2 . The method of  claim 1 , wherein 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.   
     
     
         3 . The method of  claim 1 , wherein said subject exhibits said response within six months of said administration of said inhibitor of IGF-1R signaling. 
     
     
         4 . The method of  claim 1 , wherein said subject exhibits said response within 90 days of said administration of said inhibitor of IGF-1R signaling. 
     
     
         5 . The method of  claim 1 , wherein said subject exhibits said response within 60 days of said administration of said inhibitor of IGF-1R signaling. 
     
     
         6 . The method of  claim 1 , wherein said subject exhibits said response within 30 days of said administration of said inhibitor of IGF-1R signaling. 
     
     
         7 . The method of  claim 1 , wherein said subject exhibits said response within 14 days of said administration of said inhibitor of IGF-1R signaling. 
     
     
         8 . The method of  claim 1 , wherein said subject exhibits said response within 8 days of said administration of said inhibitor of IGF-1R signaling. 
     
     
         9 - 18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein 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.   
     
     
         20 . The method of  claim 19 , wherein 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. 
     
     
         21 . The method of  claim 19 , wherein said antibody binds to the IGF-1 receptor L2 domain. 
     
     
         22 . The method of  claim 19 , wherein said antibody binds to the IGF-1 receptor FnIII 1 domain. 
     
     
         23 . The method of  claim 19 , wherein said antibody binds to the IGF-1 receptor FnIII 2 domain. 
     
     
         24 . The method of  claim 19 , wherein said antibody binds to the IGF-1 receptor L1 and FnIII 1 domains. 
     
     
         25 . The method of  claim 19 , wherein said antibody competes for binding to IGF-1R with antibody L16/H16. 
     
     
         26 . The method of  claim 19 , wherein 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. 
     
     
         27 . The method of  claim 19 , wherein said antibody comprises the light chain variable domain of L16 and the heavy chain variable domain of H16. 
     
     
         28 . The method of  claim 1 , wherein 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.   
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 1 , wherein said human subject is less than 18 years old. 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 1 , wherein said tumor is a metastatic tumor. 
     
     
         34 - 38 . (canceled) 
     
     
         39 . The method of  claim 1 , wherein said method comprises a combination therapy. 
     
     
         40 . The method of  claim 39 , wherein said combination therapy comprises administering to said subject a chemotherapeutic agent. 
     
     
         41 . (canceled) 
     
     
         42 . The method of  claim 39 , wherein 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. 
     
     
         43 . The method of  claim 39 , 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 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.   
     
     
         44 . The method of  claim 39 , 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, 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. 
     
     
         45 . The method of  claim 1 , further comprising treating said subject with high-dose chemotherapy and autologous hematopoietic stem cell rescue. 
     
     
         46 . The method of  claim 1 , further comprising treating said subject with radiation. 
     
     
         47 . The method of  claim 46 , comprising whole lung irradiation. 
     
     
         48 - 53 . (canceled) 
     
     
         54 . The method of  claim 1 , further comprising surgically removing from said subject at least a portion of said tumor. 
     
     
         55 . The method of  claim 1 , wherein 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,   l. 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.   
     
     
         56 . The method of  claim 1 , wherein said tumor is of a type selected from the group consisting of ovarian, lung, carcinoid, head and neck, colon, breast, prostate, and gallbladder, further comprising administering to said subject a therapeutically effective amount of gemcitabine. 
     
     
         57 . A method of determining the relative likelihood that a tumor in a human subject will respond to a treatment comprising administering an inhibitor of IGF-1 receptor signaling to said subject, said method comprising determining whether cells from said tumor comprise a biomarker selected from the group consisting of:
 a. an activating RAS mutation, wherein presence of said activating RAS mutation indicates that said tumor is more likely to respond to said treatment,   b. an activating mutation in codon 12 of a RAS, wherein presence of said activating mutation in codon 12 of said RAS indicates that said tumor is more likely to respond to said treatment,   c. an activating KRAS mutation, wherein presence of said activating KRAS mutation indicates that said tumor is more likely to respond to said treatment,   d. an activating mutation in codon 12 of KRAS, wherein presence of said activating mutation in codon 12 of said KRAS indicates that said tumor is more likely to respond to said treatment,   e. a KRAS G12C mutation, wherein presence of said KRAS G12C mutation indicates that said tumor is more likely to respond to said treatment,   f. a wild-type KRAS allele, wherein said treatment further comprises treating said human subject with an inhibitor of EGF receptor, and presence of said wild-type KRAS allele indicates that said tumor is more likely to respond to said treatment,   g. a wild-type KRAS allele, wherein said treatment further comprises treating said human subject with panitumumab and/or cetuximab, and presence of said wild-type KRAS allele indicates that said tumor is more likely to respond to said treatment,   h. a wild-type KRAS allele, wherein said subject previously received panitumumab and/or cetuximab, said treatment further comprises treating said human subject with panitumumab and/or cetuximab, and presence of said wild-type KRAS allele indicates that said tumor is more likely to respond to said treatment,   i. a wild-type KRAS allele, wherein said tumor is a colorectal tumor, said subject previously received panitumumab and/or cetuximab, said treatment further comprises treating said human subject with panitumumab and/or cetuximab, and presence of said wild-type KRAS allele indicates that said tumor is more likely to respond to said treatment,   j. a reduced expression of PTEN, wherein presence of said reduced expression of PTEN indicates that said tumor is less likely to respond to said treatment,   k. a missense or nonsense mutation in PTEN, wherein presence of said missence or nonsense mutation in PTEN indicates that said tumor is less likely to respond to said treatment,   l. an EWS-FLI genetic translocation, wherein presence of said EWS-FLI genetic translocation indicates that said tumor is more likely to respond to said treatment,   m. expression of an EWS-FLI hybrid gene, wherein expression of said EWS-FLI hybrid gene indicates that said tumor is more likely to respond to said treatment,   n. an EWS/ets gene rearrangement, wherein presence of said EWS/ets gene rearrangement indicates that said tumor is more likely to respond to said treatment,   o. expression of an EWS/ets hybrid gene, wherein expression of said EWS/ets hybrid gene indicates that said tumor is more likely to respond to said treatment, and   p. a t(11;22)(q24;q12) chromosomal abnormality, wherein presence of said t(11;22)(q24;q12) chromosomal abnormality indicates that said tumor is more likely to respond to said treatment.   
     
     
         58 . The method of  claim 57 , wherein said tumor is determined to be more likely to respond to said treatment, said method further comprising the subsequent step of administering said treatment to said subject. 
     
     
         59 . A composition for treating a tumor disease in a human subject, comprising:
 between 10 and 150 mg/ml of an antibody, antibody fragment, or antibody derivative that specifically bind to IGF-1 receptor,   between 1 and 100 mM acetate, pH between 4.0 and 9.0,   between 0.5% and 20.0% w/v sorbitol, and   between 0.001% and 0.010% w/v Polysorbate 20.   
     
     
         60 . The composition of  claim 59 , comprising:
 30 mg/ml of said antibody, antibody fragment, or antibody derivative,   10 mM acetate, pH 5.2,   5% w/v sorbitol, and   0.004% w/v Polysorbate 20.