Classifications

• • 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
  • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
• • 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
  • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

• the field of the invention relates to methods for treating diseases such as cancer with combinations that include an anti-IGF1 R antibody and cisplatin, pemetrexed, gemcitabine and/or irinotecan.
• the insulin-like growth factors include insulin-like growth factor-l (IGF-I) and insulinlike growth factor-l I (IGF-I I). These growth factors exert mitogenic activity on various cell types, including tumor cells, by binding to a common receptor named the insulin-like growth factor receptor-1 (IGFR1 ).
• IGF-I insulin-like growth factor-l
• IGF-I I insulinlike growth factor-l I
• IGFR1 insulin-like growth factor receptor-1
• IGF-I insulin-like Growth Factor Receptor-I
• IGFR1 insulin-like Growth Factor Receptor-I
• Therapeutic anti-cancer antibodies may be combined with a further
• chemotherapeutic agent which, for example, may provide significant therapeutic benefits to the patient, for example, by targeting a metabolic pathway distinct from that targeted by the antibody.
• the present invention provides, in part, a composition
• a composition comprising (e.g., a kit optionally further including a package insert with instructions for use) an isolated antibody or antigen-binding fragment thereof (e.g. , antibody such as a humanized antibody) comprising CDR-L1 ; CDR-L2; and CDR-L3 in a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 1 ; and/or, CDR-H1 ; CDR-H2; and CDR- H3 in a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 2; in association with cisplatin, pemetrexed, gemcitabine and/or irinotecan (e.g.
• an isolated antibody or antigen-binding fragment thereof e.g. , antibody such as a humanized antibody
• CDR-L1 ; CDR-L2; and CDR-L3 in a light chain immunoglob
• the isolated antibody or antigen- binding fragment thereof comprises a light chain immunoglobulin variable region comprising: CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 3; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 4; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 5; and/or a heavy chain immunoglobulin variable region comprising: CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 6; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 7; and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 8; e.g., wherein the antibody or fragment comprises a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO:
• the composition comprises or excludes a further chemotherapeutic agent such as, for example, a HER2 antagonist, aprepitant, topotecan, 131 -I-TM-601 , 13-cis-retinoic acid, 4-hydroxytamoxifen, 5-deooxyuridine, 5'-deoxy-5-fluorouridine, 5-fluorouracil and leucovorin; , PEG-labeled irinotecan, 6-mecaptopurine, 7-hydroxy staurosporine, a CDK inhibitor, a combination of irinotecan, 5-fluorouracil and leucovorin, a farnesyl protein transferase inhibitor, a lutenizing hormone-releasing hormone agonist, a MEK inhibitor, a progestational agent, a progestin, a Raf inhibitor, a selective estrogen receptor modulator, a VEGFR inhibitor, anti-VEGFR-2 antibody, abraxane, zotarolimus
• methylprednisolone metoclopramide, mithramycin, mitomycin, mitotane, mitoxantrone, tozasertib, MLN8054, neovastat, netupitant, neuradiab, nilotinib, nilutamide, nolatrexed, dacinostat, oblimersen, octreotide, ofatumumab, ondansetron, oregovomab, oxaliplatin, paclitaxel, palonosetron, pamidronate, panitumumab, pazopanib, PD184352, PD0325901 , pegfilgrastim, pentostatin, danusertib, phenylalanine mustard, pipendoxifene, PKI-166, plicamycin, porfimer, procarbazine, prochlorperazine, PTK787/ZK 222584, R
• the present invention also provides a method for treating or preventing a cancer
• IGF1 R expression and/or activity e.g., ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, osteosarcoma, rhabdomyosarcoma, neuroblastoma, multiple myeloma, lung cancer, colorectal cancer and cervical cancer
• a subject in need ' of such treating or preventing e.g. , a human
• administering to the subject, a therapeutically effective amount of a composition comprising an isolated antibody or antigen-binding fragment thereof (e.g., an antibody such as a humanized antibody; e.g.
• dalotuzumab comprising CDR-L1 ; CDR-L2; and CDR-L3 in a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 1 ; and/or, CDR-H1 ; CDR-H2; and CDR-H3 in a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 2; in association with cisplatin, pemetrexed, gemcitabine and/or irinotecan (e.g., pemetrexed and cisplatin) whereby the cancer growth, survival and/or metastasis is inhibited or prevented; e.g., wherein the isolated antibody or antigen- binding fragment thereof comprises: CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 3; CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 4; and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO
• the antibody or fragment comprises a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 1 ; and/or a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 2.
• the subject is administered the composition of the present invention in association with a further chemotherapeutic agent such as a HER2 antagonist, aprepitant, topotecan, 131 -I-TM-601 , 13-cis-retinoic acid, 4- hydroxytamoxifen, 5-deooxyuridine, 5'-deoxy-5-fluorouridine, 5-fluorouracil and leucovorin; , PEG-labeled irinotecan, 6-mecaptopurine, 7-hydroxy staurosporine, a CDK inhibitor, a combination of irinotecan, 5-fluorouracil and leucovorin, a farnesyl protein transferase inhibitor, a lutenizing hormone-releasing hormone agonist, a MEK inhibitor, a progestational agent, a progestin, a Raf inhibitor, a selective estrogen receptor modulator, a VEGFR inhibitor, anti-VEGFR-2 antibody, abraxane, z
• LY293646, LY293684, LY294002 marimastat, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, mesna, methotrexate,
• methylprednisolone metoclopramide, mithramycin, mitomycin, mitotane, mitoxantrone, tozasertib, MLN8054, neovastat, netupitant, neuradiab, nilotinib, nilutamide, nolatrexed, dacinostat, oblimersen, octreotide, ofatumumab, ondansetron, oregovomab, oxaliplatin, paclitaxel, palonosetron, pamidronate, panitumumab, pazopanib, PD184352, PD0325901 , pegfilgrastim, pentostatin, danusertib, phenylalanine mustard, pipendoxifene, PKI-166, plicamycin, porfimer, procarbazine, prochlorperazine, PTK787/ZK 222584, R
• CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 3;
• CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 4; and
• CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 5;
• a heavy chain immunoglobulin variable region comprises:
• CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 6;
• CDR- H2 comprises the amino acid sequence set forth in SEQ ID NO: 7;
• CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 8; e.g., wherein the antibody or fragment comprises a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 1 ; and/or a heavy chain immunoglobulin variable region comprises the amino acid sequence set forth in SEQ ID NO: 2.
• FIG. 1 Kaplan-Meier plot of progression free survival (PFS) of pancreatic cancer patients treated with gemcitabine + dalotuzumab (A); gemcitabine + erlotinib + dalotuzumab (B); or gemcitabine + erlotinib (C; control).
• PFS progression free survival
• FIG. 1 Kaplan-Meier plot of overall survival (OS) of pancreatic cancer patients treated with gemcitabine + dalotuzumab (A); gemcitabine + erlotinib + dalotuzumab (B); or gemcitabine + erlotinib (C; control).
• OS overall survival
• the present invention provides methods for treating or preventing cancers whose growth, survival and/or metastasis is mediated by IGF1 R expression and/or activity by administering a composition of the present invention that comprises an antibody or antigen- binding fragment thereof that specifically binds to IGF1 R (e.g., dalotuzumab) in association with cisplatin, pemetrexed, gemcitabine and/or irinotecan.
• a compositions comprising the antibody or fragment in association with cisplatin,
• pemetrexed pemetrexed
• gemcitabine and/or irinotecan are also part of the present invention.
• Oligonucleotide Synthesis (M.J. Gait ed. 1984); Nucleic Acid Hybridization (B.D. Hames & S.J. Higgins eds. (1985)); Transcription And Translation (B.D. Hames & S.J. Higgins, eds. (1984)); Animal Cell Culture (R.I. Freshney, ed. (1986)); Immobilized Cells And Enzymes (IRL Press, (1986)); B. Perbal, A Practical Guide To Molecular Cloning (1984); F.M.
• a polypeptide or protein comprises two or more amino acids.
• isolated protein is a protein or polypeptide that by virtue of its origin or source of derivation (1) is not associated with naturally associated components that accompany it in its native state, (2) is free of other proteins from the same species, (3) is expressed by a cell from a different species, (4) was isolated or purified e.g., by a technician and/or (5) does not occur in nature.
• a polypeptide that is chemically synthesized or synthesized in a cellular system different from the cell from which it naturally originates will be “isolated” from its naturally associated components.
• a protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well known in the art.
• a “polynucleotide”, “nucleic acid “ or “nucleic acid molecule” includes double- stranded and single-stranded DNA and RNA.
• a “polynucleotide sequence”, “nucleic acid sequence” or “nucleotide sequence” is a series of nucleotide bases (also called “nucleotides”) in a nucleic acid, such as DNA or RNA, and means any chain of two or more nucleotides.
• An amino acid sequence comprises two or more amino acids.
• a "coding sequence” or a sequence “encoding” an expression product such as an
• RNA or polypeptide is a nucleotide sequence that, when expressed, results in production of the product.
• host cell includes any cell of any organism that is selected, modified, transfected, transformed, grown, or used or manipulated in any way, for the production of a substance by the cell, for example the expression or replication, by the cell, of a gene, a DNA or RNA sequence, a protein or an enzyme.
• a host cell can be a eukaryotic cell or prokaryotic cell.
• a eukaryotic cell can be, for example, a Chinese hamster ovary cell (e.g., CHO-K1 or DXB1 1 ), a HeLa cell, an NIH 3T3 cell, or a yeast or fungal cell, such as
• a prokaryotic cell can be, for example, a bacterial cell such as E.coli (e.g., BL21 or BL21 DE3); see U.S. Patent Nos. 4,952,496, 5,693,489 and 5,869,320 and in Davanloo, P., er a/., (1984) Proc. Natl. Acad. Sci. USA 81 , 2035-2039; Studier, F. W., er a/., (1986) J. Mol. Biol. 189: 113-130; Rosenberg, A. H., er a/., (1987) Gene 56: 125-135; and Dunn, J. J., et ai, (1988) Gene 68: 259 which are herein incorporated by reference.
• E.coli e.g., BL21 or BL21 DE3
• U.S. Patent Nos. 4,952,496, 5,693,489 and 5,869,320 and in Davanloo, P
• the present invention includes methods and compositions comprising anti-IGF1 R antibodies and antigen-binding fragments thereof.
• anti-IGF1 R antibody or the like refers to a full antibody that binds specifically to IGF1 R (e.g. , human IGF1 R); for example, monoclonal antibodies, polyclonal antibodies, bispecific antibodies, chimeric antibodies, recombinant antibodies, anti-idiotypic antibodies, humanized antibodies and bispecific antibodies.
• antigen-binding fragment encompasses a fragment of an antibody, typically including at least a portion of the antigen-binding or variable regions (e.g., one or more CDRs) of the parental antibody, that retains at least some of the binding specificity of the parental antibody.
• antigen-binding fragments of an antibody include, but are not limited to, Fab, Fab', F(ab') 2 , and Fv fragments; dsFv; (dsFv) 2 , ds diabodies; dsFv-dsFv'; single-chain antibody molecules, e.g., sc-Fv, sc-Fv dimers (bivalent diabodies); and bispecific diabodies.
• Antibodies and antigen-binding fragments thereof bind specifically to IGF1 R if they exhibit a K D of about 10 "8 M or a lower number (e.g. , 10 "9 M, 10 " 0 M, 10 "1 M, 10 "12 M).
• composition of the present invention comprises an anti-IGF1 R antibody or antigen-binding fragment thereof (e.g., dalotuzumab) in association with any one or more of pemetrexed, cisplatin, gemcitabine and irinotecan; e.g. , pemetrexed and cisplatin and further in association with a further chemotherapeutic agent.
• an anti-IGF1 R antibody or antigen-binding fragment thereof e.g., dalotuzumab
• a composition of the present invention is in further association with any one or more of the following: erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, cediranib, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 1 11 , 131 -l-TM-601 , ALT-1 10, BIO 140, CC 8490, cilengitide, gimatecan, INO 1001 , IPdR, KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, berubicin, L-alanosine
• a composition of the present invention is in association with abraxane.
• Abraxane is an injectable suspension of paclitaxel protein- bound particles comprising an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nanometers.
• Abraxane is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion.
• Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin.
• Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel.
• Abraxane is free of solvents and is free of cremophor
• composition of the present invention is in
• composition of the present invention is in association with an AKT inhibitor such as
• composition of the present invention is in association with an mTOR inhibitor such as
• composition of the present invention is in association with an ERK inhibitor such as
• composition of the present invention is in association with etoposide (VP- 16).
• a composition of the present invention is in association with doxorubicin including Caelyx or Doxil® (doxorubicin HCI liposome injection; Ortho Biotech Products L.P; Raritan, NJ).
• Doxil® comprises doxorubicin in STEALTH® liposome carriers which are composed of N-(carbonyl-methoxypolyethylene glycol 2000)-1 ,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE); fully hydrogenated soy phosphatidylcholine (HSPC), and cholesterol.
• composition of the present invention is in association with 5'-deoxy-5-fluorouridine.
• composition of the present invention is in association with vincristine.
• a composition of the present invention is in association with temozolomide any CDK inhibitor such as ZK-304709, seliciclib (R- roscovitine;any MEK inhibitor such as PD0325901.selumetinib ; capecitabine (5'-deoxy-5- fluoro-N-[(pentyloxy) carbonyl]-cytidine); or L-Glutamic acid, N -[4-[2-(2-amino-4,7-dihydro- - ⁇ -1 H -pyrrolo[2,3- d ]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate
• a composition of the present invention is in association with camptothecin; Stork er a/., J. Am. Chem. Soc. 93(16): 4074-4075 (1971);
• a composition of the present invention is in association with the FOLFOX regimen components (oxaliplatin, together with infusional fluorouracil and folinic acid (Chaouche et al., Am. J. Clin. Oncol. 23(3):288-289 (2000); dexaliplatin, together with infusional fluorouracil and folinic acid (Chaouche et al., Am. J. Clin. Oncol. 23(3):288-289 (2000); de
• composition of the present invention is in association with an antiestrogen such as tamoxifen; sold as Nolvadex® by AstraZeneca
• a composition of the present invention is in association with an aromatase inhibitor such as anastrazole; sold as Arimidex® by
• AstraZeneca Pharmaceuticals LP Wilmington , DE, exemestane; sold as Aromasin® by Pharmacia Corporation; Kalamazoo, Ml or letrozole; sold as Femara® by Novartis
• a composition of the present invention is in association with an estrogen such as DES(diethylstilbestrol), estradiol; sold as Estrol® by Warner Chilcott, Inc.; Rockaway, NJ or conjugated estrogens (sold as Premarin® by Wyeth Pharmaceuticals Inc. ; Philadelphia, PA).
• an estrogen such as DES(diethylstilbestrol), estradiol; sold as Estrol® by Warner Chilcott, Inc.; Rockaway, NJ or conjugated estrogens (sold as Premarin® by Wyeth Pharmaceuticals Inc. ; Philadelphia, PA).
• a composition of the present invention is in association with one or more anti-angiogenesis agents including bevacizumab (AvastinTM; Genentech; San Francisco, CA), the anti-KDR antibody IMC-1 C1 1 , other VEGFR inhibitors such as: dovitinib, vatalanib (PTK787; ZK-222584), axitinib; and the VEGF trap (AVE-0005), a soluble decoy receptor comprising portions of VEGF receptors 1 and 2.
• bevacizumab AvastinTM; Genentech; San Francisco, CA
• the anti-KDR antibody IMC-1 C1 1 other VEGFR inhibitors
• other VEGFR inhibitors such as: dovitinib, vatalanib (PTK787; ZK-222584), axitinib; and the VEGF trap (AVE-0005), a soluble decoy receptor comprising portions of VEGF receptors 1 and 2.
• LHRH Local hormone-releasing hormone
• composition of the present invention is in association with sunitinib or sunitinib malate.
• a composition of the present invention is in association with a progestational agent such as medroxyprogesterone acetate; sold as Provera® by Pharmacia & Upjohn Co.; Kalamazoo, Ml, hydroxyprogesterone caproate, megestrol acetate or progestins.
• a progestational agent such as medroxyprogesterone acetate; sold as Provera® by Pharmacia & Upjohn Co.
• Kalamazoo, Ml hydroxyprogesterone caproate, megestrol acetate or progestins.
• a composition of the present invention is in association with a selective estrogen receptor modulator (SERM) such as raloxifene; sold as Evista® by Eli Lilly and Company; Indianapolis, IN.
• SERM selective estrogen receptor modulator
• composition of the present invention is in association with an anti-androgen including, but not limited to: bicalutamide; sold at
• a composition of the present invention is in association with one or more inhibitors which antagonize the action of the EGF Receptor or HER2, including, but not limited to, CP-724714 ); TAK-165, mubritinib; neratinib; erlotinib,
• composition of the present invention is in association with lonafarnib.
• composition of the present invention is in association with one or more FPT inhibitors such as:
• composition of the present invention is in association with Amifostine; dacinostat; Atadja et al. , Cancer Research 64: 689-695
• bleomycin bleomycin; Buserelin; (Busulfan; 1 ,4-butanediol, dimethanesulfonate; sold as Busulfex® by ESP Pharma, Inc.; Edison, New Jersey); Carboplatin; sold as Paraplatin® by Bristol-Myers Squibb; Princeton, NJ; Carmustine; Chlorambucil; Cladribine; Clodronate;
• Cyclophosphamide Cyproterone; Cytarabine; dacarbazine; Dactinomycin; Daunorubicin; Diethylstilbestrol; Epirubicin; Fludarabine; Fludrocortisone; Fluoxymesterone; Flutamide; Hydroxyurea; Idarubicin; Ifosfamide; Imatinib; sold as Gleevec® by Novartis
• composition of the present invention is in association with one or more of any of: phenylalanine mustard, uracil mustard,
• estramustine altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6- mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291 , squalamine, endostatin, semaxinib, SU6668, cilengitide, interleukin-12, L-glutamine L-tryptophan dipeptide, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin, diftitox, gefitinib, bortezimib, paclitaxel, docetaxel, epithilone B, ixabepilone
• any mTOR inhibitor any mTOR inhibitor, rapamycin, sirolimus, 40-O-(2-hydroxyethyl)- rapamycin, temsirolimus (Sehgal et al., Med. Res. Rev., 14:1-22 (1994); Elit, Curr. Opin. Investig. Drugs 3(8): 1249-53 (2002)), zotarolimus ; BC-210, LY294002, LY292223,
• LY292696, LY293684, LY293646 (Vlahos et al., J. Biol. Chem. 269(7): 5241-5248 (1994)), wortmannin, ZM336372, L-779,450, any Raf inhibitor disclosed in Lowinger et al., Curr. Pharm Des. 8:2269-2278 (2002); flavopiridol (Senderowicz, Oncogene 19(56): 6600-6606 (2000)) or 7-hydroxy staurosporine (Senderowicz, Oncogene 19(56): 6600-6606 (2000)).
• a composition of the present invention is in association with one or more of any of: pegylated or unpegylated interferon alfa-2a, pegylated or unpegylated interferon alfa-2b, pegylated or unpegylated interferon alfa-2c, pegylated or unpegylated interferon alfa n-1 , pegylated or unpegylated interferon alfa n-3 and pegylated, unpegylated consensus interferon or albumin-interferon-alpha.
• compositions of the present invention in association with one or more antiemetics including, but not limited to, casopitant (GlaxoSmithKline), Netupitant (MGI-Helsinn) and other NK-1 receptor antagonists, palonosetron (sold as Aloxi by MGI Pharma), aprepitant (sold as Emend by Merck and Co.; Rahway, NJ), diphenhydramine (sold as Benadryl® by Pfizer; New York, NY), hydroxyzine (sold as Atarax® by Pfizer; New York, NY), metoclopramide (sold as Reglan® by AH Robins Co,; Richmond, VA), lorazepam (sold as Ativan® by Wyeth;
• alprazolam sold as Xanax® by Pfizer; New York, NY
• haloperidol sold as Haldol® by Ortho-McNeil; Raritan, NJ
• droperidol Inapsine®
• dronabinol sold as
• the present invention includes compositions of the present invention in association with an agent which treats or prevents such a deficiency, such as, e.g. , pegfilgrastim, erythropoietin, epoetin alfa or darbepoetin alfa.
• an agent which treats or prevents such a deficiency such as, e.g. , pegfilgrastim, erythropoietin, epoetin alfa or darbepoetin alfa.
• compositions of the present invention in association with an agent which treats or prevents diarrhea such as an electrolyte solution, a bulking agents such as methylcellulose, guar gum or plant fibre (e.g., bran, sterculia, isabgol, an absorbents such as methylcellulose, an anti-inflammatory drug such as bismuth subsalicylate or an opioid such as loperamide.
• an agent which treats or prevents diarrhea such as an electrolyte solution, a bulking agents such as methylcellulose, guar gum or plant fibre (e.g., bran, sterculia, isabgol, an absorbents such as methylcellulose, an anti-inflammatory drug such as bismuth subsalicylate or an opioid such as loperamide.
• the present invention further comprises a method for treating or preventing any stage or type of any medical condition set forth herein by administering a composition of the present invention in association with a therapeutic procedure such as surgical tumorectomy or anti-cancer radiation treatment.
• compositions of the present invention comprise an anti-IGF1 R antibody or antigen-binding fragment thereof and one or more of cisplatin, pemetrexed, gemcitabine and/or irinotecan as well as methods of treatment using such compositions, as discussed herein, wherein the compositions exclude any further chemotherapeutic agent or therapeutic procedure (other non-therapeutic agents may be optionally included).
• the excluded further chemotherapeutic agent or further therapeutic procedure is any one or more of those set forth herein (e.g., erlotinib).
• association with indicates that the components of a composition of the present invention, optionally in association with a further chemotherapeutic agent, can be formulated into a single composition for simultaneous delivery or formulated separately into two or more compositions (e.g., a kit).
• each component of a composition of the present invention, optionally in association with a further chemotherapeutic agent can be administered, in a method of the present invention, to a subject at a different time than when the other component is administered; for example, each administration may be given non-simultaneously (e.g., separately or sequentially) at several intervals over a given period of time.
• separate components may be administered to a subject by the same or by a different route (e.g., orally and subcutaneously).
• compositions of the present invention provides compositions comprising antibodies and antigen-binding fragmetns thereof that bind specifically with IGF1 R (e.g. dalotuzumab (MK0646)) in association with cisplatin, pemetrexed, gemcitabine and/or irinotecan (e.g., pemetrexed and cisplatin).
• IGF1 R e.g. dalotuzumab (MK0646)
• irinotecan e.g., pemetrexed and cisplatin.
• the antibodies and antigen-binding fragments thereof that binds specifically to IGF1 R comprise:
• CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 3
• CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 4 (KVSNRLY)
• CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 5 (FQGSHVPWT)
• CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 6 (GGYLW )
• CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 7
• CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 8 (YGRVFFDY);
• chains are disulfide bonded as follows:
• the antibodies and antigen-binding fragments thereof that binds specifically to IGF1 R comprise any of the light chains and/or heavy chains set forth below (CDRs solid underscored; signal peptides dash underscored).
• the present invention provides methods for treating or preventing an IGF1 R- mediated medical condition using a composition comprising anti-IGF1 R and any one or more of pemetrexed, cisplatin, gemcitabine and irinotecan.
• the subject suffers from a cancer or malignancy, e.g., that expresses IGF1 R and/or whose survival, growth and/or metastasis is mediated by IGF1 R activity and/or expression; such as ovarian cancer, pancreatic cancer, breast cancer (e.g., estrogen receptor positive or negative breast cancer), prostate cancer, osteosarcoma,
• lung cancer e.g. , non-small cell lung cancer, small cell lung cancer, adenosquamous cell lung cancer, squamous cell lung cancer, recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer
• colorectal cancer e.g., advanced, metastatic or mucinous adenocarcinoma
• cervical cancer e.g., advanced, metastatic or mucinous adenocarcinoma
• subject refers to a mammal such as a human (e.g., a human adult or child) or a mouse, rat, rabbit, dog or other canine, horse, goat or primate such as a monkey, chimpanzee or gorilla.
• the IGF1 R inhibitors discussed herein e.g., anti-IGF1 R antibodies and antigen- binding fragments thereof
• compositions thereof are, in an embodiment of the invention, administered at a therapeutically effective dosage.
• terapéuticaally effective amount or “therapeutically effective dosage” means that amount or dosage of an agent that will elicit a biological or medical response of a tissue, system, patient or subject that is being sought by the administrator (such as a researcher, doctor or veterinarian) which includes any measurable alleviation of the signs, symptoms and/or clinical indicia of a medical disorder, such as cancer (e.g. , tumor growth, survival and/or metastasis) including the prevention, slowing or halting of progression of the medical disorder to any degree.
• a "therapeutically effective dosage" of any anti-IGF1 R antibody or antigen-binding fragment thereof discussed herein e.g. ,
• dalotuzumab is between about 0.3 and 20 mg/kg of body weight (e.g. , 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg), e.g., about once per week to about once every 3 weeks (e.g. , about once every 1 week or once every 2 weeks or once every 3 weeks).
• dalotuzumab is administered once per week at a rate of 10 mg/kg body weight.
• the therapeutically effective dosage of an anti-IGF1 R antibody or antigen-binding fragment thereof or any further therapeutic agent is, when possible, as set forth in Physicians Desk Reference 2010; Thomson Reuters; 64 edition (November 15, 2009); and/or in Physicians' Desk Reference 2009: Thomson Reuters; 63rd edition (November 30, 2008) or in the prescribing information of the relevant drug label (if available), such as the US FDA drug label.
• gemcitabine is administered (e.g. , intravenously) at about 1000 mg/m 2 e.g., over 30 minutes on days 1 and 8 of each 21 -day cycle; or about 1250 mg/m 2 , e.g., over 30 minutes on days 1 and 8 of each 21-day cycle; or about 1000 mg/m 2 e.g. , over 30 minutes on days 1 , 8, and 15 of each 28-day cycle or in a 3-week schedule at about 1250 mg/m 2 e.g., over 30 minutes on days 1 and 8 of each 21-day cycle; or about 1000 mg/m 2 , e.g. , over 30 minutes once weekly for up to 7 weeks e.g. , followed by a week of rest from treatment.
• subsequent cycles include infusions once weekly for 3 consecutive weeks out of every 4 weeks.
• pemetrexed is administered (e.g. , intravenously) at about 500 mg/m 2 , e.g., on day 1 of each 21 -day cycle, e.g., in combination with cisplatin 75 mg/m 2 , e.g. , intravenously, e.g. , beginning 30 minutes after pemetrexed administration; or at about 500 mg/m 2 , e.g. , on day 1 of each 21 -day cycle; e.g., wherein dose reductions or discontinuation are done based on toxicities from the preceding cycle of therapy.
• erlotinib is administered at a dose of about 100 mg.
• patients are monitored during treatment with a composition of the invention for neutropenia, dermatitis acneiform, leucopenia, nausea, decreased appetite, diarrhoea, stomatitis, fatigue, paronychia, constipation, lymphopenia, weight decrease, hyperglycaemia and/or hypoalbuminaemia. If an adverse event is observed, a treating physician can them determine whether to alter or discontinue the treatment regimen.
• the present invention also includes methods for making a composition of the present invention which comprises placing the anti-IGF1 R antibody or antigen-binding fragment thereof in association with the pemetrexed, cisplatin, gemcitabine and/or irinotecan, e.g., in a kit.
• the antibody or fragment is the product of a process wherein a host cell (e.g., a Chinese hamster ovary cell or a Pichia cell such as Pichia pastoris) is transformed with one or more expression vectors having one or more polynucleotides encoding the light and/or heavy immunoglobulin chains of the antibody or fragment operably linked to one or more promoters that drive expression of the chains; the transformed host cell is cultured in a medium under conditions that allow expression of the chains, and, optionally, the chains of the antibody or fragment are isolated from the host cell and/or the medium.
• a host cell e.g., a Chinese hamster ovary cell or a Pichia cell such as Pichia pastoris
• the transformed host cell is cultured in a medium under conditions that allow expression of the chains, and, optionally, the chains of the antibody or fragment are isolated from the host cell and/or the medium.
• the present invention includes methods for using a pharmaceutical composition comprising an anti-IGF1 R antibody or antigen-binding fragment thereof.
• compositions may be prepared by any methods well known in the art of pharmacy; see, e.g., Gilman, er a/., (eds.) (1990), The Pharmacological Bases of
• a pharmaceutical composition e.g. , containing an anti-IGF1 R antibody or antigen- binding fragment thereof can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques.
• pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
• injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
• the injectables, solutions and emulsions can also contain one or more excipients. Excipients are, for example, water, sugar, buffer, salt (e.g. , NaCI), amino acids (e.g.
• compositions to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
• nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
• pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
• aqueous vehicles examples include Sodium Chloride Injection, Ringers Injection,
• Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
• Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
• Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate.
• Antioxidants include sodium bisulfate.
• Local anesthetics include procaine hydrochloride.
• Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
• Emulsifying agents include Polysorbate 80 (TWEEN- 80).
• a sequestering or chelating agent of metal ions includes EDTA.
• Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
• preparations for parenteral administration can include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions.
• the solutions may be either aqueous or nonaqueous. Examples
• Example 1 Clinical testing of dalotuzumab/gemcitabine combination in human cancer patients
• Arm A gemcitabine (1000 mg/m 2 Days 1 , 8, 15) + dalotuzumab (10 mg/kg; once a week);
• Arm B gemcitabine (1000 mg/m 2 Days 1 , 8, 15) + erlotinib (100 mg Days 1-28) + dalotuzumab (10 mg/kg; once a week);

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