Anti-IGF-I receptor antibody

Abstract

Antibodies, humanized antibodies, resurfaced antibodies, antibody fragments, derivatized antibodies, and conjugates of same with cytotoxic agents, which specifically bind to, and inhibit, insulin-like growth factor-I receptor, antagonize the effects of IGF-I, IGF-II and serum on the growth and survival of tumor cells, and which are substantially devoid of agonist activity. Said antibodies and fragments thereof may be used, optionally in conjunction with other therapeutic agents, in the treatment of tumors that express elevated levels of IGF-I receptor, such as breast cancer, colon cancer, lung cancer, ovarian carcinoma, synovial sarcoma, prostate cancer and pancreatic cancer, and said derivatized antibodies may be used in the diagnosis and imaging of tumors that express elevated levels of IGF-I receptor.

1 .- 31 . (canceled)  
     
     
         32 . Isolated antibody, or one of its functional fragments, said antibody or one of said fragments being able to bind to the human insulin-like growth factor I receptor (IGF-IR), and when applicable, to inhibit the natural adhesion of its ligands IGF1 and/or IGF2, and/or able to specifically inhibit the tyrosine kinase activity of said IGF-IR receptor, characterized in that it includes one light chain with at least one CDR region determining the complementarity chosen from among the CDRs of sequence SEQ ID no. 2, 4 or 6, or at least one CDR whose sequence has at least an 80% match when optimally aligned with sequence SEQ ID no. 2, 4 or 6, or in that it includes at least one heavy chain with at least one CDR chosen from among the CDRs of sequence SEQ ID no. 8, 10 and 12, or at least one CDR whose sequence has at least an 80% match when optimally aligned with sequence SEQ ID no. 8, 10 and 12.  
     
     
         33 . Antibody, or one of its functional fragments, as described in  claim 32 , characterized in that it includes one heavy chain with at least one CDR of sequence SEQ ID no. 12 or a sequence with at least an 80% match when optimally aligned with sequence SEQ ID no. 12.  
     
     
         34 . Antibody, or one of its functional fragments, as described in claims  32  or  33 , characterized in that it includes one heavy chain with at least two of the three CDRs or the three CDRs of sequence SEQ ID no. 8, 10 and 12, or at least two of three CDRs or three CDRs of a sequence with at least an 80% match when optimally aligned with sequence SEQ ID no. 8, 10 and 12, respectively.  
     
     
         35 . Antibody, or one of its functional fragments, as described in  claims 32  to  34 , characterized in that it includes one light chain with at least one CDR chosen from among the CDRs of sequence SEQ ID no. 2, 4 or 6, or one CDR whose sequence has at least an 80% match when optimally aligned with sequence SEQ ID no. 2, 4 or 6.  
     
     
         36 . Antibody, or one of its functional fragments, as described in  claims 32  to  35 , characterized in that it includes one light chain with at least two of the three CDRs or the three CDRs of sequence SEQ ID no. 2, 4 and 6, or at least two of three CDRs or three CDRs of a sequence with at least an 80% match when optimally aligned with sequence SEQ ID no. 2, 4 and 6, respectively.  
     
     
         37 . Antibody, or one of it functional fragments, as described in  claims 32  to  36 , characterized in that it does not adhere significantly to the human insulin receptor IR.  
     
     
         38 . Antibody as described in  claims 32  to  37 , characterized in that said functional fragment is chosen from among fragments Fv, Fab, (Fab′) 2 , Fab′, scFv, scFv-Fc and the diabodies, or any fragment of which the half-life would have been increased like pegylated fragments.  
     
     
         39 . Mouse hybridoma capable of secreting an antibody as described in one of  claims 32  to  37 .  
     
     
         40 . Mouse hybridoma as described in  claim 39  registered with the CNCM ( Collection nationale de cultures de micro - organismes  [French National Collection of Microorganism Cultures]), Institut Pasteur, Paris, on Sep. 19, 2001 under number I-2717.  
     
     
         41 . Antibody, or one of its functional fragments, characterized in that said antibody is secreted by the hybridoma described in  claim 40 .  
     
     
         42 . Antibody, or one of its function fragments, as described in  claims 32  to  38 , characterized in that said antibody includes one light chain with a sequence that includes amino acid sequence SEQ ID no. 54, or a sequence with at least an 80% match when optimally aligned with sequence SEQ ID no. 54, and/or in that it includes one heavy chain with a sequence including amino acid sequence SEQ ID no. 69, or a sequence with at least an 80% match when optimally aligned with sequence SEQ ID no. 69.  
     
     
         43 . Antibody, or one of its functional fragments, as described in  claim 42 , characterized in that said antibody is a chimeric antibody and also includes the constant light chain and heavy chain regions derived from an antibody from a species that is xenogeneic to a mouse.  
     
     
         44 . Chimeric antibody, or one of its functional fragments, as described in  claim 43 , characterized in that said xenogeneic species is a human being.  
     
     
         45 . Chimeric antibody, or one of its function fragments, as described in  claim 44 , characterized in that the constant light chain and heavy chain regions derived from a human antibody are the kappa region, and the gamma-1, gamma-2 or gamma-4 region, respectively.  
     
     
         46 . Antibody, or one of its functional fragments, as described in  claims 32  to  38 , characterized in that said antibody is a humanized antibody and includes one light chain and/or one heavy chain in which the skeletal segments FR1 to FR4 of said light chain and/or heavy chain are derived from human antibody light chain and/or heavy chain skeletal segments FR1 to FR4, respectively.  
     
     
         47 . Humanized antibody, or one of its functional fragments, as described in  claim 46 , characterized in that said antibody includes one light chain with amino acid sequence SEQ ID no. 61 or 65, or a sequence with at least an 80% match when optimally aligned with sequence SEQ ID no. 61 or 65, and/or in that it includes one heavy chain with amino acid sequence SEQ ID no. 75, 79 or 83, or a sequence with at least an 80% match when optimally aligned with sequence SEQ ID no. 75, 79 or 83.  
     
     
         48 . Humanized antibody, or one of its functional fragments, as described in  claim 46  or  47 , characterized in that said antibody includes one heavy chain with amino acid sequence SEQ ID no. 65, and in that it includes one sequenced heavy chain with amino acid sequence SEQ ID no. 79 or 83, and preferably SEQ ID no. 83.  
     
     
         49 . Isolated nucleic acid characterized in that it is chosen from among the following nucleic acids: 
 a) a nucleic acid, DNA or RNA, coding for an antibody, or one of its functional fragments, as described in  claims 32  to  37  and  41  to  48 ;    b) a nucleic acid that is complementary to a nucleic acid as defined in a); and    c) a nucleic acid of at least 18 nucleotides capable of hybridizing under highly stringent conditions with at least one of the CDRs of sequence SEQ ID no. 1, 3, 5, 7, 9 or 11, or with a sequence that has at least an 80% match when optimally aligned with sequence SEQ ID no. 1, 3, 5, 7, 9 or 11.    
     
     
         50 . Vector with a nucleic acid as described in  claim 49 .  
     
     
         51 . Host cell with a vector as described in  claim 50 .  
     
     
         52 . Transgenic animal, with the exception of a human being, with at least one cell transformed by a vector as described in  claim 50 .  
     
     
         53 . Procedure for producing an antibody, or one of its functional fragments, as described in  claims 32  to  38  and  41  to  48 , characterized in that it includes the following steps: 
 a) the culture, in an appropriate culture medium and under appropriate conditions, of a cell as described in  claim 51;  and    b) the collection of said antibodies, or one of its functional fragments, produced from the culture medium or said cultivated cells.    
     
     
         54 . Antibody, or one of its functional fragments, that can be obtained through a process as described in  claim 53 .  
     
     
         55 . Antibody, or one of its functional fragments, as described in any one of  claims 32  to  38 ,  41  to  48  and  54 , characterized in that it is, additionally, capable of adhering specifically to the human epidermal growth factor receptor (EGFR) and/or capable of specifically inhibiting the tyrosine kinase activity of said EGFR receptor.  
     
     
         56 . Antibody as described in  claim 55 , characterized in that it consists of one bispecific antibody, and in that it includes a second motive that specifically inhibits the adhesion of the EGF to the human epidermal growth factor receptor and/or that specifically inhibits the tyrosine kinase activity of said EGFR receptor.  
     
     
         57 . Antibody as described in  claim 56 , characterized in that it is bivalent or tetravalent.  
     
     
         58 . Antibody as described in claims  56  or  57 , characterized in that said second motive is selected from among fragments Fv, Fab, (Fab′) 2 , Fab′, Fab′PEG, scFv, scFv-Fc and the diabodies, or any form for which the half-life would be increased.  
     
     
         59 . Antibody as described in any of  claims 56  to  58 , characterized in that said second anti-EGFR motive comes from mouse monoclonal antibody 225, its human-mouse chimeric derivative C225, or a humanized antibody derived from this antibody 225.  
     
     
         60 . Antibody, or one of its functional fragments, as described in any one of  claims 32  to  38 ,  41  to  48  and  54  to  58 , as a medication.  
     
     
         61 . Substance, the active principle of which includes a compound consisting of an antibody, or one of its functional fragments, as described in  claims 32  to  38 ,  41  to  48  and  54  to  60 .  
     
     
         62 . Substance as described in  claim 61 , characterized in that it includes a second compound chosen from among the compounds that are able to specifically inhibit the adhesion of the EGF to the human epidermal growth factor receptor EGFR and/or able to specifically inhibit the tyrosine kinase activity of said EGFR receptor.  
     
     
         63 . Substance as described in  claim 62 , characterized in that said second compound is chosen from among the isolated anti-EGFR antibodies, or their functional fragments, capable of inhibiting, through competition, the adhesion of the EGF to the EGFR.  
     
     
         64 . Substance as described in  claim 63 , characterized in that said anti-EGFR antibody is chosen from among the chimeric or humanized monoclonal anti-EGFR antibodies, or their functional fragments.  
     
     
         65 . Substance as described in one of claims  63  or  64 , characterized in that said functional fragments of the anti-EGFR antibody are chosen from among the fragments Fv, Fab, (Fab′) 2 , Fab′, scFv-Fc and the diabodies, or any fragment for which the half-life would be increased like pegylated fragments.  
     
     
         66 . Substance as described in  claims 63  to  65 , characterized in that said anti-EGFR antibody is mouse monoclonal antibody 225, its human-mouse chimeric derivative C225, or a humanized antibody derived from this antibody 225.  
     
     
         67 . Substance as described in any one of  claims 61  to  66 , characterized in that it includes, additionally, as a combining chemical for use simultaneously, separately or spread out over time, a cytotoxic/cytostatic agent and/or a tyrosine kinase activity inhibitor for IGF-I and/or EGF receptors, respectively.  
     
     
         68 . Substance as described in  claim 67 , characterized in that said cytotoxic/cytostatic agent is chosen from among agents that interact with DNA, antimetabolites, topoisomerase I or II inhibitors, or agents that inhibit or stabilize the spindle or even any agent that can be used in chemotherapy.  
     
     
         69 . Substance as described in  claim 67  or  68 , characterized in that said cytotoxic/cytostatic agent is chemically bonded to at least one of the elements of said substance for simultaneous use.  
     
     
         70 . Substance as described in  claim 68  or  69 , characterized in that said cytotoxic/cytostatic agent is chosen from among agents that inhibit or stabilize the spindle, preferably vinorelbine, vinflunine or vincristine.  
     
     
         71 . Substance as described in one of  claims 67  to  70 , characterized in that said tyrosine kinase activity inhibitor of the IGF-I and/or EGF receptors, respectively, is selected from the group consisting of natural derivative agents, dianilinophthalimides, pyrazolo- or pyrrolo-pyridopyrimidines or even quinazolines.  
     
     
         72 . Substance as described in any one of  claims 61  to  71 , characterized in that it includes, additionally, another antibody compound directed against the extracellular region of the HER2/neu receptor, as a combining chemical for use simultaneously, separately or spread out over time, intended to prevent and treat cancer.  
     
     
         73 . Substance as described in  claim 72 , characterized in that said antibody directed against the extramembrane region of the HER2/neu receptor is Trastuzumab, or one of its functional fragments.  
     
     
         74 . Substance as described in  claims 61  to  73 , characterized in that at least one of said antibodies, or one of their functional fragments, is combined with a cellular toxin and/or a radioactive element.  
     
     
         75 . Substance as described in  claims 61  to  74 , as a medication.  
     
     
         76 . Use of an antibody, or one of its functional fragments, as described in  claims 32  to  38 ,  41  to  48  and  54  to  60  and/or a substance as described in any one of  claims 61  to  75 , for the preparation of a medication intended to prevent or treat an illness related to an over-expression and/or an abnormal activation of the IGF-IR and/or EGFR receptor, and/or related to a hyperactivation of the transduction path of the signal mediated by the interaction of the IGF1 or IGF2 with the IGF-IR and/or of the EGF with the EGFR.  
     
     
         77 . Use as described in  claim 76 , characterized in that the administration of said medication causes no or few side effects related to the inhibition of the insulin receptor (IR).  
     
     
         78 . Use as described in  claim 76  or  77 , for the preparation of a medication intended to inhibit the transformation of normal cells into cells of a tumoral nature, preferably IGF, particularly dependent IGF1 and/or IGF2, and/or dependent EGF and/or dependent HER2/neu.  
     
     
         79 . Use as described in any of  claims 76  to  78  for the preparation of a medication intended to inhibit the growth and/or proliferation of tumoral cells, preferably IGF, particularly dependent IGF1 and/or IGF2, and/or dependent EGF and/or estrogens and/or dependent HER2/neu.  
     
     
         80 . Use as described in one of  claims 76  to  79 , for the preparation of a medication intended to prevent or treat cancer.  
     
     
         81 . Use as described in  claim 80 , characterized in that said cancer is a cancer chosen from among prostate cancer, osteosarcoma, lung cancer, breast cancer, endometrium cancer or colon cancer.  
     
     
         82 . Use as described in  claims 76  to  79 , for the preparation of a medication intended to prevent or treat psoriasis.  
     
     
         83 . In vitro diagnostic method for illnesses caused by an over-expression or an under-expression of the IGF-IR and/or the EGFR receptor, based on a biological sample in which the abnormal presence of an IGF-IR and/or EGFR receptor is suspected, characterized in that said biological sample is put in contact with an antibody as described in  claims 32  to  38 ,  41  to  48  and  54  to  60 , where said antibody can be marked, when necessary.  
     
     
         84 . Kit or necessary materials for the implementation of a method for diagnosing illnesses caused by an over-expression or an under-expression of the IGF-IR and/or EGFR receptor, or for the implementation of a process intended to detect and/or quantify an over-expression or an under-expression of the IGF-IR and/or EGFR receptor in a biological sample, preferably an over-expression of said receptor, characterized in that said kit or necessary materials include the following items: 
 a) an antibody, or one of its functional fragments, as described in  claims 32  to  38 ,  41  to  48  and  54  to  60 ;    b) when applicable, the reagents for the creation of a medium that is favorable for the immunological reaction;    c) when applicable, the reagents that highlight the IGF-IR/antibody and/or EGFR/antibody compounds produced by the immunological reaction.    
     
     
         85 . Use of an antibody, or one of its functional fragments, as described in  claims 32  to  38 ,  41  to  48  and  54  to  60 , for the preparation of a medication intended to specifically aim a biologically active compound toward cells that express or over-express the IGF-IR and/or EGFR receptor.  
     
     
         86 . A humanized, chimeric or human monoclonal antibody or antigen-binding portion thereof that specifically binds to insulin-like growth factor I receptor (IGF-IR).  
     
     
         87 . The antibody or portion thereof according to  claim 86 , wherein the IGF-IR is human.  
     
     
         88 . The antibody or antigen-binding portion thereof according to any one of claims  86  or  87 , wherein the antibody or portion thereof has at least one property selected from the group consisting of: a) does not bind to mouse, rat, dog or rabbit IGF-IR; b) binds to cynomologous or rhesus IGF-IR but not to marmoset IGF-IR; c) inhibits the binding of IGF-I or IGF-II to IGF-IR. d) has a selectivity for IGF-IR that is at least 50 times greater than its selectivity for insulin receptor; e) inhibits tumor growth in vivo; f) causes IGF-IR disappearance from the cell surface when incubated with a cell expressing IGF-IR; g) inhibits IGF-IR-induced tyrosine phosphorylation; h) binds to IGF-IR with a K d  of 8×10 −9  M or less; and i) has an off rate for IGF-IR of K off  of 10 −4  or smaller.  
     
     
         89 . The antibody or antigen-binding portion thereof according to  claim 88 , wherein the antibody or portion thereof has all of said properties.  
     
     
         90 . The antibody or antigen-binding portion thereof according to any one of claims  86  or  87 , wherein the antibody or portion thereof has at least one property selected from the group consisting of: a) cross-competes for binding to IGF-IR with an antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; b) binds to the same epitope of IGF-IR as an antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; c) binds to the same antigen as that bound by the antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; d) binds to IGF-IR with substantially the same K d  as an antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; and e) binds to IGF-IR with substantially the same off rate as an antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3.  
     
     
         91 . The antibody or antigen-binding portion thereof according to  claim 90 , wherein the antibody or portion thereof comprises all of said properties.  
     
     
         92 . The antibody or antigen-binding portion thereof according to any one of claims  86 - 91 , wherein said antibody or portion thereof inhibits binding between IGF-IR and IGF-I or IGF-II with an IC 50  of less than 100 nM.  
     
     
         93 . The antibody or antigen-binding portion thereof according to any one of claims  86 - 92 , wherein said antibody or antigen-binding portion thereof comprises a variable region of a .kappa. light chain, wherein the sequence of said variable region of said .kappa. light chain comprises no more than ten amino acid changes from the amino acid sequence encoded by a germline VκA30, A27 or O12 gene.  
     
     
         94 . The antibody or antigen-binding portion thereof according to  claim 93 , wherein the variable region of the .kappa. light chain comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 14, SEQ ID NO: 18 and SEQ ID NO: 22, or an amino acid sequence having 1-10 amino acid insertions, deletions or substitutions therefrom.  
     
     
         95 . The antibody or antigen-binding portion thereof according to any one of claims  86 - 92 , wherein said antibody or antigen-binding portion thereof comprises a variable region of a heavy chain, wherein the sequence of said variable region comprises no more than eight amino acid changes from the amino acid sequence encoded by a germline V H  DP47, DP35, DP71 or VIV-4 gene.  
     
     
         96 . The antibody or antigen-binding portion thereof according to  claim 95 , wherein the variable region of the heavy chain comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 20 and SEQ ID NO: 24, or an amino acid sequence having 1-10 amino acid insertions, deletions or substitutions therefrom.  
     
     
         97 . The antibody or antigen-binding portion thereof according to any one of claims  86 - 96  that is a) an immunoglobulin G (IgG), an IgM, an IgE, an IgA or an IgD molecule, or is derived therefrom; or b) an Fab fragment, an F(ab′) 2  fragment, an F v  fragment, a single chain antibody, a humanized antibody, a chimeric antibody or a bispecific antibody.  
     
     
         98 . The antibody or antigen-binding portion thereof according to any one of claims  86 - 97 , wherein the antibody or portion thereof comprises an amino acid sequence of at least one CDR region from a variable region, wherein said variable region is selected from the group consisting of: a) a variable region of the light chain of an antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; b) a variable region of a light chain comprising an amino acid sequence selected from SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 14, SEQ ID NO: 18 and SEQ ID NO: 22, or an amino acid sequence having 1-10 amino acid insertions, deletions or substitutions therefrom; c) a variable region of the heavy chain of an antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; and d) a variable region of a heavy chain comprising an amino acid sequence selected from SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 20 and SEQ ID NO: 24, or an amino acid sequence having 1-10 amino acid insertions, deletions or substitutions therefrom.  
     
     
         99 . The antibody or antigen-binding portion thereof according to  claim 98 , wherein the antibody or portion thereof comprises all of the amino acid sequences of the CDR regions a variable region, wherein said variable region is selected from the group consisting of selected from the group consisting of: a) a variable region of the light chain of an antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; b) a variable region of a light chain comprising an amino acid sequence selected from SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 14, SEQ ID NO: 18 and SEQ ID NO: 22, or an amino acid sequence having 1-10 amino acid insertions, deletions or substitutions therefrom; c) a variable region of the heavy chain of an antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; d) a variable region of a heavy chain comprising an amino acid sequence selected from SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 20 and SEQ ID NO: 24, or an amino acid sequence having 1-10 amino acid insertions, deletions or substitutions; and e) the variable regions of the light chain and the heavy chain of an antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3.  
     
     
         100 . The antibody according to  claim 86 , wherein the antibody is selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3.  
     
     
         101 . The antibody according to  claim 86 , wherein said antibody comprises a heavy chain and a light chain, and wherein the amino acid sequences of the light chain and heavy chain are selected from the group consisting of: a) the amino acid sequence of the heavy chain and the amino acid sequence of the light chain of 2.12.1; b) the amino acid sequence of the heavy chain and the amino acid sequence of the light chain of 2.13.2; c) the amino acid sequence of SEQ ID NO: 45 and the amino acid sequence of SEQ ID NO: 47; and d) the amino acid sequence of SEQ ID NO: 49 and the amino acid sequence of SEQ ID NO: 51.  
     
     
         102 . The antibody according to  claim 86 , wherein said antibody has an amino acid sequence comprising the amino acid sequences of the CDRs of antibodies 2.12.1 or 2.13.2, or CDRs of that antibody having no more than 5 conservative amino acid changes.  
     
     
         103 . A pharmaceutical composition comprising the antibody or portion thereof according to any one of claims  86 - 102  and a pharmaceutically acceptable carrier.  
     
     
         104 . The pharmaceutical composition according to  claim 103 , further comprising an antineoplastic, chemotherapeutic or anti-tumor agent.  
     
     
         105 . A process for making an antibody that binds to IGF-IR, comprising the steps of: a) immunizing a non-human mammal with an immunogen comprising IGF-IR, wherein the mammal is capable of expressing human antibodies in B cells of the animal; b) isolating B cells from the mammal; c) screening said B cells, or cell lines derived therefrom, to identify a cell line that produces antibodies that bind to IGF-IR; d) culturing the cell line that expresses antibodies that bind to IGF-IR; and e) isolating antibodies that bind to IGF-IR from the cell line.  
     
     
         106 . An isolated cell line that produces the antibody according to any one of claims  86 - 102 .  
     
     
         107 . The cell line according to  claim 105  that produces an antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3, or wherein the antibody has the same amino acid sequences thereof  
     
     
         108 . A method of diagnosing the presence or location of an IGF-IR-expressing tumor in a subject in need thereof, comprising the steps of a) injecting the antibody according to any one of claims  86 - 102  into the subject, b) determining the expression of IGF-IR in the subject by localizing where the antibody has bound, c) comparing the expression in part (b) with that of a normal reference subject or standard, and d) diagnosing the presence or location of the tumor.  
     
     
         109 . A method of treating cancer in a human with an antibody or antigen-binding portion thereof that specifically binds to IGF-IR, comprising the step of administering to the human an amount of the antibody effective to treat said cancer.  
     
     
         110 . A method of treating a patient in need thereof with the antibody or antigen-binding portion thereof according to any one of claims  86 - 102 , comprising the step of administering to the patient an effective amount of the antibody.  
     
     
         111 . The method according to either of claims  109  or  110 , further comprising the step of administering an anti-neoplastic, anti-tumor, anti-angiogenic or chemotherapeutic agent.  
     
     
         112 . An isolated nucleic acid molecule that comprises a nucleic acid sequence that encodes a heavy chain or antigen-binding portion thereof or a light chain or antigen-binding portion thereof of an antibody according to any one of claims  86 - 102 .  
     
     
         113 . The isolated nucleic acid molecule according to  claim 112 , wherein the nucleic acid molecule comprises a nucleic acid sequence selected from the group consisting of: a) a nucleic acid sequence encoding at least one CDR region from the heavy chain of the antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; b) a nucleic acid sequence encoding the three CDR regions from the heavy chain of the antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; c) a nucleic acid sequence encoding the amino acid sequence of the heavy chain or the antigen-binding portion thereof of the antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; d) a nucleic acid sequence encoding at least one CDR sequence from the light chain of the antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; e) a nucleic acid sequence encoding the three CDR sequences from the heavy chain of the antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; f) a nucleic acid sequence encoding the amino acid sequence of the light chain or the antigen-binding portion thereof of the antibody selected from the group consisting of 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3; g) a nucleic acid sequence encoding the amino acid sequence of selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22; and h) a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21 and 23; wherein said nucleic acid molecule optionally comprises a nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 26.  
     
     
         114 . A vector comprising the nucleic acid molecule according to either of claims  112  or  113 , wherein the vector optionally comprises an expression control sequence operably linked to the nucleic acid molecule.  
     
     
         115 . A host cell comprising the vector according to  claim 114  or the nucleic acid molecule according to either of claims  112  or  113 .  
     
     
         116 . A method of making an anti-IGF-IR antibody or antigen-binding portion thereof, comprising culturing the host cell according to  claim 115  or the cell line according to  claim 106  under suitable conditions and recovering said antibody or antigen-binding portion.  
     
     
         117 . A non-human transgenic animal comprising the nucleic acid according to either of claims  112  or  113 , wherein the non-human transgenic animal expresses said nucleic acid.  
     
     
         118 . A method of treating a subject in need thereof with an antibody or antigen-binding portion thereof that specifically binds to IGF-IR, comprising the steps of (a) administering an effective amount of an isolated nucleic acid molecule encoding the heavy chain or the antigen-binding portion thereof, an isolated nucleic acid molecule encoding the light chain or the antigen-binding portion thereof, or both the nucleic acid molecules encoding the light chain and the heavy chain or antigen-binding portions thereof; and (b) expressing the nucleic acid molecule.