MXPA06005779A - Anti-igfr1 antibody therapeutic combinations - Google Patents
Anti-igfr1 antibody therapeutic combinationsInfo
- Publication number
- MXPA06005779A MXPA06005779A MXPA/A/2006/005779A MXPA06005779A MXPA06005779A MX PA06005779 A MXPA06005779 A MX PA06005779A MX PA06005779 A MXPA06005779 A MX PA06005779A MX PA06005779 A MXPA06005779 A MX PA06005779A
- Authority
- MX
- Mexico
- Prior art keywords
- seq
- cancer
- inhibitor
- cdr
- cell
- Prior art date
Links
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Abstract
The present invention provides combinations including a binding composition, such as an anti-IGFR1 antibody, in association with a chemotherapeutic agent. Methods for using the combinations to treat medical conditions, such as cancer, are also provided.
Description
THERAPEUTIC COMBINATIONS OF ANTIBODY ANT1-IGFR1
This application claims the benefit of the provisional patent application U.S. No. 60 / 524,732; presented on November 21, 2003, which is incorporated here for reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to therapeutic combinations comprising one or more anti-IGFR1 antibodies and one or more chemotherapeutic agents.
BACKGROUND OF THE INVENTION
Insulin-like growth factors, also known as somatomedins, include insulin-like growth factor-l (IGF-I) and insulin-like growth factor-ll (IGF-II) (Klapper, et al., (1983) Endocrine! 112: 2215 and Rinderknecht, et al., (1978) Febs.Lett. 89: 283). These growth factors exert mitogenic activity on several cell types, including tumor cells (Macaulay, (1992) Br. J. Cancer 65: 311), by binding to a common receptor called growth factor-1 receptor. insulin (IGFR1) (Sepp-Lorenzino, (1998) Breast Cancer Research and Treatment 47: 235). The interaction of IGFs with IGFR1 activates the receptor by triggering receptor autophosphorylation on the tyrosine residues (Butler, et al., (1998) Comparative Biochemistry and Physiology 121: 19). Once activated, IGFR1, in turn, phosphorylates intracellular targets to activate cell signaling pathways. This activation of the receptor is critical for the stimulation of tumor cell growth and survival. Therefore, inhibition of IGFR1 activity represents a potential, valuable method for treating or preventing the growth of human cancers and other proliferative diseases. Several lines of evidence indicate that IGF-I, IGF-II and its IGFR1 receptor are important mediators of the malignant phenotype. Levels of IGF-I in plasma have been shown to be the strongest predictor of prostate cancer risk (Chan, et al., (1998) Science 279: 563) and similar epidemiological studies strongly linked IGF-1 levels in plasma at risk of breast, colon and lung cancer. Overexpression of the I-receptor of the insulin-like growth factor has also been demonstrated in several cancer cell lines and tumor tissues. IGFR1 is overexpressed in 40% of all breast cancer cell lines (Pandini, et al., (1999) Cancer Res. 5: 1935) and in 15% of lung cancer cell lines. In breast cancer tumor tissue, IGFR1 is overexpressed 6-14 fold and IGFR1 exhibits 2-4 times the highest kinase activity as compared to normal tissue (Webster, et al., (1996) Cancer Res. 56: 2781 and Pekonen, et al., (1998) Cancer Res. 48: 1343). Furthermore, colorectal cancer tissue has been reported to exhibit extremely high IGFR1 levels (Weber et al., Cancer 95 (10): 2086-95 (2002)). Analysis of cultures of cervical cancer cells and cervical cancer cell lines revealed an overexpression of IGFR1, 3 and 5 times, respectively, compared to normal ectocervical cells (Steller, et al., (1996) Cancer Res. 56: 1762). The expression of IGFR1 in synovial sarcoma cells is also correlated with an aggressive phenotype (i.e., metastasis and high proliferation regimen; Xie, et al., (1999) Cancer Res. 59: 3588). Acromegaly, a slowly developing disease, is caused by hypersecretion of growth hormone and IGF-I (Ben-Schlomo, et al., (2001) Endocrin, Metab.Clin.No. Am. 30: 565 -583). Antagonism of IGFR1 function is useful to treat the disease. There are several antibodies, which are known in the art, that inhibit the activity of IGFR1. However, these are of relatively low therapeutic value. For example, -IR3 (Kull, et al., (1983) J. Biol. Chem. 258: 6561), 1 H7 (Li et al., (1993) Biochem. Biophys. Res. Comm. 196.92-98 and Xiong. ei al., (1992) Proc. Nati, Acad. Sci., USA 89: 5356-5360; Santa Cruz biotechnology, Inc .; Santa Cruz, CA) and MAB391 (R &D Systems; Minneapolis, MN) are mouse monoclonal antibodies that interact with IGFR1 and inhibit their activity. Because they are mouse antibodies, their therapeutic utility in humans is limited. When a dose of a murine antibody is administered to an immunocompetent human subject, said subject produces antibodies against the mouse immunoglobulin sequences. These human anti-mouse antibodies (HAMA) neutralize therapeutic antibodies and can induce acute toxicity (ie, a HAMA response). A method by which a response can be prevented
HAMA is through the use of whole human antibodies lacking any foreign amino acid sequence (eg, mouse). Although the use of fully human antibodies is an effective method by which the human host immunodeficiency of the therapeutic antibody can be reduced or prevented, rejection of the fully human antibody can occur. Human rejection of human antibodies, may be termed, an anti-human antibody response in humans (HAHA response). The HAHA response can be mediated by factors such as the presence of rare amino acid sequences that occur rarely, in fully human antibodies. For this reason, therapeutic antibodies can also be optimized by including sequences of human antibody structure, non-immunogenic or only weakly immunogenic. Preferably, the sequences occur frequently in other human antibodies. Although anti-IGFR1 antibodies are effective means by which diseases intermediated by the receptor (eg, cancer or acromegaly) can be treated, the efficacy of such treatments would be increased by the use of one or more additional chemotherapeutic agents. For example, an anti-IGFR1 antibody can be administered to a subject in association with a second anti-IGFR1 antibody or with a small molecule IGFR1 antagonist. The present invention provides, among other things, said treatments and compositions to be used in the treatments.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides a combination comprising (a) one or more binding compositions, such as any anti-IGFR1 antibody, preferably a fully human isolated monoclonal antibody, preferably comprising a member selected from the group consisting of: (i) a light chain amino acid sequence comprising CDR-L1 defined by SEQ ID NO: 5, CDR-L2 defined by SEQ ID NO: 6 and CDR-L3 defined by SEQ ID NO: 7; and (ii) a heavy chain amino acid sequence comprising CDR-H1 defined by SEQ ID NO: 8, CDR-H2 defined by SEQ ID NO: 9 and CDR-H3 defined by SEQ ID NO: 10; in association with (b) one or more chemotherapeutic agents and, optionally, a pharmaceutically acceptable carrier.
In one embodiment, a binding composition (e.g., a fully human isolated monoclonal antibody) comprises a light chain amino acid sequence comprising CDR-L1 defined by SEQ ID NO: 5, CDR-L2 defined by SEQ ID NO. : 6 and CDR-L3 defined by SEQ ID NO: 7; and a heavy chain amino acid sequence comprising CDR-H1 defined by SEQ ID NO: 8, CDR-H2 defined by SEQ ID NO: 9 and CDR-H3 defined by SEQ ID NO: 10. In one embodiment, a binding composition comprises a light chain immunoglobulin comprising mature LCF (amino acids 20-128 of SEQ ID NO: 2) and a heavy chain immunoglobulin comprising mature HCA (amino acids 20-137 of SEQ ID NO: 4) ).
A binding composition can be any binding composition (e.g., a fully human monoclonal antibody) which is set forth in the co-pending US Patent application. No. 10 / 443,466, filed on May 22, 2003.
A chemotherapeutic agent can be one or more members selected from the group consisting of a taxane, a topoisomerase inhibitor, a signal transduction inhibitor, a cell cycle inhibitor, a modulator of the IGF / IGFR1 system, a transferase inhibitor of the farnesyl protein (FPT), an epidermal growth factor receptor (EGFR) inhibitor, a HER2 inhibitor, an inhibitor of vascular epidermal growth factor receptor (VEGF), a mitogen-activated protein kinase (MAP) inhibitor, a MEK inhibitor, an AKT inhibitor, an mTOR inhibitor, a pl3 kinase inhibitor, a Raf inhibitor, a cyclin-dependent kinase inhibitor (CDK), a microtubular stabilizer, a microtubule inhibitor, a SERM / Antiestrogen, an aromatase inhibitor, an anthracycline, a proteasome inhibitor, an agent that inhibits the production of insulin-like growth factor (IGF) and / or an anti-inhibitor. sense of IGFR1, IGF-1 or IGF2. A taxane may be, for example, paclitaxel or docetaxel. A microtubular inhibitor can be, for example, vincristine, vinblastine, a podophyllotoxin, an epothilone B, BMS-247550 or BMS-310705. An inhibitor of the epidermal growth factor receptor (EGFR) can be, for example, gefitinib, erlotinib, cetuximab, ABX-EGF, lapatanib, canertinib, EKB-569 or PKI-166. A transferase inhibitor of the famesyl protein can be, for example, lonafarnib or tipifamib (R155777). A selective estrogen receptor (SERM) / antiestrogen modulator can be, for example, tamoxifen, raloxifene, fulvestrant, acolbifen, pipendoxifen, arzoxifene, toremifene, lasofoxifene, bazedoxifene (TSE-424), idoxifen, HMR-3339 and ZK-186619 . An anthracycline can be doxorubicin, daunorubicin or epirubicin. A HER2 inhibitor can be, for example, trastuzumab, HKI-272, CP-724714 or TAK-165. A topoisomerase inhibitor can be, for example, etoposide, topotecan, camphexine or irinotecan.
In one embodiment, the present invention comprises a combination comprising: (a) one or more binding compositions (e.g., a fully human monoclonal antibody isolated) comprising a light chain immunoglobulin comprising amino acids 20-128 of the SEQ ID NO: 2 and a heavy chain immunoglobulin comprising amino acids 20-137 of SEQ ID NO: 4; in association with (b) one or more chemotherapeutic agents selected from:
twenty
Also provided by the present invention is a method for the treatment or prevention of a disease in a subject, wherein said disease is mediated by an expression or elevated activity of the I-Receptor of the Insulin-Type Growth Factor, which comprises administering (e.g. , parenterally or non-parenterally), to the subject, a composition comprising a therapeutically effective amount of (a) one or more binding compositions (e.g., a fully human isolated monoclonal antibody), such as an anti-IGFR1 antibody, which preferably comprises a member selected from the group consisting of: (i) a light chain amino acid sequence comprising CDR-L1 defined by SEQ ID NO: 5, CDR-L2 defined by SEQ ID NO: 6 and CDR- L3 defined by SEQ ID NO: 7; and (ii) a heavy chain amino acid sequence comprising CDR-H1 defined by SEQ ID NO: 8, CDR-H2 defined by SEQ ID NO: 9 and CDR-H3 defined by SEQ ID NO: 10; optionally in association with (b) a therapeutically effective amount of one or more chemotherapeutic agents and, optionally, a pharmaceutically acceptable carrier. In one embodiment of the invention, the disease is treated with a therapeutically effective amount of any isolated anti-IGFR antibody or antigen-binding fragment thereof of the invention alone.
In one embodiment, the binding composition (e.g., a fully human isolated monoclonal antibody) comprises a light chain immunoglobulin comprising amino acids 20-128 of SEQ ID NO: 2 and a heavy chain immunoglobulin comprising amino acids 20 -137 of SEQ ID NO: 4. In one embodiment, a chemotherapeutic agent is one or more members selected from the group consisting of:
/. ' * > r. { CM
In one embodiment, the disease treated by the method of the present invention is selected from the group consisting of Rheumatoid Arthritis, Grave's disease, Multiple Sclerosis, Systemic Lupus Erythematosus, Hashimoto's Thyroiditis, Grave Myasthenia, Auto-Immune Thyroiditis, Bechet's Disease , acromegaly, bladder cancer, Wilm cancer, ovarian cancer, pancreatic cancer, benign prostatic hyperplasia, breast cancer, prostate cancer, bone cancer, lung cancer, colorectal cancer, cervical cancer, synovial sarcoma, diarrhea associated with metastatic carcinoids, vasoactive intestinal peptide secretion tumors, gigantism, psoriasis, atherosclerosis, restenosis of smooth muscle of blood vessels and inappropriate microvascular proliferation.
One embodiment of the present invention includes a method for the treatment or prevention of a disease in a subject (e.g., rheumatoid arthritis, Grave's disease, multiple sclerosis, systemic lupus erythematosus, Hashimoto's thyroiditis, Myasthenia Grave, autoimmune thyroiditis, Bechet's disease, acromegaly, bladder cancer, Wilm's cancer, ovarian cancer, pancreatic cancer, benign prostatic hyperplasia, breast cancer, prostate cancer, bone cancer, lung cancer, colorectal cancer, cervical cancer, synovial sarcoma, diarrhea associated with metastatic carcinoids, vasoactive intestinal peptide secretory tumors, gigantism, psoriasis, atherosclerosis, restenosis of smooth muscle of blood vessels or inappropriate microvascular proliferation) comprising administering to the subject a combination comprising: (a) a therapeutically effective amount of one or more binding compositions (eg, a monoclonal antibody) totally human isolated ovalone) comprising a light chain immunoglobulin comprising amino acids 20-128 of SEQ ID NO: 2 and a heavy chain immunoglobulin comprising amino acids 20-137 of SEQ ID NO: 4; in association with (b) a therapeutically effective amount of one or more chemotherapeutic agents selected from:
to the subject.
Also provided by the present invention is a method for inhibiting the growth or proliferation of any cell (e.g., an in vitro cell or a cell in vivo (e.g., in the body of a subject)), e.g., a malignant cell, which includes, but is not limited to, an NCI-H322 cell, an A2780 cell, an MCF7 cell, a lung cancer or non-small cell carcinoma cell, a breast cancer cell, an ovarian cancer cell , a colorectal cancer cell, a prostate cancer cell, a pediatric cancer or pancreatic cancer cell, comprising contacting the cells with a combination comprising (a) one or more binding compositions such as any anti-cancer antibody. -IGFR1 isolated, preferably, an isolated fully human monoclonal antibody, preferably comprising a member selected from the group consisting of: (i) an amino acid sequence of ac light DNA comprising CDR-L1 defined by SEQ ID NO: 5, CDR-L2 defined by SEQ ID NO: 6 and CDR-L3 defined by SEQ ID NO: 7; and (ii) a heavy chain amino acid sequence comprising CDR-H1 defined by SEQ ID NO: 8, CDR-H2 defined by SEQ ID NO: 9 and CDR-H3 defined by SEQ ID NO: 10; in association with (b) one or more chemotherapeutic agents and, optionally, a pharmaceutically acceptable carrier. In one embodiment, a binding composition comprises a light chain immunoglobulin comprising amino acids 20-128 of SEQ ID NO: 2 and a heavy chain immunoglobulin comprising amino acids 20-137 of SEQ ID NO: 4. One embodiment, a chemotherapeutic agent is one or more members selected from the group consisting of:
; and V, The present invention also provides a kit comprising (a) one or more binding compositions (e.g., a fully human isolated monoclonal antibody) comprising a member selected from the group consisting of: a light chain amino acid sequence comprising CDR-L1 defined by SEQ ID NO: 5, CDR-L2 defined by SEQ ID NO: 6 and CDR-L3 defined by SEQ ID NO: 7; and a heavy chain amino acid sequence comprising CDR-H1 defined by SEQ ID NO: 8 or 12, CDR-H2 defined by SEQ ID NO: 9 and CDR-H3 defined by SEQ ID NO: 10; in association with (b) one or more chemotherapeutic agents. The binding composition may be in a container separate from the chemotherapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides combinations and methods for the treatment of diseases that are characterized by a high level of IGFR1 expression, ligand binding or activity or a high level of IGF-1 or IGF-2, such as cancer. Combinations of the invention, which may be used to treat diseases, include one or more anti-IGFR1 antibodies (eg, an isolated, fully human monoclonal antibody) in association with one or more chemotherapeutic agents.
Combinations of the invention include the component of the binding composition and the component of the chemotherapeutic agent "in association" with each other. The term "in association" indicates that the components of the combinations of the invention can be formulated in a single combination to be released simultaneously or formulated separately into two or more compositions (e.g., a kit). In addition, each of the components of a combination of the invention can be administered to a subject at a time different from that of the administration of the other component; for example, each administration can be administered in a non-simultaneous way, in several intervals for a determined period of time. In addition, the separate components may be administered to a subject by the same route or by a different route (e.g., orally, intravenously, intratumorally).
The compositions of the invention provide a particularly effective means for the treatment of diseases mediated by IGFR1, IGF-1 and / or IGF-2. The therapeutic efficacy of both the binding composition of the invention and the chemotherapeutic agent (s), when administered in an associated manner, is far superior to that of any of the components alone.
The present invention includes any isolated polypeptide or isolated nucleic acid (e.g., a fully human isolated monoclonal antibody) comprising one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or 8) of any of the nucleic acids or polypeptides (including mature fragments thereof) which are indicated below, in Table 1.
TABLE 1 Summary of the nucleotide amino acid sequences of the invention.
Molecular Biology According to the present invention, conventional techniques of molecular biology, microbiology and recombinant DNA that are within the skill in the art may be employed. These techniques are fully explained in the literature. See, for example, Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual. Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (here "Sambrook, et al., 1989"); DNA Cloning: A Practical Approach. Volumes I and II (D.N. Glover ed., 1985); Oligonucleotide Svnthesis (M.J. Gait ed., 1984); Nucleic Acid Hvbridization (B. D. Hames &S.J. Higgins eds. (1985)); Transcription and Translation (B. D. Hames &S.J. Higgins, eds. (1984)); Animal Cell Culture (R. Freshney, ed. (1986)); Immobilized Cells And Enzymes (IRL Press, (1986)); B. Perbal, A Practical Guide to Molecular Cloning (1984); F.M. Ausubel, e to al. (eds.), Current Protocols in Molecular Biology. John Wiley & Sons, Inc. (1994). A "polynucleotide", "nucleic acid" or "nucleic acid molecule" can refer to the polymeric form of the phosphate ester of ribonucleosides (adenosine, guanosine, uridine or cytidine, "RNA molecules") or deoxyribonucleosides (deoxyadenosine, deoxyguanosine , deoxythymidine or deoxycytidine; "DNA molecules"), or any phosphoester analogue thereof, such as phosphorothioates and thioesters, in a single-stranded, double-stranded or other form. A "polynucleotide sequence", "nucleic acid sequence" or "nucleotide sequence" is a series of nucleotide bases (also referred to as "nucleotides") in a nucleic acid, such as DNA or RNA, and means any chain of two or more nucleotides . A "coding sequence" or a sequence that "encodes" an expression product, such as an RNA, polypeptide, protein, or enzyme is a nucleotide sequence which, when expressed, results in the production of the product. The term "gene" means a DNA sequence that encodes or corresponds to a particular sequence of ribonucleotides or amino acids that comprise all or part of one or more molecules, proteins or RNA enzymes, and which may or may not include Regulatory DNAs, such as promoter sequences, which determine, for example, the conditions under which the gene is expressed. The genes can be transcribed from DNA or RNA that can be translated or not into an amino acid sequence. "Amplification" of the DNA as used herein may denote the use of a polymerase chain reaction (PCR) to increase the concentration of a particular DNA sequence within a mixture of DNA sequences. For a description of PCR see Saiki, et al., Science (1988) 239: 487. In a specific embodiment, the present invention includes a nucleic acid, which encodes an anti-IGFR1 antibody, a light chain or heavy chain of an antibody anti-IGFR1, a variable region of a light chain or of a heavy chain of an anti-IGFR1, a constant region of a light chain or of a heavy chain of an anti-IGFR1 antibody or CDR of an anti-IGFR1 antibody (for example, CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 or CDR-H3) that can be amplified by PCR.
As used herein, the term "oligonucleotide" refers to a nucleic acid, generally of at least 10 (eg 10, 11, 12, 13 or 14), preferably at least 15 (eg, 15, 16 , 17, 18 or 19) and more preferably at least 20 nucleotides (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30), preferably not more than 100 nucleotides (e.g., 40, 50, 60, 70, 80 or 90), which can be hybridizable to a genomic DNA molecule, a cDNA molecule, or an mRNA molecule that encodes a gene, an mRNA, a cDNA, or another nucleic acid of interest. Oligonucleotides can be labeled, for example, by the incorporation of 32 P-nucleotides, 3 H-nucleotides, 14 C-nucleotides, 35 S-nucleotides or nucleotides to which a tag has been covalently conjugated, such as biotin. In one embodiment, a labeled oligonucleotide can be used as a probe to detect the presence of a nucleic acid. In another embodiment, the nucleotides (one or both of which may be labeled) can be used as PCR primers, either for full-length cloning or as a fragment of the gene, or to detect the presence of nucleic acids. In general, the oligonucleotides are prepared synthetically, preferably in a nucleic acid synthesizer. The sequence of any nucleic acid (eg, a nucleic acid encoding an IGFR1 gene or a nucleic acid encoding an anti-IGFR1 antibody or a fragment or portion thereof), can be determined by any method known in the art (e.g. , chemical sequencing or enzymatic sequencing). "Chemical sequencing" of DNA can denote methods such as Maxam and Gilbert (1977) (Proc Nati, Acad Sci USA 74: 560), in which DNA is randomly dissociated using individual base specific reactions. "Enzymatic sequencing" of DNA can denote methods such as that of Sanger (Sanger, et al., (1977) Proc. Nati, Acad. Sci. USA 74: 5463). The nucleic acids present may be flanked by natural regulatory sequences (expression control), or may be associated with heterologous sequences, including promoters, internal ribosome entry sites (IRES) and other sequence ribosome binding sites, enhancers, response elements, suppressors, signal sequences, polyadenylation sequence, introns, 5 'and 3' non-coding regions, and the like. A "promoter" or "promoter sequence" is a DNA regulatory region that is capable of binding an RNA polymerase in a cell (e.g., directly or through other proteins or promoter-linked substances) and initiating the transcription of a coding sequence. (for example, LCF or HCA). A promoter sequence is, in general, linked at its 3 'terminus by a transcription initiation site and extended upstream (5' direction) to include the minimum amount of bases or elements necessary to initiate transcription at any level. Within the promoter sequence can be found a transcription initiation site (conveniently defined, for example, by mapping with S1 nuclease), as well as the protein binding domains (consensus sequences) responsible for the binding of the RNA polymerase. The promoter may be operatively associated with other expression control sequences that include enhancer and repressor sequences or with a nucleic acid of the invention. Promoters that can be used to control gene expression include, but are not limited to, cytomegalovirus (CMV) promoters (U.S. Patent Nos. 5,385,839 and 5,168,062), the SV40 early promoter region (Benoist, et al., (1981)). Nature 290: 304-310), the promoter contained in the 3 'long terminal repeat of the Rous sarcoma virus (Yamamoto, et al., (1980) Cell 22: 787-797), the herpes thymidine kinase promoter (Wagner , et al., (1981) Proc. Nati, Acad. Sci. USA 78: 1441-1445), the regulatory sequences of the metallothionein gene (Brinster, et al., (1982) Nature 296: 39-42); prokaryotic expression vectors such as a β-lactamase promoter (Villa-Komaroff, et al., (1978) Proc. Nati, Acad. Sci. USA 75: 3727-3731), or the tac promoter (DeBoer, et al. ., (1983) Proc. Nati, Acad. Sci. USA 80: 21-25); see also "Useful proteins from recombinant bacteria" in Scientific American (1980) 242: 74-94; and promoter elements of yeast or other fungi such as the Gal 4 promoter, the ADC (alcohol dehydrogenase) promoter, the PGK (phosphoglycerol kinase) promoter or the alkaline phosphatase promoter. A coding sequence is "under the control of",
"functionally associated with" or "operably associated with" transcription and translation control sequences in a cell, when the sequences direct RNA-mediated transcription of the coding sequence into RNA, preferably mRNA, which can then be trans-spliced RNA (if it contains introns) and, optionally, translated to a protein encoded by the coding sequence. The terms "expresses" and "expression" mean allowing or causing the information in a gene, in an RNA or DNA sequence, to manifest; for example, producing a protein by activating the cellular functions involved in the transcription and translation of a corresponding gene. A DNA sequence is expressed in or by a cell to form an "expression product" such as an RNA (e.g., mRNA) or a protein. It can be said that the expression product itself can also be "expressed" by the cell. The terms "vector", "cloning vector" and "expression vector" refer to the vehicle (eg, a plasmid) by which the DNA or RNA sequence can be introduced into a host cell, to transform the host and , optionally, to promote the expression and / or replication of the introduced sequence. The term "transfection" or "transformation" means the introduction of a nucleic acid into a cell. These terms may refer to the introduction of a nucleic acid encoding an anti-IGFR1 antibody or a fragment thereof into a cell. The introduced gene or sequence can be referred to as "clone". A host cell that receives the introduced DNA or RNA has been "transformed" and is a "transformant" or a "clone". The DNA or RNA introduced into a host cell, can come from any source, including cells of the same genus or species, such as the host cell, or cells of a different genus or species. The term "host cell" means any cell of any organism that is selected, modified, transfected, transformed, cultured or used or manipulated in any form, for the production of a substance by the cell, for example expression or replication, by the cell, of a gene, a sequence, a protein or an enzyme of DNA or RNA. The term "expression system" means a host cell and a compatible vector which, under appropriate conditions, can express a protein or a nucleic acid that is transported by the vector and introduced into the host cell. Common expression systems include E. coli host cells and plasmid vectors, insect host cells, and Baculovirus vectors, and vectors and host cells of mammals. In a specific embodiment, the IGFR1 or an antibody and an antigen-binding fragment of the invention can be expressed in human embryonic kidney cells (HEK293). Other suitable cells include CHO cells (from Chinese hamster ovary), HeLa cells and NIH 3T3 cells, and NSO cells (line of murine myeloma cells that do not produce Ig). Nucleic acids encoding an antibody or an antigen-binding fragment of the invention, sIGFRI (see below) or IGFR1 can be expressed at high levels in an E.colifT7 expression system as described in US Patents. Nos. 4,952,496, 5,693,489 and 5,869,320 and in Davanloo, P., et al., (1984) Proc. Nati Acad. Sci. USA 81, 2035-2039; Studier, F. W., et al., (1986) J. Mol. Biol. 189: 113-130; Rosenberg, A. H., et al., (1987) Gene 56: 125-135; and Dunn, J. J., et al., (1988) Gene 68: 259 which are incorporated herein by reference. The present invention contemplates any surface or light modification of the amino acid or nucleotide sequences corresponding to the antibodies or antigen-binding fragments of the invention. In particular, the present invention contemplates variants of conservative sequences of the nucleic acids encoding the antibodies or antigen-binding fragments of the invention. "Sequence-preserving variants" of a polynucleotide sequence are those in which a change of one or more nucleotides in a given codon does not cause alterations in the amino acid encoded in that position. Conservative variants of the function of the antibodies of the invention, are also contemplated in the present invention. "Functional conservative variants" are those in which one or more amino acid residues in a protein or enzyme have been changed without altering the overall conformation and function of the polypeptide, including, but not limited to, the replacement of an amino acid by another that has similar properties. Amino acids with similar properties are well known in the art. For example, polar / hydrophilic amino acids may interchangeably include asparagine, glutamine, serine, cysteine, threonine, lysine, arginine, histidine, aspartic acid, and gytamic acid.; the non-polar / hydrophobic amino acids that can be interchangeable include glycine, alanine, valine, leucine, isoleucine, proline, tyrosine, phenylalanine, tryptophan and methionine; The amino acids that are acids that can be interchangeable include aspartic acid and glutamic acid and the basic amino acids that can be interchangeable include histidine, lysine and arginine. The present invention includes anti-IGFR1 antibodies and fragments thereof which are encoded by the nucleic acids described in Table 1, as well as the nucleic acids that hybridize thereto. Preferably, the nucleic acids hybridize under conditions of low stringency most preferably under conditions of moderate stringency, and more preferably under conditions of high stringency and preferably exhibit IGFR1 binding activity. A nucleic acid molecule is "hybridizable" with another nucleic acid molecule such as a cDNA, a genomic DNA, or an RNA, when a single-stranded form of the nucleic acid molecule can be coupled to the other nucleic acid molecule under the conditions of temperature and concentration of the ionic solution (see Sambrook, et al., supra). The conditions of temperature and ionic concentration determine the "stringency" of the hybridization. Typical low stringency hybridization conditions include 55 ° C, 5X SSC, 0.1% SDS and no formamide; or 30% formamide, 5X SSC, 0.5% SDS at 42 ° C. Typical hybridization conditions, of moderate stringency, are similar to low stringency conditions except that hybridization is carried out in 40% formamide, with 5X or 6X SSC and 0.1% SDS at 42 ° C. The high stringency hybridization conditions are similar to the low stringency conditions except that the hybridization conditions are carried out in 50% formamide, 5X or 6X SSC at 42 ° C or, optionally, at a higher temperature (for example of 57 ° C, 59 ° C, 60 ° C, 62 ° C, 63 ° C, 65 ° C or 68 ° C). In general, the SSC is NaC1 0.15M and Na citrate 0.015M. Hybridization requires that the two nucleic acids contain complementary sequences, although depending on the stringency of the hybridization, mismatches between the bases are possible. The proper stringency to hybridize nucleic acids depends on the length of the nucleic acids and the degree of complementation, which are variables well known in the art. The greater the degree of similarity or homology between two nucleotide sequences, the higher the stringency under which the nucleic acids can hybridize. For hybrids more than 100 nucleotides in length, the equations for calculating the melting temperature have been derived (see, Sambrook, et al., Supra, 9.50-9.51). For hybridization with shorter nucleic acids, ie oligonucleotides, the position of the mismatches is more important, and the length of the oligonucleotide determines its specificity (see Sambrook, et al., Supra, 11, 7-11, 8). Also included in the present invention are nucleic acids comprising nucleotide sequences and polypeptides comprising amino acid sequences that are at least about 70% identical, preferably at least about 80% identical, more preferably at least about 90% identical and even more preferably at least about 95% identical (eg, 95%, 96%, 97%, 98%, 99%, 100%) with the reference nucleotide and the amino acid sequences of Table 1 when carried to perform the comparison by means of the BLAST algorithm in which the parameters of the algorithm are selected to provide the widest pairing between the respective sequences along the entire length of the respective reference sequences. Polypeptides comprising amino acid sequences that are at least about 70% similar, preferably at least about 80% similar, more preferably at least about 90% similar and even more preferably at least about 95% similar (eg, 95%, 96%, 97%, 98%, 99%, 100%) to any of the sequences of reference amino acid of Table 1 when the comparison is carried out with a BLAST algorithm in which the parameters of the algorithm are selected to provide the widest pairing between the respective sequences along the entire length of the respective reference sequences, they are also included in the present invention. Sequence identity refers to the exact matches between the nucleotides or amino acids of two sequences that are being compared. "Sequence similarity" refers to the exact pairings between the amino acids of two polypeptides being compared, in addition to the pairings between non-identical biochemically related amino acids. Biochemically related amino acids that share similar properties and that can be interchangeable have been discussed above. The following references with respect to the algorithm BLAST ALGORITHMS: are incorporated herein by reference Altschul, S.F., et al., (1990) J. Mol. Biol. 215: 403-410; Gish, W., et al., (1993) Nature Genet. 3: 266-272; Madden, T.L., et al., (1996) Meth. Enzymol. 266: 131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25: 3389-3402; Zhang, J., et al., (1997) Genome Res. 7: 649-656; Wootton, J.C., et al., (1993) Comput. Chem. 17: 149-163; Hancock, J.M. ei al., (1994) Comput. Appl. Biosci. 10: 67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O., et al., "A model of evolutionary change in proteins." In Atlas of Protein Sequence and Structure. (1978) vol. 5, suppl. 3. M.O. Dayhoff (ed.), Pp. 345-352, Nati. Biomed. Res. Found., Washington, DC; Schwartz, R.M., et al., "Matrices for detecting distant relationships." In Atlas of Protein Seguence and Structure. (1978) vol. 5, suppl. 3. "MO Dayhoff (ed.), Pp. 353-358, Nati. Biomed, Res. Found., Washington, DC; Altschul, SF, (1991) J. Mol. Biol. 219: 555-565; DJ, et al., (1991) Methods 3: 66-70; Henikoff, S., et al., (1992) Proc. Nati, Acad. Sci. USA 89: 10915-10919; Altschul, SF, et al. , (1993) J. Mol. Evol. 36: 290-300; ALIGNMENT STATISTICS: Karlin, S., et al., (1990) Proc. Nati, Acad. Sci. USA 87: 2264-2268; Karlin, S. , et al., (1993) Proc. Nati, Acad. Sci. USA 90: 5873-5877, Dembo, A., et al., (1994) Ann. Prob. 22: 2022-2039, and Altschul. SF " Evaluating the statistical significance of multiple distinct local alignments. "In Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, New York.Structure of the Antibodies It is generally known that the basic structural unit of the antibody comprises a tetramer. Each tetramer includes two identical pairs of polypeptide chains, where each pair has a "light" chain of (approximately 25 kDa) and a "heavy" chain (approximately 50-70 kDa). The amino-terminal portion of each chain may include a variable region of about 100 to 110 or more amino acids that are primarily responsible for the recognition of the antigen. The carboxy-terminal portion of each chain can define a constant region that is primarily responsible for effector function. Typically, human light chains are classified as light chains kappa and lambda. In addition, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the isotype of the antibody as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are joined by a "J" region of approximately 12 or more amino acids, where the heavy chain also includes a "D" region of approximately 10 more amino acids. See, in general, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)) (which is incorporated herein by reference in its entirety for any purpose). The variable regions of each light / heavy chain form the antibody binding site. Therefore, in general, an intact IgG antibody has two binding sites. Except for bifunctional or bispecific antibodies, the two binding sites are generally the same. Normally, all chains exhibit the same general structure of relatively conserved structural regions (FR) joined by three hypervariable regions also called complementarity determining regions or CDRs. The CDRs of the two strands of each pair are usually aligned by the structural regions, which allows binding to a specific epitope. In general, from the N-terminus to C-terminal, both the light chains and the heavy chains comprise the FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 domains. The assignment of the amino acids to each domain is, generally, in accordance with the definitions of Seguences of Proteins of Immunological Interest. Kabat, ei al .; National Institutes of Health, Bethesda, Md .; 5th ed .; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat, et al., (1977) J. Biol. Chem. 252: 6609-6616; Chothia, ei al., (1987) J Mol. Biol. 196: 901-917 or Chothia, et al., (1989) Nature 342: 878-883.
Binding Compositions Binding compositions of the combinations of the present invention include any composition that specifically binds IGFR1. A "binding agent" or composition refers to a molecule that binds with IGFR1 specificity, for example in a ligand-receptor type manner or in an antibody-antigen interaction, for example proteins that specifically associate with IGFR1, for example, in a protein-to-natural physiologically relevant protein interaction, either covalently or non-covalently. The term "binding composition" includes small organic molecules, nucleic acids and polypeptides, such as a whole antibody (preferably an isolated monoclonal human antibody) or an antigen-binding fragment thereof, of the present invention (eg, the antibody 19D12 / 15H12, the 19D12 / 15H12 LCF / HCA antibody or any peptide set forth above in Table 1). Antibodies and antigen-binding fragments thereof, include, but are not limited to monoclonal antibodies, polyclonal antibodies, bispecific antibodies, Fab antibody fragments, F (ab) 2 antibody fragments, Fv antibody fragments (e.g. ., VH or VL), fragments of single chain Fv antibodies and dsFv antibody fragments. In addition, the antibodies of the invention may be fully human antibodies or chimeric antibodies.
The combinations of the present invention include any antibody or antigen-binding fragment thereof, or any polynucleotide encoding said antibody or fragment thereof that binds to the antigen as indicated in the U.S. Patent Application. No. 10 / 443,466, filed May 22, 2003 and in WO 03/100008. Preferably, the antibody molecules are isolated human monoclonal antibodies. Preferably, the antibodies of the invention comprise one or more, more preferably all of the 6 CDRs comprising an amino acid sequence set forth in any of SEQ ID NOs: 5-10. Preferably, an antibody of the invention includes a mature F (LCF) F 19D12 / 15H12 light chain (see SEQ ID NO: 2) paired with a mature 19D12 / 15H12 heavy A chain (HCA) (see SEQ ID NO: 4) ( for example, the fully human monoclonal antibody) 19D12 / 15H12 LCF / HCA). The amino acid sequences of the nucleotide of the preferred antibody chains are shown below. With a dot underline, the signal peptide is indicated. What is not underlined indicates the CDRs. The simple type indicates the structural regions. In the embodiment, the antibody chains are mature fragments lacking the signal peptide.
D12 / 15H12 Light-F Chain (LCF; SEQ ID NO: 1) ATG TCG CCA TCA CA CTC ATT GGG TTT CTG CTG CTC TGG GTT CCA GCC TCC
AGG GGT GAA ATT GTG CTG ACT CAG AGC CCA GGT ACC CTG TCT GTG TCT CCA
GGC GAG AGA GCC ACC CTC TCC TGC CGG GCC AGT CAG AGC ATT GGT AGT AGC
TTA CAC TGG TAC CAG CAG AAA CCA GGT CAG GCT CCA AGG CTT CTC ATC AAG
TAT GCA TCC CAG TCC CTC TCA GGG ATC CCC GAT AGG TTC AGT GGC AGT GGA
TCT GGG ACÁ GAT TTC ACC CTC ACC ATC AGT AGA CTG GAG CCT GAA GAT TTC
GCA GTG TAT TAC TGT CAT CAG AGT AGT CGT TTA CCT CAC ACT TTC GGC CAÁ
GGG ACC AAG GTG GAG ATC AAA CGT ACÁ
(SEQ ID NO: 2) M S P_ S Q. L I G _F L _L L ..... V P ..... A _S
R G E I V L T Q S P G T L S V S P
G E R A T L S C R A S Q S I G S S
L H W Y Q Q K P G Q A P R L L I K
Y A S Q S L S G I P D R S G S G S G T D F T L T I S R L E P E D F
G T K V E I K R T
D12 / 15H12 heavy chain-A (HCA; SEQ ID NO: 3) AT-G..GAG.TTT__GGG_CT_G_AGC ^ _CAG__TGT GAG GTT CAG CTG GTG CAG TCT GGG GGA GGC TTG GTA AAG CCT GGG GGG TCC CTG AGA CTC TCC TGT GCC GCC TCT GGA TTC ACC TTC AGT AGC TTT GCT ATG CAC TGG GTT CGC CAG GCT CGA GGA AAA GGT CTG GAG TGG ATA TCA GTT ATT GAT ACT CGT GGT GCC AC TAC TAT GCA GCC TCC GTG AAG GGC CGA TTC ACC ATC TCC AGA GAC AAT GCC AAG AAC TCC TTG TAT CTT CA ATG AAC AGC CTG AGA GCC GAG GAC ACT GCT GTG TAT TAC TGT GCA AGA CTG GGG AAC TTC TAC TAC GGT ATG GAC TGG GGC CAG GGG ACC GGG ACC GTC GCC TCC TCA
(SEQ ID NO: 4)? .t_Glu..Phe._Gly _Leu S_e_r__T ^ Gln Cy_s_ Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly
Gly Ser Leu Arg Leu Ser Cys Wing Wing Ser Gly Phe Thr Phe Ser Ser Phe
Wing Met Hls Trp Val Arg Gln Wing Pro Gly Lys Gly Leu Glu Trp He Ser Val He Asp Thr Arq Gly Wing Thr Tyr Tyr Wing Asp Ser Val Lys Gly Arg
Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Gly Asn
Phe Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
Be
The three plasmids comprising the CMV promoter operably linked to 15H12 / 19D12 LCF (K) (variable region sequence set forth in SEQ ID NOs: 1 and 2), to 15H12 / 19D12 HCA (? 4) (variable region sequence) established in SEQ ID NOs: 3 and 4) or 15H12 / 19D12 HCA (? 1) (variable region sequence established in SEQ ID NOs: 3 and 4), has been deposited in the American Type Culture Collection (ATCC); 10801 University Boulevard; Manassas, Virginia 20110-2209 on May 21, 2003. The deposit number and ATCC access numbers for the plasmids are indicated below: CMV promoter-15H12 / 19D12 HCA (? 4) - Deposit Name: "15H12 / 19D12 HCA (? 4) "; ATCC Accession Number: PTA-5214; CMV promoter-15H12 / 19D12 HCA (? 1) - Deposit Name: "15H12 / 19D12 HCA (? 4)"; ATCC Accession Number: PTA-5216; CMV promoter-15H12 / 19D12 LCF (K) - Deposit Name: "15H12 / 19D12 LCF (K)"; ATCC Accession Number: PTA-5220. All restrictions on access to the plasmids deposited in ATCC will be eliminated when the patent is granted. Each of the plasmids previously cited as reference constitutes part of the present invention. In addition, the nucleic acid located within each expression cassette together with the immunoglobulin variable region thereof together with the processed mature version thereof (i.e., which lacks the signal sequence), particularly SEQ ID NO. : 3, mature HCA (nucleotides 58-411 of SEQ ID NO: 3), SEQ ID NO: 1 or mature LCF (nucleotides 58-384 of SEQ ID NO: 1), optionally include an immunoglobulin constant region together with any polypeptide encoded by any of the above nucleic acids, including mature or unprocessed chains, and optionally including an immunoglobulin constant region, forms part of the present invention. In addition, any antibody or antigen binding fragment thereof, comprising one of the encoded polypeptides forms part of the present invention. The scope of the present invention includes the variable regions of antibodies of the present invention (e.g., any variable region, mature or unprocessed, indicated in Table 1) linked to any immunoglobulin constant region. If a light chain variable region is bound to a constant region, it is preferably a K chain. If a heavy chain variable region is linked to a constant region, it is preferably a constant region? 1,? 2,? 3 or? 4 , more preferably,? 1,? 2 or? 4 even more preferably? 1 or? 4. The anti-IGFR1 antibody molecules of the invention preferably recognize human IGFR1, preferably a soluble fragment of IGFR1 (ie, sIGFRI) such as amino acids 30-902 or SEQ ID NO: 11; however, the present invention includes antibody molecules that recognize IGFR1 from different species, preferably from mammals (eg mouse, rat, rabbit, sheep or dog). The present invention also includes an anti-IGFR1 antibody (for example LCF / HCA) or antigen-binding fragments thereof that complex with IGFR1 or with any fragment thereof (eg, sIGFRI, such as amino acids 30-902). of SEQ ID NO: 11) or with any cell expressing IGFR1 or any portion or fragment thereof on the surface of the cell (eg, HEK293 cells stably transformed with human IGFR1 or MCF7 (e.g., the Cell Line. No. HTB-22 of ATCC)). These complexes can be prepared by placing the antibody or the antibody fragment with the IGFR1 or the IGFR1 fragment. In a preferred embodiment, fully human monoclonal antibodies directed against IGFR1 are generated using transgenic mice carrying parts of the human immune system instead of a mouse system. These transgenic mice, which may be referred to herein as "HuMAb" mice, contain a human immunoglobulin gene miniplug encoding non-rearranged K chain and human chain immunoglobulin (μ and γ) sequences, together with targeting mutations that inactivate the places of endogenous chains μ and K (Lonberg, N., et al., (1994) Nature 368 (6474): 856-859). Accordingly, the mice exhibit reduced expression of mouse or K IgM, and in response to immunization, the introduced light chain and heavy chain transgenes undergo class shift and somatic mutation to generate monoclonal antibodies IgG? high affinity humans (Lonberg, N., et al., (1994), supra; reviewed in Lonberg, N. (1994) Handbook of Experimental Pharmacology 113: 49-101; Lonberg, N., et al., (1995 ) Intern Rev. Immunol., 13: 65-93, and Harding, F., et al., (1995) Ann. N. and Acad. Sci 764: 536-546). The preparation of HuMab mice is commonly known in the art and has been described for example in Taylor, L., et al., (1992) Nucleic Acids Research 20: 6287-6295; Chen, J., et al., (1993) International Immunology 5: 647-656; Tuaillon, ei al., (1993) Proc. Nati Acad. Sci USA 90: 3720-3724; Choi, et al., (1993) Nature Genetics 4: 117-123; Chen, J., et al., (1993) EMBO J. 12: 821- 830; Tuaillon, ei al., (1994) J Immunol. 152: 2912-2920; Lonberg, et al., (1994) Nature 368 (6474): 856-859; Lonberg, N. (1994) Handbook of Experimental Pharmacology 113: 49-101; Taylor, L., et al., (1994) International Immunology 6: 579-591; Lonberg, N., et al., (1995) Intern. Rev. Immunol. Vol. 13: 65-93; Harding, F., et al., (1995) Ann. N. And Acad. Sci 764: 536-546; Fishwild, D., et al., (1996) Nature Biotechnology 14: 845-851 and Harding, et al., (1995) Annals NY Acad. Sci. 764: 536-546; the content of all of which is incorporated here as a reference in its entirety. See additionally, the Patents of E.U.A. Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,789,650; 5,877,397; 5,661, 016; 5,814,318; 5,874,299; 5,770,429 and 5,545,807; and International Patent Application Publication Nos. WO 98/24884; WO 94/25585; WO 93/12227; WO 92/22645 and WO 92/03918, all descriptions of which are incorporated herein by reference in their entirety. To generate fully human monoclonal antibodies to IGFR1, HuMab mice can be immunized with an antigenic IGFR1 polypeptide, preferably amino acids 30-902 of SEQ ID NO: 11, as described by Lonberg, N., et al., (1994). ) Nature 368 (6474): 856-859; Fishwild, D., et al., (1996) Nature Biotechnology 14: 845-851 and WO 98/24884. Preferably, the mice will be 6-16 weeks of age in the first immunization. For example, a purified preparation of IGFR1 or sIGFRI can be used to immunize the HuMab mice intraperitoneally. Mice can also be immunized with complete HEK293 cells, which are stably transfected with an IGFR1 gene. An "antigenic IGFR1 polypeptide" can refer to an IGFR1 polypeptide of any fragment thereof, preferably amino acids 30-902 of SEQ ID NO: 11, which provides an anti-IGFR1 immune response, preferably in HuMab mice. In general, HuMAb transgenic mice respond well when they are initially immunized intraperitoneally (IP) with antigen in complete Freund's adjuvant, followed by IP immunizations one week and one (usually up to a total of 6) with antigen in adjuvant incomplete by Freund. Mice can be immunized, first with cells expressing IGFR1 (e.g., markedly transfected HEK293 cells), and then with a soluble fragment of IGFR1 (e.g., amino acids 30-902 of SEQ ID NO: 11), and can receive continuously alternate immunizations with the two antigens. The immune response can be monitored in the course of the immunization protocol with plasma samples obtained from retro-orbital blood extractions. Plasma can be screened for the presence of anti-IGFR1 antibodies, for example by ELISA, and mice with sufficient immunoglobulin titers can be used for fusions. The mice can receive intravenous reinforcement with antigen, three days before sacrificing them and extracting the spleen. It is considered that it may be necessary to carry out 2-3 fusions for each antigen. Several mice can be immunized for each antigen. For example, a total of twelve HuMAb mice of the strains HC07 and HC012 can be immunized. Hybridoma cells that produce the fully human, monoclonal anti-IGFR1 antibodies can be produced by methods that are commonly known in the art. These methods include, but are not limited to, the hybridoma technique originally developed by Kohler, et al., (1975) (Nature 256: 495-497), as well as the trioma technique (Hering, et al., (1988). ) Biomed, Biochim, Acta 47: 211-216 and Hagiwara, et al., (1993) Hum Antibod, Hybridomas 4:15), the human B-cell hybridoma technique (Kozbor, et al., (1983) Immunology Today 4:72 and Cote, et al., (1983) Proc. Nati Acad. Sci. U.S.A 80: 2026-2030), and the EBV-hybridoma technique (Colé, et al., In Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96, 1985). Preferably, mouse splenocytes are isolated and fused with PEG in a mouse myeloma cell line, based on conventional protocols. The resulting hybridomas can then be screened to determine the production of the antigen-specific antibodies. For example, single cell suspensions of spleen lymphocytes can be fused with one sixth of the number of non-secretory mouse myeloma cells P3X63-Ag8.653 (ATCC, CRL 1580) with 50% PEG. Cells should be deposited at approximately 2 x 10 5 cells / ml, in a flat bottom microtiter plate, followed by a two week incubation in a selective medium containing 20% Fetal Clone Serum, 18% conditioned medium. 653", 5% of origin (IGEN), 4 mM of L-glutamine, 1 mM of L-glutamine, 1 mM of sodium pyruvate, 5 mM of HEPES, 0.055 mM of 2-mercaptoethanol, 50 units / ml of penicillin , 50 mg / ml streptomycin, 50 mg / ml gentamicin and 1X HAT (Sigma; the HAT is added 24 hours after the fusion). After two weeks, the cells can be cultured in a medium in which the HAT is replaced with HT. Individual wells are then screened with ELISA for human anti-IGFR1 monoclonal IgG antibodies. Once extensive hybridoma growth occurs, the medium can usually be observed after 10-14 days. The antibody that secretes the hybridomas can be re-deposited, screened again, and if it is still positive for human IgG, anti-IGFR1 monoclonal antibodies can be subcloned, at least twice by limited dilution. The stable subclones can then be cultured in vitro to generate small amounts of antibody in a tissue culture medium for characterization. The anti-IGFR1 antibodies and the antigen-binding fragments thereof according to the present invention can also be produced recombinantly (for example, in an E.CO.sub.///T7 expression system such as that discussed above). In this embodiment, the nucleic acids encoding the antibody molecules of the invention (eg, VH or VL) can be inserted into a pET-based plasmid and can be expressed in the E.colifT7 system. There are several methods by which recombinant antibodies are produced which are known in the art. An example of a method for the production of recombinant antibodies is described in the patent of E.U.A. No. 4,816,567, which is incorporated herein by reference. The transformation can be effected by any known method for the introduction of polynucleotides into a host cell. Methods for the introduction of heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, calcium phosphate precipitation, polybrene intermediated transfection, protoplast fusion, electroporation, encapsulation of polynucleotides in liposomes, injection biolistics and direct microinjection of DNA within the nuclei. In addition, nucleic acid molecules can be introduced into mammalian cells by viral vectors. Cell transformation methods are well known in the art. See, for example, US Patents. Nos. 4,399,216; 4,912,040; 4,740,461 and 4,959,455. The Anti-IGFR1 antibodies can also be synthesized by any of the methods indicated in the patent of E.U.A. No. 6,331,415. Mammalian cell lines available as hosts for expression are known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC). These include, among others, Chinese hamster ovary (CHO) cells, NSO cells, SP2 cells, HeLa cells, lactating hamster kidney cells (BHK), monkey kidney cells (COS), human hepatocellular carcinoma cells (for example., Hep G2), A549 cells, 3T3 cells, HEK-293 cells and a variety of other cell lines. Mammalian host cells include human, mouse, rat, dog, monkey, pig, goat, bovine, equine and hamster cells. Particularly preferred cells are selected through the determination of which cell lines have high levels of expression. Other cell lines that can be used are insect cell lines, such as Sf9 cells, amphibian cells, bacterial cells, plant cells and fungal cells. When recombinant expression vectors encoding the heavy chain or the antigen-binding portion thereof, the light chain and / or the antigen-binding portion thereof, are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow the exclusion of the antibody in the host cells or, more preferably, the secretion of the antibody within the culture medium in which the host cells are grown. The antibodies can be recovered from the culture medium using conventional methods and protein purification. further, the expression of the antibodies of the invention (or other portions thereof) from cell lines for production, can be increased using a variety of known techniques. For example, the glutamine synthetase gene expression system (the GS system) is a common method to improve expression under certain conditions. The GS system has been discussed in whole or in part with reference to European Patents Nos. 0 216 846, 0 256 055, and 0 323 997 and European Patent Application No. 89303964.4. It is likely that antibodies that are expressed by different cell lines or in transgenic animals will have different glycosylations from one another. However, all antibodies encoded by the nucleic acid molecules provided herein, or comprising the amino acid sequences provided herein, form part of the present invention, independently of the glycosylation of the antibodies. The term "monoclonal antibody," as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible natural mutations that may be present in amounts minors Monoclonal antibodies are highly specific, and are directed against a single antigenic site. Monoclonal antibodies are advantageous because they can be synthesized by a culture of hybridomas, essentially uncontaminated by other immunoglobulins. The "monoclonal" modifier indicates that the character of the antibody is between a population of substantially homogeneous antibodies, and the production of the antibody by any particular method should not be considered to be required. As mentioned above, the monoclonal antibodies that are used in accordance with the present invention can be prepared by the hybridoma method first described by Kohler, et al., (1975) Nature 256: 495. A polyclonal antibody is an antibody that was produced between or in the presence of one or more other antibodies that are not identical. In general, polyclonal antibodies are produced from a B lymphocyte in the presence of several other B lymphocytes that produced non-identical antibodies. Usually, polyclonal antibodies are obtained directly from an immunized animal. A bispecific or bifunctional antibody is an artificial hybrid antibody that has two different heavy / light chain pairs, and two different binding sites. Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or binding of Fab 'fragments. See, for example, Songsívilai, et al., (1990) Clin. Exp. Immunol. 79: 315-321, Kostelny, et al., (1992) J Immunol. 148: 1547-1553.
In addition, bispecific antibodies can be formed as "diabodies" (Holliger, et al., (1993) PNAS USA 90: 6444-6448) or as "Janusins" (Traunecker, et al., (1991) EMBO J. 10: 3655-3659 and Traunecker, et al., (1992) Int. J. Cancer Suppl 7: 51-52). The term "fully human antibody" refers to an antibody that comprises only the human immunoglobulin protein sequences. A fully human antibody can contain murine carbohydrate chains if it is produced in a mouse, in a mouse cell or in a hybridoma derived from a mouse cell. Similarly, "mouse antibody" refers to an antibody that comprises only mouse immunoglobulin sequences. The present invention includes "chimeric antibodies" - an antibody comprising a variable region of the present invention fused or chimerized with one region of antibody (e.g., constant region) of another, non-human species (e.g., mouse, horse, rabbit, dog, cow, chicken). These antibodies can be used to modulate the expression or activity of IGFR1 in non-human species. "Single chain" Fv "or" sFv "antibody fragments have the VH and VL domains of an antibody, where these domains are present in a single polypeptide chain In general, the sFv polypeptide further comprises a polypeptide linker between the V domains and VL which allows the sFv to form the desired structure for antigen binding.The techniques described for the production of the single chain antibodies (U.S. Patent Nos. 5,476,786; 5,132,405 and 4,946,778) can be adapted to produce single chain antibodies Specific anti-IGFR1 For a review of sFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, Vol 113, Rosenburg and Moore eds Springer-Verlag, NY, pp. 269-315 (1994). "Fragments of Fv Stabilized with Disulfide "and" dsFv "refer to antibody molecules that comprise a variable heavy chain (VH) and a variable light chain (VL) that are linked by a disulfide bridge. Within the scope of the present invention, they also include F (ab) 2 fragments which can be produced by enzymatic cleavage of IgG by, for example, pepsin. Fab fragments can be produced by, for example, reduction of F (ab) 2 with dithiothreitol or mercaptoethylamine. A fragment of Fab is a VL-CL chain added to a VH-CHI chain by a disulfide bridge. An F (ab) 2 fragment represents two Fab fragments which, in turn, are added by two disulfide bridges. The Fab portion of an F (ab) 2 molecule includes a portion of the Fc region between which the disulfide bridges are located. An Fv fragment is a VL or V region. Depending on the amino acid sequences of the constant domain of their heavy chains, the immunoglobulins can be assigned to different classes. There are at least five major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of these can be further divided into subclasses (isotypes), eg, IgG-1, IgG-2, IgG-3 and IgG- 4; IgA-1 and IgA-2. The anti-IGFR1 antibody molecules of the invention can also be conjugated with a chemical moiety. The chemical moiety may be, among other things, a polymer, a radionuclide or a cytotoxic factor. Preferably, the chemical moiety is a polymer that increases the half-life of the antibody molecule in the body of a subject. Suitable polymers include but are not limited to polyethylene glycol (PEG) (e.g., PEG with a molecular weight of 2 kDa, 5 kDa, 10 kDa, 12 kDa, 20 kDa, 30 kDa or 40 kDa), dextran and monomethoxy polyethylene glycol (mPEG). Lee, et al., (1999) (Bioconj.Chem.10: 973-981) describe single chain antibodies conjugated with PEG. Wen, et al., (2001) (Bioconj.Chem.12: 545-553) describe antibodies conjugated with PEG that bind to a radiometal chelator (diethylenetriaminpentaacetic acid (DTPA)). The antibodies and antibody fragments of the invention can also be conjugated with labels such as 99Tc, 90Y, 111ln, 32P, 14C,
125 | ) 3Hj 131, t 11C (1ßQ> 13N j 18 ^ 35 ^ 51 ^ 57- ^ 226 ^ 60 ^ 59 ^ 57 ^ 152 ^
67CU, 217Ci, 211At, 212Pb, 47Sc, 109Pd, 23 Th, and 40K, 157Gd, 55Mn, 52Tr and 56Fe. The antibodies and antibody fragments of the invention can also be conjugated to fluorescent or chemiluminescent labels including fluorophores such as rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanate, phycoerythrin, phycocyanin, allophycocyanin, o-phthaladehyde, fluorescamine. , 152Eu, dansium, umbelliferone, luciferin, luminal label, isoluminal label, an aromatic acridinium ester label, an imidazole label, an acridinium salt label, an oxalate ester label, an equorin label, 2,3 -dihydroftalazineadiones, biotin / avidin, rotating brands and stable free radicals. The antibody molecules can also be configured with a cytotoxic factor such as a diphtheria toxin, A chain of Pseudomonas aeruginosa exotoxin, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, proteins and compounds of Aleurites fordii (eg, fatty acids), diantine proteins, PAPI, PAPII, and PAP-S proteins from Phytoiacca americana, inhibitor of momordica charantia, curcinia, crotina, inhibitor of saponaria officinalis, mitogeline, restrictocin, fenomycin, and enomycin . Any method known in the art can be employed for the configuration of the antibody molecules of the invention to the various portions, including the methods described by Hunter, ei ai, (1962) Nature 144: 945; David, et al., (1974) Biochemistry 13: 1014; Pain, et al., (1981) J. Immunol. Meth. 40: 219; and Nygren, J., (1982) Histochem. and Cytochem. 30: 407. The methods for conjugating antibodies are conventional and very well known in the art.
Chemotherapeutic Agents The present invention includes combinations and methods comprising one or more binding compositions such as an anti-IGFR1 antibody or a fragment thereof linked to the antigen, in association with one or more chemotherapeutic agents. A chemotherapeutic agent provides a therapeutic effect that is useful in the treatment of any medical disorder treated by the administration of a binding composition according to the invention (eg, LCF / HCA). For example, if a binding composition is administered to treat cancer in a subject, (e.g., a human), the chemotherapeutic agents provide an additional anti-cancer therapeutic effect or some other therapeutic effect that will improve the outcome of the subject's treatment. . The component of the chemotherapeutic agent of a combination according to the invention can function by any mechanism (ie, by the same mechanism by which the binding composition acts or by a different mechanism). Chemotherapeutic agents in combinations of the methods of the present invention include, but are by no means limited to, signal transduction inhibitors, cell cycle inhibitors, IGF / IGFR1 modulators (eg, inhibitors or activators), inhibitors. of farnesyl protein transferase (FPT) epidermal growth factor receptor (EGFR) inhibitors, HER2 inhibitors, vascular epidermal growth factor receptor (VEGF) inhibitors, mitogen-activated protein kinase (MAP) inhibitors, MEK inhibitors, AKT inhibitors, TORm inhibitors, p3 kinase inhibitors, Raf inhibitors, cyclin-dependent kinase inhibitors (CDK), microtubule stabilizers, microtubule inhibitors, SERM / Antiestrogens, aromatase inhibitors, anthracyclines, proteasome inhibitors and agents that inhibit the production of nonsulinic growth factor (IGF) and inhibit anti-sense generators of IGFR1. IGF-1 or IGF2. FPT inhibitors including tricyclic amide compounds such as those described in U.S. Pat. No. 5,719,148 or in the U.S. Patent. No. 5,874,442 can be combined with an anti-IGFR antibody. Any compound represented by formula I, below, may be included in the combinations of the invention:
or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c and d represents N or NR9 wherein R9 is O-, -CH3 or - (CH2) nC02H wherein n is 1 to 3, and the remainder of groups a, b, c and d represents CR1 or CR2; or each of a, b, c and d is independently selected from CR1 or CR2;
each of R1 and R2 is independently selected from H, halo, -CF3, -OR10 (for example, -OCH3), -COR10, -SR10 (for example, -SCH3 and
-SCH2C6H5), -S (0) tR11 (where t is 0, 1 or 2, for example -SOCH3 and-S02CH3), -SCN, -N (R10) 2, -NR10R11, -N02, -OC ( 0) R1 °, -C02R1 °, -OC02R11, -NC, -NHC (0) R10, -NHS02R10, -CONHR10, -CONHCH2CH2OH, -NR10COOR11,
-SR11C (0) OR11 (eg, -SCH2CO2CH3), -SR11N (R75) 2 wherein each R75 is independently selected from H and -C (0) OR11 (eg, -S (CH2) 2NHC (0) 0 -t-butyl and -S (CH 2) 2 NH 2, benzotriazol-1-yloxyl, tetrazol-5-yl, or substituted tetrazol-5-ylthio (for example, tetrazol-5-ylthio substituted with alkyl such as 1-methyl) -tetrazole-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, -OR10 or -C02R1 °; R3 and R4 are the same or different and each independently represents H, any of the substituents R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated C5-C7 ring fused to the benzene ring (ring III): R5, R6, R7 and R8 independently represents H -CF3, -COR10, alkyl or aryl, said aryl or alkyl being optionally substituted with -OR10, -SR10, -S (0) tR11, -NR10COOR11, -N (R10) 2, -N02, -COR10, -OCOR10, -OC02R11, -C02R10, OP03R10 or one of R5, R6, R7 and R8 can be taken in combination with R40 as defined below to represent - (CH2) r- where r is 1 to 4 which can be substituted with lower alkyl, lower alkoxy, -CF3 or aryl, or R5 is combined with R6 to represent = O or = S and / or R7 is combined with R8 to represent = O or = S; R10 represents H, alkyl, aryl or aralkyl (for example, benzyl); R11 represents alkyl or aryl; X represents N, CH or C, where C can contain an optional double bond (represented by the dotted line) to carbon atom 11; the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent -R10, halo, -OR11, -OC02R11 or -0C (0) R1 °, and when a double bond is not represented between the carbon atoms 5 and 6, A and B each independently represents H2, - (OR11) 2; H and halo, dihalo, alkyl and H, (alkyl) .. -H and -OC (0) R1 °, H and -OR10, = O, aryl and H, = ÑOR10 or -0- (CH2) p-0 - where p is 2, 3 or 4; R represents R40, R42, R44, or R54, as defined below; R 40 represents H, aryl, alkyl, cycloalkyl, alkenyl, alkynyl or -D, where D represents
where R3 and R4 are as previously defined and W is O, S or NR10 wherein R10 is as defined above; said R40, alkenyl and alkynyl cycloalkyl groups being optionally substituted with 1 to 3 groups selected from halo, -CON (R10) 2, aryl, -C02R10, -OR12, -SR12, -N (R10) 2l -N (R10) CO2R11 , -COR12, -N02 or D, where -D, R10 and R11 are as defined above and R12 represents R10, - (CH2) mOR10 or - (CH2) qC02R1 ° where R10 is as previously defined, m is 1 to 4 and q is 0 to 4; said alkenyl and alkynyl groups R40 not containing -OH, -SH or -N (R10) 2 on a carbon atom containing a double or triple bond, respectively; or R40 represents phenyl substituted with a group selected from -S02NH2, -NHS02CH3, -S02NHCH3, -S02CH3, -SOCH3, -SCH3, or -NHSO2CF3, preferably said group is located in the para position (p-) of the phenyl ring; or R40 represents a group selected from
R s42 represents R20 - C-R46 R21
wherein R20, R21 and R each is independently selected from the group consisting of: (1) H; (2) - (CH2) qSC (0) CH3 where q is 1 to 3 (eg, -CH2SC (0) CH3); (3) - (CH2) qOS02CH3 where q is 1 to 3 (for example, -
CH2OS02CH3); (4) -OH; (5) -CS (CH2) w (substituted phenyl) where w is 1 to 3 and the substituents on said substituted phenyl group are the same substituents as those described below for said substituted phenyl (e.g., -CS-CH2-4- methoxyphenyl);
(6) -NH2; (7) -NHCBZ (where CBZ represents carbonylbenzyloxy, is
say, CBZ represents -C (0) OCH2C6H5); (8) -NHC (0) OR22 wherein R22 is an alkyl group having
1 to 5 carbon atoms (for example, R22 is t-butyl to form in this manner -NHBOC wherein BOC represents tert-butyloxycarbonyl, ie BOC represents -C (0) OC (CH3) 3), or R22 represents substituted phenyl with 1 to 3 alkyl groups (for example, 4-methylphenyl); (9) alkyl (for example, ethyl); (10) - (CH2) kphenyl wherein k is 1 to 6, usually 1 to 4 and preferably 1 (for example, benzyl); (11) phenyl; (12) substituted phenyl (e.g., phenyl substituted with 1 to 3 substituents, preferably one) wherein the substituents are selected from the group consisting of: halo (e.g., Br, Cl, or I with Br being preferred); N02; -OH; -OCH3; -NH2; -NHR22; -N (R22) 2; alkyl (for example, alkyl having from 1 to 3 carbon atoms with methyl being preferred); -0 (CH2) t phenyl (wherein t is from 1 to 3, with preferred 1); and -0 (CH2) t substituted phenyl (wherein t is from 1 to 3, with preferred 1); examples of substituted phenyls include, but are not limited to, p-bromophenyl, m-nitrophenyl, o-nitrophenyl, m-hydroxy-phenyl, o-hydroxyphenyl, methoxyphenyl, p-methylphenyl, m-methylphenyl, and -OCH2C6H5; (13) naphthyl; (14) substituted naphthyl, wherein the substituents are as defined for the above substituted phenyl; (15) bridged polycyclic hydrocarbons having from 5 to 10 carbon atoms (eg, adamantyl and norbornyl); (16) cycloalkyl having from 5 to 7 carbon atoms (for example, cyclopentyl and cyclohexyl);
(17) heteroaryl (e.g., pyridyl, and pyridyl N-oxide); (18) hydroxyalkyl (e.g., -0 (CH2) vOH where v is 1 to 3, such as for example, -CH2OH); (19) substituted pyridyl or substituted pyridyl N-oxide wherein the substituents are selected from methylpyridyl, morpholinyl, imidazolyl, 1-piperidinyl, 1- (4-methylpiperazinyl), -S (0) rR11, or any of the substituents provided above for said substituted phenyl, and said substituents are attached to a ring carbon atom by replacement of the hydrogen attached to said carbon;
(20) (21) (22)
(23) -NHC (0) - (CH2) k-phenyl or -NH (0) - (CH2)? -substituted phenyl, wherein said k is as defined above (i.e., from 1 to 6, usually 1 to 4, and preferably 1); (24) Piperidine V ring:
wherein R50 represents H, alkyl (e.g., methyl), alkylcarbonyl (e.g., -CH3C (0) -), alkyloxycarbonyl (e.g., -C (0) 0-t-C4Hg, -C (0) OC2H5 and -C (0) OCH3), haloalkyl (for example, trifluoromethyl), or -C (0) NH (R10) wherein R10 is H or alkyl; the V ring includes
Examples of the V ring include:
(25) -NHC (0) CH2C6H5 or -NHC (0) CH2-substituted-C6H5, for example, -NHC (0) CH2-p-hydroxyphenyl, -NHC (0) CH2-m-hydroxyphenyl, and - NHC (0) CH2-OH-hydroxyphenyl; (26) -NHC (0) OC6H5; (27) (28) (29)
(30) -OC (0) -heteroaryl, for example
(31) -O-alkyl (e.g., -OCH3); (32) -CF3; (33) -CN; (34) a heterocycloalkyl group of the formula
(35) a piperidinyl group of the formula
wherein R85 is H, alkyl or alkyl substituted with -OH or SCH3; or R20, R21 taken together form a group = 0 and the remainder of R46 is as defined above; or two of R20, R21 and R46 taken together form the piperidine ring V
wherein R50 represents H, alkyl (e.g., methyl), alkylcarbonyl (e.g., CH3C (0) -), alkyloxycarbonyl (e.g., -C (0) 0-t-C4H, -C (0) OC2H5, and -C (0) OCH3), haloalkyl (for example, trifluoromethyl), or -C (O) NH (R10 end where R10 is H or aluyl: the ring V inoluvfi
and examples of the V ring include:
with the condition that R46. R20I and R21 are carbon to which they are attached does not contain more than one heteroatom (i.e., R46, R0 and R21 are selected so that the carbon atom to which they are attached contains 0 or 1 heteroatom); R44 represents
wherein R 25 represents heteroaryl (e.g., pyridyl or pyridyl N-oxide), N-methylpiperidinyl or aryl (e.g., phenyl and substituted phenyl); and R48 represents H or alkyl (e.g., methyl); R54 represents a heterocyclic N-oxide group of the formula (i), (ii), (iii) or (iv):
wherein R56, R58, and R6 ° are the same or different and each is independently selected from H, halo, -CF3, -OR10, -C (0) R10, -SR10, -S (0) eR1 (wherein e is 1 or 2), -N (R10) 2, -NO2, -CO2R10, -OCO2R1 1, -OCOR10, alkyl, aryl, alkenyl or alkynyl, alkyl which may be substituted with -OR10, -SR10 or -N (R 0) 2 and alkenyl which may be substituted with OR 1 1 or SR 1 1; or R54 represents a heterocyclic N-oxide group of the formula (ia), (ia), (iiia) or (iva):
where Y represents N + -0 'and E represents N; or R54 represents an alkyl group substituted with one of said heterocyclic groups of N-oxide (i), (ii), (iii), (v), (a), (iia), (iiia) or (iva); Z represents O or S so that R can be taken in combination with R5, Rβ, R7 or R8 as defined above, or R represents R 0, R42, R44 or R54.
Examples of R2 °, R21. and R46 for the above formulas include:
Examples of R25 groups include:
wherein Y represents N or NO, R28 is selected from the group consisting of: Ci to C4 alkyl, halo, hydroxy, NO2, amino (-NH2), -NHR30, and -N (R30) 2 wherein R30 represents alkyl from C1 to C6 - In one embodiment, the following tricyclic amide is included with an anti-IGFR antibody:
(lonafarnib; Sarasar ™; Schering-Plow; Kenilworth, NJ). In another embodiment, one of the following FPT inhibitors is included with an anti-IGFR antibody:
; or
FPT inhibitors, which can be included with an antibody
anti-IGFR include BMS-214662 (; Hunt et al., J.
Med. Chem. 43 (20): 3587-95 (2000); Dancey eí al., Curr. Pharm. Des. 8: 2259-2267 (2002); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1 H -imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-thienylsulfonyl) -1 H-1, 4-benzodiazepine)) and R155777 (tipifarnib; Garner et al., Drug Metab, Dispos. 30 (7): 823-30 (2002); Dancey et al., Curr. Pharm., Des. 8: 2259-2267 (2002) ); (B) -6- [amino (4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) -methyl] -4- (3-chlorophenyl) -1-methyl-2 (1 H) -quinolinone];
which is sold as Zamestra ™; Johnson & Johnson; New Brunswick, NJ). Inhibitors that antagonize the action of the EGF or HER2 receptor, which may be included with an anti-IGFR, include trastuzumab (sold as Herceptin®, Genentech, Inc., S. San Francisco, CA); CP-724714 Suppl 1: 33-40 (2000); ZD-1893; 4- (3-chloro-4-fluoranilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline; sold as Iressa ™; AstraZeneca;
Wilmington, DE; ); OSI-774
l.
19 (1-GW2016; Rusnak et al., Molecular Cancer Therapeutics 1: 85-94 (2001); N- { 3-Chloro-4 - [(3-fluorobenzyl) oxy] phenyl.}. -6- [ 5- ( { [2- (Methylsulfonyl) ethyl] amino.} Methyl) -2-furyl] -4-quinazolinamine; PCT Application No. W099 / 35146), Canertinib (CI-1033;
(Abgenix, Inc., Freemont, CA, Yang et al., Cancer Res. 59 (6): 1236-43 (1999); Yang et al., Crit Rev Oncol Hematol. 38 (1): 17-23 (2001). )), erbitux (US Patent No. 6,217,866; IMC-C225, cetuximab; Imclone; New York, NY), EKB-569
75166), GW-572016, any anti-EGFR antibody and any anti-HER2 antibody. Numerous other small molecules that have been described as useful for inhibiting EGFR can be combined with an anti-IGFR antibody. For example, U.S. Patent 5,656,655, describes styryl-substituted heteroaryl compounds, which inhibit EGFR. U.S. Patent 5,646,153 describes mono and / or bicyclic arylheteroarylcarbocyclic and heterocarbocyclic bis compounds that inhibit EGFR and / or PDGFR. U.S. Patent 5,679,683 describes tricyclic pyrimidine compounds that inhibit EGFR. U.S. Patent 5,616,582 discloses quinazoline derivatives having tyrosine kinase receptor inhibitory activity. Fry et al., Science 265 1093-1095 (1994) describes a compound having a structure that inhibits EGFR (see Figure 1 of Fry et al.). U.S. Patent 5,196,446, describes heteroarylenediyl or heteroarylenediilaryl compounds that inhibit EGFR. Panek, et al., Journal of Pharmacoiogy and Experimental Therapeutics 283, 1433-1444 (1997) describe a compound identified as PD166285 that inhibits the EGFR, PDGFR, and FGFR receptor families. PD166285 is identified as 6- (2,6-dichlorophenyl) -2- (4- (2-diethylaminoethoxy) phenylamino) -8-methyl-8H-pyrido (2,3-d) pyrimidin-7-one. VEGF receptor inhibitors, which can be combined with an anti-IGFR antibody, include PTK787 / ZK 222584 (Thomas et al., Semin Oncol.30 (3 Suppl 6): 32-8 (2003)) and the anti-VEGF antibody. humanized Bevacizumab (sold under the trade name Avastin ™; Genentech, Inc .; South San Francisco, CA). MAP kinase inhibitors that can be combined with an anti-IGFR antibody, include VX-745 (Haddad, Curr Opin, Investigation Drugs 2 (8): 1070-6 (2001)).
MAP kinase kinase (MEK) inhibitors, which can be combined with an anti-IGFR antibody, include PD 184352 (Sebolt-Leopold, et al., Nature Med. 5: 810-816 (1999)). Inhibitors of mTOR, which can be combined with an anti-IGFR antibody, include rapamycin and CCI-779 (Sehgal et al., Med. Res. Rev., 14: 1-22 (1994); Elit, Curr. Opin. Drugs 3 (8): 1249-53 (2002)). The p13 kinase inhibitors, which may be combined with an anti-IGFR antibody, include LY294002, LY292223, LY292696, LY293684, LY293646 (Vlahos et al., J. Biol. Chem. 269 (7): 5241-5248 (1994)) and wortmannina. Raf inhibitors, which may be combined with an anti-IGFR antibody, include BAY-43-9006, (Wilhelm et al., Curr. Pharm.Des 8: 2255-2257 (2002)), ZM336372, L-779,450 or another Raf inhibitor described in Lowinger et al., Curr. Pharm Des. 8: 2269-2278 (2002). Cyclin-dependent kinase inhibitors, which can be combined with an anti-IGFR antibody, include flavopiridol (L86-8275 / HMR 1275, Senderowicz, Oncogene 19 (56): 6600-6606 (2000)) and UCN-01 (7). -hydroxy staurosporine; Senderowicz, Oncogene 19 (56): 6600-6606 (2000)). IGF / IGFR inhibitors, which can be combined with an anti-IGFR antibody, include the IGF inhibitor peptides, (Request for
US Patent Published No. 20030092631 A1; Publications of the
PCT Application Nos. WO 03/27246 A2; WO 02/72780), 4-amino-5-phenyl-7-cyclobutyl-pyrrolo [2,3-d] pyrimidine derivatives such as those described in Publication No. WO 02/92599 of the PCT Application (e.g.
), flavonoid glycosides such as quercetin (PCT Application Publication No. WO 03/39538) and anti-IGFR1 antibodies other than those of the present invention. Other anti-IGFR1 antibodies, which can be combined with an anti-IGFR antibody of the invention, have been described, for example, in
French Patent Applications FR2834990, FR2834991 and FR2834900 and in the Publications of PCT Applications Nos. WO 03/59951; WO
04/71529; WO 03/106621; WO 04/83248; WO 04/84456 and WO 02/53596. Agents that inhibit the production of IGF, which can be combined with an anti-IGFR antibody, include octreotide (L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptopyl-L-lysyl-L-threonyl-N - [2-hydroxy-1 - (hydroxymethyl) propyl] -, (2_7) -cyclic disulfide; [RR *, R *) j;
; Katz went to, Clin Pharm. 8 (4): 255-73 (1989); sold as Sandostatin LAR® Depot; Novartis Pharm. Corp; E. Hanover, NJ).
7
Proteasome inhibitors, which can be combined with an anti-IGFR antibody, include bortezomib (
; [(1 R) -3-methyl-1 - [[(2S) -1-oxo-3-phenyl-2 - [(pyrazinylcarbonyl) amino] propyl] amino] butyl] boronic acid; sold as Velcade ™; Millennium Pharm., Inc.; Cambridge, MA). The stabilizers and microtubules and depolymerizers / microtubule inhibitors, which can be combined with an anti-IGFR antibody, include paclitaxel
; sold as Taxol®;
Bristol-Myers Squibb; New York, NY) and docetaxel (
; sold as Taxotere®;
Aventis Pharm, I
vinblastine (
), epothilone B and BMS-
(ImSvm; ü§ ??. "Lee et al., Clin. Cancer Res.
7 (5): 1429-37 (2001)), podofillotoxins and derivatives thereof, which include Etoposide (VP-16;
Temozolomide (
also combined with an anti-IGFR antibody of the invention. Anthracyclines that can be combined with an anti-IGFR antibody include doxorubicin (
as Doxil®; Ortho
Biotech Products L.P .; Raritan, NJ); daunorubicina
(; sold as Cerubidine®; Ben
Venue Laboratories, Inc .; Bedford, OH) and epirubicin (; sold as Ellence®; Pharmacia
& Upjohn Co; Kalamazoo, Ml). Anti-estrogens and selective estrogen receptor modulators (SERMs), which can be combined with the anti-IGFR antibodies of the invention include droloxifene (3-hydroxy tamoxifen), 4-hydroxy tamoxifen
), tamoxifen
(; sold as Nolvadex®; Astra Zeneca;
Wilmington, DE); pipendoxifene
Greenberger etal., Clin. Cancer Res. 7 (10): 3166-77 (2001)); arzoxifene; LY353381; Sato et al., J. Pharmacol. Exp. Ther. 287 (1): 1-7 (1998)); raloxifene (
sold as Evista®; Eli Lilly & Co.; Indianapolis, IN); fulvestrant
(; ICI-182780; sold as Faslodex;
Astra Zeneca; Wilmington, DE); Aneibifen (EM-652;
lasofoxifene (CP-336,156; e e al., Endocrinology 139 (4): 2068-76 (1998)); idoxifen (pyrroiidino-4-yodotamoxifen;
; Nuttall et al., Endocrinology 139 (12): 5224-34 (1998)); TSE-424 (
; Bazedoxifene; WAY-140424); HMR-3339yZK-186619. Aromatase inhibitors, which may be included with an anti-IGFR antibody, include anastrazole (
; Dukes et al., J. Steroid.
Biochem. Mol. Biol. 58 (4): 439-45 (1996)), letrozole (
; sold as Femara®; Novartis Pharmaceuticals Corp .; E. Hanover, NJ) and exemestane (
sold as Aromasin®; Pharmacia Corp .; Kalamazoo, Ml). Oxaliplatin (
sold as Eloxatin ™ by Sanofi-Synthelabo Inc .; New York, NY), may also be combined with an anti-IGFR antibody of the invention.
An anti-IGFR antibody can also be combined with gemcitabine HCl (
) with retinoic acid or any IGFR inhibitor set forth in any of Mitsiades et al., Cancer Cell 5: 221-230 (2004); Garcia-Echeverria eí. al., Cancer Cell 5: 231-239, 2004; WO 2004/030627 or WO 2004/030625. Topoisomerase inhibitors that can be combined with an anti-IGFR antibody include camptothecin (
; Stork e al., J. Am. Chem. Soc.
93 (16): 4074-4075 (1971); Beisler et al., J. Med. Chem. 14 (11): 1116-1117 (1962)), topotecan
(", sold as Hycamtin®; GlaxoSmithKIine, Research Triangle Park, NC; Rowinski et al., J. Clin. Oncol. 10 (4): 647-656 (1992)), etoposide) and irinotecan (
; sold as Camptosar®; Pharmacia & Upjohn Co .; Kalamazoo, Ml). Antisense oligonucleotides which are complementary to the IGFR1 mRNA, IGF-1 or IGF-2 gene can be produced and can be used to inhibit the transcription or translation of the genes. The production of antisense oligonucleotides effective for therapeutic uses is well known in the art. Antisense oligonucleotides are often produced using derived or modified nucleotides to increase half-life or bioavailability. The primary sequence of the IGFR1, IGF-1 or
IGF-2 can also be used to design ribozymes. Most synthetic ribozymes are generally hammerhead, tetrahimena and haripin ribozymes. Methods for designing and using ribozymes to dissociate specific RNA species are well known in the art.
Chemical structures and other useful information regarding many of the preceding agents can be found in the Phvsicians' Desk Reference. 57th ed., 2003; Thompson PDR; Montvale, NJ
The categorization of a particular agent within a particular class (e.g., FPT inhibitor or microtubule stabilizer) is effected solely for descriptive purposes and in no way signifies a limitation of the invention.
The scope of the present invention includes compositions and methods comprising an anti-IGFR antibody together with one or more of the preceding chemotherapeutic agents or any salt, hydrate, isomer, solvate formulation or prodrug thereof.
Pharmaceutical compositions
A combination, or any component thereof, according to the invention can be incorporated into a pharmaceutical composition, together with a pharmaceutically acceptable carrier, suitable for administration to a subject in vivo. The scope of the present invention includes pharmaceutical compositions that can be administered to a subject by any route, such as non-parenteral route (eg, oral, ocular, topical or pulmonary (inhalation)) or parenterally (eg, intratumoral injection). , intravenous injection, intraarterial injection, subcutaneous injection or intramuscular injection). In one embodiment, the pharmaceutical compositions of the invention comprise an antibody comprising 15H12 / 19D12 LCF and 15H12 / 19D12 HCA in association with one or more chemotherapeutic agents and a pharmaceutically acceptable carrier.
As stated above, combinations of the invention include the component of the binding composition of the chemotherapeutic agent "in association" with one another. The term "in association" indicates that the compounds of the combinations of the invention can be formulated in a single composition to be released simultaneously or can be formulated separately into two or more compositions (e.g., a kit). For example, the scope of the present invention includes combinations comprising an anti-IGFR1 antibody formulated for parenteral (e.g. intravenous) administration to a subject, and a chemotherapeutic agent formulated to be orally released (e.g., pill, tablet, capsule). Alternatively, both components of the combination can be formulated separately or together, for parenteral release or non-parenteral release (for example oral).
For general information with reference to the formulations, see for example Gilman, et al., (Eds.) (1990), The Pharmacological Bases of Therapeutics. 8th Ed., Pergamon Press; A. Gennaro (ed.), Remington's Pharmaceutical Sciences. 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania; Avis, ei al., (Eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications Dekker, New York; Lieberman, et al., (Eds.) (1990) Pharmaceutical Dosage Forms: Tablets Dekker, New York; and Lieberman, et al., (eds.) (1990), Pharmaceutícal Dosage Forms: Disperse Systems Dekker, New York, Kenneth A. Walters (ed.) (2002) Dermatological! and Transdermal Formulations (Drugs and the Pharmaceutical Sciences), Vol 119, Marcel Dekker.
The pharmaceutically acceptable carriers are conventional and are well known in the art. Examples include aqueous and non-aqueous carriers, stabilizers, antioxidants, solvents, dispersion media, coatings, antimicrobial agents, pH regulators, whey proteins, isotonic and absorption-delaying agents, and the like, which are physiologically compatible. Preferably, the carrier is appropriate to be injected into the body of a subject. Examples of aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and appropriate mixtures thereof, vegetable oils, such as olive, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained for example by the use of coating materials such as lecithin, for the maintenance of the required particle size in the case of dispersions, and for use as surfactants. Stabilizers, such as α, α-trehalose dihydrate, may be included to stabilize the antibody molecules of the invention against the degrading effects of desiccation or freeze drying. Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; and oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. The prevention of the presence of microorganisms can be ensured either by sterilization procedures, or by the inclusion of various antimicrobial agents such as EDTA, EGTA, paraben, chlorobutanol, phenol, sorbic acid and the like.
Suitable pH regulators that can be included in the pharmaceutical compositions of the invention include pH regulators based on L-histidine, phosphate-based pH regulators (eg, phosphate buffered saline, pH ~ 7), pH regulators based on phosphate or pH regulators based on glycine.
Serum proteins that can be included in the pharmaceutical compositions of the invention can include human serum albumin.
Isotonic agents, such as sugars, ethanol, polyalcohols (for example glycerol, propylene glycol, liquid polyethylene glycol, mannitol or sorbitol), sodium citrate or sodium chloride may also be included.
(for example saline regulated pH), in the pharmaceutical compositions of the invention.
Prolonged absorption of an injectable pharmaceutical form can be accomplished by the inclusion of agents that can delay absorption such as aluminum monostearate and / or gelatin.
Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils.
The pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of said media and agents for pharmaceutically active substances is well known in the art. Sterile injectable solutions can be prepared by incorporating a combination of the invention or any component thereof (e.g., a binding composition and / or a chemotherapeutic agent), in the required amount in an appropriate solvent, optionally with one or a combination of ingredients listed above, as required, followed by microfiltration by sterilization. In general, dispersions are prepared by incorporating the active ingredient (e.g., a binding composition and / or a chemotherapeutic agent) into a sterile vehicle that contains a basic dispersion medium and the other ingredients required among those that have been listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying (lyophilization) which provide a powder of the active ingredient in addition to any additional desired ingredient, of a solution previously filtered by sterilization thereof. A combination of the invention or any component thereof (e.g., a binding composition and / or a chemotherapeutic agent) can also be administered orally. Pharmaceutical compositions for oral administration may include additives and carriers such as starch (eg, potato, corn or wheat starch or cellulose), starch derivatives (eg, silica or microcrystalline cellulose), sugars (eg, lactose), talc, lactose , stearate, magnesium carbonate or calcium phosphate. To ensure that the oral compositions are well tolerated by the patient's digestive system, mucus formers or resins may be included. It may also be desirable to improve the tolerance for formulation in a capsule that is insoluble in gastric juices. An example of a pharmaceutical composition of this invention in the form of a capsule is prepared by filling a conventional two-part hard gelatin capsule with the combination of the invention or with any component thereof in powder form, lactose, talc and magnesium stearate. . Oral administration of immunoglobulins has been described (Foster, et al., (2001) Cochrane Datbase System rev. 3: CD001816). A combination of the invention or any component thereof (e.g., a binding composition and / or a chemotherapeutic agent) in a pharmaceutical composition for topical administration may also be included. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site at which treatment is required, such as liniments, lotions, creams, ointments or pastes, and appropriate drops for administration in the eyes, ears or nose.
The drops according to the present invention can comprise sterile aqueous or oily solutions or suspensions and can be prepared by dissolving the combination of the invention or any component thereof (eg a binding composition and / or a chemotherapeutic agent) in an aqueous solution. of a bactericidal and / or fungicidal agent and / or any other appropriate preservative, and preferably including a surface active agent. The resulting solution can then be clarified by filtration. Lotions according to the present invention include lotions that are suitable for application to the skin or eyes. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and which can be prepared by methods similar to those for the preparation of the drops. Lotions or liniments for application to the skin may also include an agent that accelerates drying and cools the skin such as an alcohol or acetone, and / or a humectant such as glycerol or an oil such as castor oil or arachis oil. . The creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They can be prepared by mixing the combination of the invention or any component thereof in the form of a powder or finely divided alone or in solution or in suspension in an aqueous or non-aqueous fluid with the aid of appropriate machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor oil or olive oil; wool fat or its derivatives, or a fatty acid such as stearic acid or oleic acid together with an alcohol such as propylene glycol or macrogels. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or nonionic surface active agent such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as siliceous silicas and other ingredients such as lanolin may also be included. A combination of the invention or any component thereof (e.g., a binding composition and / or a chemotherapeutic agent) can also be administered by inhalation. A pharmaceutical composition suitable for inhalation may be an aerosol. An example of a pharmaceutical composition for inhalation of a combination of the invention or any component thereof may include: an aerosol container with a capacity of 15-20 ml comprising the active ingredient (e.g., a binding composition and / or a chemotherapeutic agent), a lubricating agent such as polysorbate 85 or oleic acid, dispersed in a propellant such as freon preferably in a combination of 1,2-dichlorotetrafluoroethane and difluorchloromethane. Preferably, the composition is an appropriate aerosol container adapted for administration by intranasal or oral inhalation.
Dosage Preferably, a combination of the invention is administered to a subject in a "therapeutically effective dose" or "therapeutically effective amount" which preferably inhibits a disease or disorder (e.g., the growth of a tumor) to any degree-preferably at less than about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80% -100% relative to untreated subjects. The ability of a combination of the invention or any component thereof to inhibit cancer can be evaluated in a system of an animal predictor of efficacy in human tumors. Alternatively, this property can be evaluated by examining the ability of a combination of the invention or any component thereof to inhibit the growth of tumor cells in vitro by assays well known to those skilled in the art. A person skilled in the art will be able to determine such amounts based on factors such as the weight of the subject, the severity of the subject's symptoms, and the particular composition or route of administration selected. Dosage regimens can be adjusted to provide the desired optimal response (e.g., a therapeutic response). For example, a dose may be administered, several divided doses may be administered over time, or the dose may be reduced or increased proportionally as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in unit dosage forms to facilitate administration and uniformity of dosage. A physician or veterinarian with ordinary skill in the art can easily determine and prescribe the effective amount of pharmaceutical composition required. For example, the doctor or veterinarian could begin the doses of antibody or antigen binding fragment according to the invention used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and could gradually increase the dose until obtaining the desired effect. The efficacy of a desired dose or treatment regimen of an antibody or combination of the invention can be determined for example by determining whether the tumor being treated in the subject shrinks or stops growing. The size of the tumor can be easily determined, for example by X-rays, magnetic resonance imaging (MRI) or visually in a surgical procedure.
In general, an appropriate daily dose of a combination of the invention or any component thereof can be that amount which is the lowest effective dose to produce a therapeutic effect. Said effective dose will generally depend on the factors described above. It is preferred that the administration be effected by injection, preferably close to the target site (for example the tumor). If desired, a therapeutically effective daily dose of an antibody or a combination of chemotherapeutic agent / antibody according to the invention, or a pharmaceutical composition thereof in two, three, four, five, six or more sub-doses administered can be administered. separately at appropriate intervals throughout the day. In one embodiment, a "therapeutically effective" dose of any anti-IGFR antibody of the present invention is in the range of about 3 mg / kg (body weight) to about 10 mg / kg (eg, 3, 4, 5, 6, 7, 8, 9 or 10 mg / kg) per day. In a preferred embodiment, a "therapeutically effective dose" of a chemotherapeutic agent is as set forth in the Physicians' Desk Reference 2003 (Thomson Healthcare, 57th edition (November 1, 2002)) which is incorporated herein by reference. For example, in one embodiment, the daily dose of gefitinib is 250 mg / day or the daily dose of paclitaxel is about 135 mg / m2 to about 175 mg / m2.
Methods and therapeutic administration A combination of the invention or an anti-IGFR antibody or antigen-binding fragment thereof can be used according to the invention, alone, to inhibit or reduce the growth or proliferation of any cell, such as a cell malignant, either in vitro (for example, in a cell culture) or in vivo (for example, within the body of a subject suffering from a disease mediated by expression or elevated IGFR1 activity or by elevated expression of its ligand ( for example IGF-I or IGF-II)). Said inhibition or reduction of growth or proliferation of a cell can be achieved by contact of the cell with the combination. A combination of the invention or an anti-IGFR antibody or a fragment of an antigen-binding fragment thereof, alone, according to the invention can be used to treat or prevent any disease or disorder in a subject in need of such treatment or prevention that is mediated, for example, by high expression or activity of IGFR1 or by elevated expression of its ligand (eg, IGF-I or IGF-II)) and that can be treated or prevented by modulation of binding, activity or expression to the IGFR1 ligand. Preferably, the disease or disorder is mediated by an increasing level of IGFR1, IGF-I or IGF-II, and is treated or prevented by decreasing IGFR1 ligand binding activity (eg, autophosphorylation activity) or expression. Preferably, the disease or disorder is malignant, more preferably a malignant tumor characterized in that it is a tumor expressing IGFR1, such as, but not limited to, bladder cancer, Wilm cancer, bone cancer, prostate cancer, lung cancer. , colorectal cancer, breast cancer, cervical cancer, synovial sarcoma, ovarian cancer, pancreatic cancer, benign prosthetic hyperplasia (BPH), diarrhea associated with metastatic carcinoids and tumors that secrete vasoactive intestinal peptides (eg, VIPoma or Werner syndrome) Morrison). Acromegaly can also be treated with a combination of the invention. Antagonism of IGF-I has been reported for the treatment of acromegaly (Drake, et al., (2001) Trends Endocrin, Metab.12: 408-413). Other non-malignant medical disorders that can also be treated in a subject by administration of a combination of the invention include gigantism, psoriasis, atherosclerosis, restenosis of smooth muscle of blood vessels or inappropriate microvascular proliferation, such as that found as a complication of diabetes, especially rheumatoid arthritis of the eyes, Grave's disease, multiple sclerosis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, autoimmune thyroiditis and Bechet's disease. The term "subject" can refer to any organism, preferably to an animal, more preferably to a mammal (e.g. rat, mouse, dog, cat, rabbit) and more preferably a human being. In one embodiment of the invention, when possible, a composition of the invention is administered to a subject according to the Physicians' Desk Reference 2003 (Thomson Healthcare, 57th edition (November 1, 2002)). A combination of the invention or any component thereof can be administered by an invasive route such as by injection (see above). Administration by a non-invasive route (e.g., orally, e.g., in a pill, capsule or tablet) is also within the scope of the present invention. In one embodiment of the invention, an anti-IGFR antibody of the invention or a pharmaceutical composition thereof, is administered intravenously, subcutaneously, intramuscularly, intraarterially or intratumorally while a chemotherapeutic agent of the invention (e.g. gefitinib (e.g., Iressa ™)) is administered orally in the form of a tablet. In another embodiment, the chemotherapeutic agent is paclitaxel (e.g., Taxol®) which is administered intravenously. The compositions can be administered with medical devices known in the art. For example, a pharmaceutical composition of the invention can be administered by injection with a hypodermic needle. The pharmaceutical compositions of the invention can also be administered with a needleless hypodermic injection device.; such as the devices described in U.S. Patent Nos. 6,620,135; 6,096,002; 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824 or 4,596,556.
Examples of well-known implants and modules for administration of the pharmaceutical compositions include: US Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled regimen; U.S. Patent No. 4,447,233 which describes a medication infusion pump to deliver the medication to a precise infusion regimen; U.S. Patent No. 4,447,224 which discloses an implantable variable flow infusion apparatus for continuous drug delivery; U.S. Patent No. 4,439,196 which discloses an osmotic drug delivery system, which has multi-chamber compartments. Many other implants, delivery systems, and modules are well known to those skilled in the art.
Equipment The present invention also provides equipment comprising the components of the combinations of the invention in the form of a device. A kit of the present invention includes one or more components that include, but are not limited to, a binding composition, as discussed herein, that binds specifically to IGFR1 (e.g., 19D12 / 15H12 LCF / HCA) in association with one or more additional components that include but are not limited to a chemotherapeutic agent such as that discussed herein. The binding composition and / or the chemotherapeutic agent can be formulated as a pure composition or in combination with a pharmaceutically acceptable carrier in a pharmaceutical composition. In one embodiment, the kit includes a binding composition of the invention (e.g., 19D12 / 15H12 LCF / HCA) or a pharmaceutical composition thereof in a container (e.g., in a sterilized glass or plastic bottle) and an agent chemotherapeutic or a pharmaceutical composition thereof in another container (for example in a sterilized plastic or glass bottle). In another embodiment of the invention, the kit comprises a combination of the invention that includes a component of a binding composition (for example 19D12 / 15H12 LCF / HCA) together with a component of a chemotherapeutic agent formulated together, optionally, with a pharmaceutically acceptable carrier, in a pharmaceutical composition, in a single common container.
If the kit includes a pharmaceutical composition, for parenteral administration to a subject, the equipment may include a device for carrying out said administration. For example, the equipment may include one or more hypodermic needles or other injection devices such as those discussed above.
The team can include a package insert that includes
Information concerning the pharmaceutical compositions and dosage forms of the equipment. Generally, such information helps patients and physicians to use the packaged pharmaceutical compositions and dosage forms in an effective and safe manner. For example, the following information may be provided in the insert with respect to the combination of the invention: pharmacokinetics, pharmacodynamics, clinical studies, efficacy parameters, indications and use, contraindications, warnings, precautions, adverse reactions, overdose, appropriate dose and administration, the form of supply, adequate storage conditions, references, manufacturer / distributor information and patent information.
EXAMPLES
The following examples are provided to further describe the present invention and should not be construed as limiting the scope of the invention in any of its forms.
EXAMPLE 1 Proliferation assay using an anti-IGFR1 antibody and a chemotherapeutic agent
The ability of the culture cells to proliferate when exposed to various concentrations of the wild type 19D12 / 15H12 antibody or the 19D12 / 15H12 LCF / HCA anti-IGFR1 antibody and either paclitaxel, gefitinib, lonafarnib 4-hydroxy tamoxifen or doxorubicin is evaluated in this example.
Preparation of the cell
H322 NSCLC or MCF7 cells were cultured for several passages not exceeding 80% confluence in filtered flasks treated with TC T-75. The cells were trypsinized, counted and resuspended at a concentration of 25,000 cells / ml in RPMI medium with 10% HI-FBS (heat inactivated fetal bovine serum) containing NEAA (non-essential amino acids). L-Glu, vitamins MEM and PS. 100ul of cell suspension (2500 cells) was added to each well of a 96-well, clear bottom black BD Falcon plate treated with CT. The cells were allowed to attach and spread overnight at 37 ° C. The 10% RPMI solution was replaced with 100μl of RPMI containing 2% HI-FBS containing NEAA, L-Glu, vitamins MEM and PS.
Preparation of the solution All test reagents were prepared in RPMI containing 2% HI-FBS at a concentration of 20X and diluted serially for a total of 10 assay concentrations per treatment. Each assay site was prepared in triplicate in separate assay plates. Each plate included experimental wells containing either (i) the 19D12 / 15H12 antibody and paclitaxel, (i) the 19D12 / 15H12 antibody and gefitinib; (iii) the antibody 19D12 / 15H12 LCF / HCA and lonafarnib; (iv) the 19D12 / 15H12 antibody and 4-hydroxy tamoxifen; or (v) the 19D12 / 15H12 antibody and doxorubicin together with internal controls that contained either (a) no treatment, (b) reagent 1 (paclitaxel, gefitinib, lonafarnib, 4-hydroxy tamoxifen or doxorubicin) alone, and (c) antibody 19D12 / 15H12 or 19D12 / 15H12 LCF / HCA alone. Reagent 1 and 19D12 / 15H12 or 19D12 / 15H12 LCF / HCA were individually fixed as responses to the dose, as well as in combination with each other. Cell proliferation was measured on day 4. Assay Cell proliferation was measured using the Promega Cell Titer-Glo Luminescent Cell Viability Assay (Promega Corp, Madison, Wl). This assay provided a method to determine the amount of viable cells in the culture based on the quantification of ATP in the culture, which indicates the presence of metabolically active cells. The test reagents and the test plates were equilibrated at room temperature and prepared immediately before addition to the test plates. One volume of assay reagent was added to each well of the assay plate and agitated on an orbital platform for at least ten minutes to allow equilibration of the ATP reaction and to ensure total lysis of all cells on the test plate. The reaction had a half-life of five hours but in no case effected 10
the reading after 30 minutes after the addition of the reagent. The luminescence was detected in a Wallac 420 Plate Reader with stacker. The results of these experiments are shown below in Tables 2-6. The units in the tables (proliferation index) are arbitrary and are proportional to the number of viable cells observed in the culture under each respective disorder. The data from the "no treatment" experiments indicate the rate of proliferation observed in the absence of any drug (ie, antibody or chemotherapeutic composition). In Tables 2-6, "ug" indicates micrograms and "uM" indicates micromoles.
TABLE 2 Proliferation of H322 NSCLC cells in the presence of anti- body antibodies.
Taxo! (ng / ml) S 1000 200 40 1.6 2 0.064 0.012- 0.0025. 0-100512 s 20 14883 14933 16272 23966 47176 54106 522ES 50233 48568 52870 4 15794 16310 15258 2I95S 41402 48236 51500 49332 48732 4831 OJ I77E2 16948 14S7B 23406 1633 S 52140 51214 49554 53374 52252 0.1- 18754 16032 16574 23634 46632 49704 S406S 53720 5542a 54010
S- 0? 32 17468 16762 14752 2S406 51334 5973 * 53324 50734 58049 60332 ¡? 0.W64 JS0S6 190R0 18210 27712 53038 60690 70632 63172 60690 6S6S2 O-W120 t9952 20250 20094 34790 61030 60,190 71192 65035 62998 71744
| 0XP00256 20876 20890 20222 35418 S8662 6S950 64904 68834 71162 72808
_5 S.12EH5 22304 21462 73232 46896 80714 77044 79658 73562 80006 84546 i 1.02E-0S 25400 23394 2289T 44033 74S4S 77406 7595B 78316 79680 87? 24 3? Taxol (ng / ml) .c. a 200 40 0 I 0.32 0? G4 0.0128 n.fltt-SC 0.000512 20 14870 15094 15452 25194 • 40292 46498 45024 50218 51442 53750 i 4 1651E 15038 15492 __2? s or 33982 45616 4S408 6S6 50517 50264 chili 14796 14110 1 022 219T4 44657 47570 472S0 46848 47332 60384 r > # 0.16 16538 14426 14312 22256 41066 52DS0 52339 £ 4362 61SB4 49BT2
£ - * asna 17S74 17616 16876 Z75T0 51035 55700 63276 55798 58766 64396 0-3064 21998 18662 IT6S8 30754 S54O0 65974 72874 70T78 72164 70396 g 0.0012 < ! 23030 20380 20806 32318 61330 75383 73734 72076 72602 74059 o.oosz.6 22758 19894 21232 34332 61662 7ES33 71674 72S76 76362 80456
& 5.121.05 21702 22424 22344 39334 670S5 6636 »742S8 72708 73390 77974 1? 2E? 5 23323 22234 71764 3S960 68346 7090S 71034 74208 73766 7518S
* < Taxol (pg / ml) _f 1 1000 TOO 40 8 1-¡032 0JK4 0? 12S 0JW2S- 0JJOT51Z 20 15334 14704 13960 23694 41147 44472 48242 48976 46744 48044 4 16416 1S484 15SO0 21644 37994 45112 43838 48S9D 49494 51944
1 0.0 14844 14994 ISS1G 21136 37026 4T134 46824 47710 48653 48484 0.16 16762 16766 15532 23T70 43976 49102 495EB 51606 52426 51598 0X0? 19140 ITISO 17670 27456 55760 616B8 65654 65422 60994 59536 0.0064 22596 20462 20124 29964 S7072 76988 7129S 74152 69218 68814 S 0.0I12U 23930 21322 23646 33882 62218 73947 7E0TD 79882 76866 78952 H 0.0002SG 24970 21794 22122 33302 62960 83316 80T68 6S064 77932 75714 S 5.12E 5 21220 19870 20390 3B634 66106 74250 79393 72524 68150 69686 or & -U? EJK 21408 21358 20574 37962 68052 S7S64 73422 72328 74388 72110 1 I _f? B S5I0S 50680 49038 56114 57446 51626 S2490 46302 44120 a 4 48804 49992 5050B 47256 £ 6998 54936 51436 44703 42312 a =. o.ß 47470 5201O «9636 55228 53703 56984 49396 47060 40944 d 0.16 59594 S2620 53196 55123 63138 5B778 50902 43702 51550 0.032 67110 60794 60018 584Z2 S9S0E 65230 63764 61432 59276 eye» 79014 7-5ST 69060 64B18 74062 76374 63206 7022S 51654 § s 0 ? O12S 77870 7B5D2 70644 72430 75326 82604 64198 72520 77014 0.0002 »74154 8333? 74100 B4234 83206 83634 82674 71784 73420 5.12C4JS 87030 83536 79310 79650 S0294 88S40 86762 74996 74406
1000 25882 24582 23334 23712 25990 24 = 22 24842 20306 20332 700 23650 23668 23164 23482 24314 25752 239G0 2I 20 19372 40 25204 22624 22020 22956 24152 23300 24834 22462 22160 0 33SS 34598 31 £ 56 36038 35906 34498 53256 41416 38354 c 1.6 6143Ü 55962 58780 65654 6,345 6,545 7,568 7,556 7,546 7,656 7,556 7,556 7,576 6,745 76081 76081 76081 76081 76077 77077 83545 87640 78068 77570 77570 77526 77570 77570 77570 77570 76070 76070 76070 76370 76970 76370 76970 79270 79270 89290 716S2 72122 77618 81720 80172 76770 72498
in treatment: 71974; 81788; 75410; 75124; 75558; 79618; 77860; 83468; 78992; 79840; 85414; 87962; 84304; 88926; 77074; 86696; 74354; 77454.
TABLE 3 Proliferation of H322 NSCLC cells in the pree of anti-IGFR1 19D12 / 15H12 and gefitinib ("Iressa") antibodies
lroeea { nM) __ooao 4000 eco ico 32 64? .te 025d 00512 001024 20 S558 15828 19263 21734 31862 «1595 47762 52134 55934 6112B 4 10375 16138 20236 24352 33156 41640 43994 54620 £ - (205 62870 08 101 B 16045 19B10 23G68 350G2 45258 50218 49512 53KJ4 60038 o.te 8932 159Z2 22342 2B574 35768 51783 50193 58236 59784 6S564 0.032 10334 20756 22894 36754 34428 41602 47362 4S520 4SU66 60414
S 0.0064 9272 23412 27042 29930 41028 48906 52394 58162 55702 65372 5 0.00128 1 1306 26630 31304 33550 46508 55014 56390 56336 59654 74452 i 0000256 11030 25926 3167B 33980 41866 55438 55030 55860 55694 76508 5.I2E-05 11312 25776 32iee 34046 503S6 E9746 61846 56170 61912 77B56 1 02E-r_5 114. »25536 31772 33518 43816 55198 56520 60394 62178 75432 Irasa (nlU) 20000 4000 800 160 64 1.28 0.256 0.0512 0.01C34 20 10256 14646 19414 2074T 26104 29688 36636 34063 38366 44984 t 4 7434 13982 18762 20553 23708 31514 3387B 33178 33814 43776
2 or ß..ee 9 9445500 15536 17874 2034 26830 37782 35146 37854 33790 48940 0 ..1166 8 8221166 16648 20086 21762 27672 3S674 37632 38746 43660 50204 0.0 B322 1 100660000 20332 24214 26092 37170 43970 45310 47656 50738 58834
ü 0 000006644 9 9447722 23840 27740 31753 «3434 49736 52576 53350 56270 69503 d 0" 0-012"8" 1Q994 25304 30786 35254 46102 51-56 57464 53340 6"8572 74S5G 0000256 11074 2" 5"614- 30444" 345"45" 4"" 46'8"0 S" 32"B" 4 S "75" S "2 5" 6 ~ 74"3 £ 9_ ~ S4" 70748
__ 5.126-05 10856 2S726 32516 33914 45230 53468 59308 58268 61B42 74782 e¡ 1.02e-05 12316 2722D 32274 36732 44376 5S024 57706 58968 69576 77220 lre * sa (pW) 5 70000 4000 833 160 32 6.4 IJZß 0.256 00512 0.01074
"20 8794 15734 18284 20542 27156 35040 36962 36560 40938 48488
• í 4 7278 14032 18810 20753 23414 32396 33706 338S2 35ES0 46774 fe 0.D 10144 15324 10633 21026 27062 33376 37008 37674 40920 45608
«0.16 8443 15310 19562 22450 26856 34532 37372 39046 4U020 43212 0.032 9564 19962 23350 26014 31130 45406 46394 50528 4B256 60600
00064 9S54 22866 26700 30752 39610 45272 S5464 53 IES 55538 67S54
S 000.128 10746 26120 20034 32110 42170 SD76S S9264 56 28 60524 70960
£ 0.0002 = 6 11152 26246 29536 34322 42410 51262 53546 55492 67306 74614
§_ 5 12E-C5 13086 26320 29186 35546 40932 66044 61442 57638 60426 69352 you 1,026-05 10B94 27054 32100 34B78 44726 52768 62750 60396 65332 73544
2C 58S9S 49444 49155 51033 48730 43594 4S06 < 52120 51960 4 63472 47736 49492 49964 49606 52550 49972 50764 45330 0.0 65622 50708 49757 4930G 49694 53460 50044 48780 49206 0.16 67002 £ 1304 S3J6Ó 49398 50474 53774 52510 48004 49650 0 032 82944 £ 5364 59636 64806 60S90 58934 SS9S8 61) 178 € 3730 00064 100862 69748 72446 68396 6,384 7,730 7,394 7 7,330 7,730 77430 77472 77972 7754 77530 77530 77530 73530 79430 77430 77430 77430 77430 77472 77972 77860 77560 77560 77560 77530 77530 77430 77430 77430 77460 81360 73360 81372 2CD00 10810 11294 10994 11770 11460 9734 13088 11650 12396 4000 278) 0 24546 24376 26742 3156 24S2S 28442 27026 27738 800 40002 31290 30354 31000 31390 30396 3232 31356 32326 160 43032 32072 3272B 33332 35076 34864 36144 34946 35044 32 53272 41254 40952 44162 42054 43124 45062 41426 4S712 B.4 7158 ? 52692 49154 52268 57264 57770 80032 0.256 73246 58760 53474 57314 53394 59443 6E805 64B54 55753 0.0512 7B032 61018 E9690 63253 53688 60730 74464 65002 59448 No treatment: 107584; 107042; 73770; 80360; 80730; 83682; 82196; 81768; 76594; 74958; 78190; 83348; 81032; 78026; 81010; 81632; 72058; 74778. TABLE 4 Proliferation of H322 NSCLC cells in the presence of anti-IGFR1 19D12 (LCF / HCA) and lonafarnib antibodies
lonafamlb (uM), £ - í5 za § o a 5 S s? S lonafarnlb (uM)
Onafamlb (uM)
se E o.ote .ra unes 15
Without treatment: 114280; 118325; 135058; 129246; 125513; 119709; 134363; 129286; 138048; 132272; 138562; 134026; 135510; 138660; 132918; 131451; 140071; 135689.
TABLE 5 Proliferation of MCF7 cells in the presence of anti-IGFR1 19D12 / 15H12 v 4-hydroxy tamoxifen antibodies
4-HIDROXI TAMOXIFEN (ng / mL)
4-HIDROXI TAMOXIFEN (ng / mL)
4-HIDROXI TAMOXIFEN (ng / mL) eo _f ir'-tso o.a ss s o.ooo2se? E
-_ ssec ftoo z é: g - Without treatment: 38094; 32799; 43225; 30131; 35545; 28400; 35256; 18441; 34641; 24138; 28849; 21562; 36446; 25365; 34561; 21852;
40120; 23587. TABLE 6 Proliferation of MCF7 cells in the presence of anti-lGFR1 19D12 / 15H12 and doxorubicin antibodies
DOXORUBICINE (ug / mL)
r.f? íta DOXORUBYCIN (ug / mL)% ü o.a o s DOXORUBICIN (ug / mL) • ^ &r * s s If § or more or 12
sis § V 8 0.16 §_ 0 032 or 0.0064 or oo? 28 __ > 5 ? ___. : o.e z o m or o X o No treatment: 126997; 128567; 116244; 117342; 112806; 114636; 122023; 117403; 121666; 112160; 123333; 118499; 117737; 120728; 115823; 128693; 124935; 126222.
EXAMPLE 2 Assay of inhibition of the anti-IGFR and paclitaxel tumor in vivo using a xenoinqerto model H322. NSCLC.
In this example, the efficacy of an anti-IGFR paclitaxel combination of the invention for the inhibition of tumor growth was demonstrated in vivo. They were inoculated five million human NSCLC H322 cells in Matrigel subcutaneously in mice without having been subjected to prior treatment. Treatment with anti-IGFR 19D12 antibody and / or paclitaxel was started when the tumor size had reached -105-115 mm3 on day 0. Doses of both 19D12 and paclitaxel were administered twice a week. Anti-IGFR 19D12 antibody doses were administered at a rate of 0.5 mg per mouse. Paclitaxel at 15 mpk. Ten animals per group. The tumor volumes were measured with Labcat.
TABLE 7 Inhibition of tumor growth in mice
The present invention is not limited in scope by the specific embodiments described herein. In fact, various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description and the accompanying figures. Said modifications fall within the scope of the appended claims.
Patents, patent applications, access numbers to
Genbank and publications cited throughout this application, whose descriptions, particularly, inclu the antibody amino acid sequences and the chemical structures described are incorporated herein by reference.
Claims (29)
1. - A combination comprising: (a) one or more binding compositions comprising a member selected from the group consisting of: a light chain amino acid sequence comprising CDR-L1 defined by SEQ ID NO: 5, CDR-L2 defined by SEQ ID NO: 6 and CDR-L3 defined by SEQ ID NO: 7; and a heavy chain amino acid sequence comprising CDR-H1 defined by SEQ ID NO: 8 or 12, CDR-H2 defined by SEQ ID NO: 9 and CDR-H3 defined by SEQ ID NO: 10; in association with (b) one or more chemotherapeutic agents.
2. The combination according to claim 1, further characterized in that the binding composition comprises an isolated light chain amino acid sequence comprising CDR-L1 defined by SEQ ID NO: 5. CDR-L2 defined by SEQ ID NO: 6 and CDR-L3 defined by SEQ ID NO: 7; and an isolated heavy chain amino acid sequence comprising CDR-H1 defined by SEQ ID NO: 8 or 12, CDR-H2 defined by SEQ ID NO: 9 and CDR-H3 defined by SEQ ID NO: 10.
3 The combination according to claim 2, further characterized in that a binding composition comprises an isolated light chain immunoglobulin comprising amino acids 20-128 of SEQ ID NO: 2 and an isolated heavy chain immunoglobulin comprising amino acids of 20 -137 of SEQ ID NO: 4.
4. The combination according to claim 1, further characterized in that a chemotherapeutic agent is one or more members selected from the group consisting of a taxane, a topoisomerase inhibitor, an inhibitor of signal transduction, a cell cycle inhibitor, a modulator of the IGF / IGFR1 system, a farnesyl protein transferase inhibitor (FPT), an inhibitor of the epidermal growth factor receptor (EGFR), an inhi HER2, a vascular epidermal growth factor receptor (VEGF) inhibitor, an inhibitor of mitogen-activated protein kinase (MAP), an inhibitor of MEK, an inhibitor of AKT, an inhibitor of mTOR, a inhibitor of pl3 kinase, a Raf inhibitor, a cyclin-dependent kinase inhibitor (CDK), a microtubule stabilizer, a microtubule inhibitor, a SERM / Antiestrogen, an aromatase inhibitor, an anthracycline, a proteasome inhibitor, an agent that inhibits production of the insulin-like growth factor (IGF) and an anti-sense inhibitor of IGFR1, IGF-1 or IGF2.
5. The combination according to claim 4, further characterized in that the chemotherapeutic agent is a taxane selected from: paclitaxel and docetaxel.
6. The combination according to claim 4, further characterized in that a chemotherapeutic agent is a microtubular inhibitor selected from: vincristine, vinblastine, a podophyllotoxin, epothilone B, BMS-247550 and BMS-310705.
7. The combination according to claim 4, further characterized in that a chemotherapeutic agent is an inhibitor of the epidermal growth factor receptor (EGFR) selected from: gefitinib, erlotinib, cetuximab, ABX-EGF, lapatanib, canertinib, EKB- 569 and PKI-166.
8. The combination according to claim 4, further characterized in that a chemotherapeutic agent is a transferase inhibitor of farnesyl protein selected from: lonafarnib and tipifarnib (R155777).
9. The combination according to claim 4, further characterized in that a chemotherapeutic agent is an agent selected from the estrogen receptor modulator (SERM) / antiestrogen selected from: tamoxifen, raloxifene, fulvestrant, acoibiphene, pipendoxifen, arzoxifene, toremifene, lasofoxifene , bazedoxifene (TSE-424), idoxifen, HMR-3339 and ZK-186619.
10. The combination according to claim 4, further characterized in that a chemotherapeutic agent is an anthracycline selected from: doxorubicin, daunorubicin and epirubicin.
11. The combination according to claim 4, further characterized in that a therapeutic agent is a HER2 inhibitor selected from: trastuzumab, HKI-272, CP-724714 and TAK-165.
12. The combination according to claim 4, further characterized in that a chemotherapeutic agent is a topoisomerase inhibitor selected from: etoposide, topotecan, camptothecin and irinotecan.
13. A pharmaceutical composition comprising a combination of claim 1 together with a pharmaceutically acceptable carrier.
14. A combination comprising: (a) one or more fully human monoclonal antibodies comprising a light chain immunoglobulin comprising amino acids 20-128 of SEQ ID NO: 2 and a heavy chain immunoglobulin comprising amino acids 20 -137 of SEQ ID NO: 4; in association with (b) one or more chemotherapeutic agents selected from
15. - The use of a combination of claim 1 for preparing a medicament for the treatment or prevention of a medical disorder in a subject, wherein said medical disorder is mediated by an expression or elevated activity of Receptor-1 of the Insulin-like Growth Factor (IGFR1).
16. The use as claimed in claim 15, wherein the binding composition comprises an isolated light chain immunoglobulin comprising amino acids 20-128 of SEQ ID NO: 2 and an isolated heavy chain immunoglobulin which comprises the amino acids 20-137 of SEQ ID NO: 4.
17. The use as claimed in claim 15, wherein a chemotherapeutic agent is one or more members selected from the group consisting of:
18. - The use as claimed in claim 15, wherein the medical disorder is selected from the group consisting of acromegaly, bladder cancer, Wilm cancer, ovarian cancer, pancreatic cancer, benign prostatic hyperplasia, breast cancer, prostate cancer, bone cancer, lung cancer, colorectal cancer, cervical cancer, synovial sarcoma, diarrhea associated with metastatic carcinoid, tumors that secrete vasoactive intestinal peptide, gigantism, psoriasis, atherosclerosis, restenosis of smooth muscle of blood vessels, proliferation inappropriate microvascular disease, rheumatoid arthritis, Grave's disease, multiple sclerosis, systemic lupus erythematosus, Hashimoto's thyroiditis, Myasthenia Grave, autoimmune thyroiditis and Bechet's disease.
19. Use as claimed in claim 15, wherein the drug is parenterally administrable.
20. The use of: one or more fully human monoclonal antibodies comprising a light chain immunoglobulin comprising amino acids 20-128 of SEQ ID NO: 2 and a heavy chain immunoglobulin comprising amino acids 20-137 of the SEQ ID NO: 4; in association with (b) one or more chemotherapeutic agents selected from: , to prepare a medicament for the treatment or prevention of a medical disorder in a subject.
21. The use as claimed in claim 20, wherein the medical disorder is selected from acromegaly, bladder cancer, Wilm's cancer, ovarian cancer, pancreatic cancer, benign prostatic hyperplasia, breast cancer, cancer of the prostate, bone cancer, lung cancer, colorectal cancer, cervical cancer, synovial sarcoma, diarrhea associated with metastatic carcinoid, tumors that secrete vasoactive intestinal peptide, gigantism, psoriasis, atherosclerosis, restenosis of smooth muscle of blood vessels, inappropriate microvascular proliferation , rheumatoid arthritis, Grave's disease, multiple sclerosis, systemic lupus erythematosus, Hashimoto's thyroiditis, Myasthenia Grave, autoimmune thyroiditis and Bechet's disease.
22. A method for inhibiting the growth or proliferation of a malignant cell comprising contacting the cell with a combination of claim 1.
23. The method according to claim 22, further characterized in that the cell is in vitro.
24. The method according to claim 22, further characterized in that the binding composition comprises an isolated light chain immunoglobulin comprising amino acids 20-128 of SEQ ID NO: 2 and an isolated heavy chain immunoglobuyin comprising the amino acids 20-137 of SEQ ID NO: 4.
25.- The method according to claim 22, further characterized in that a chemotherapeutic agent is one or more members selected from the group consisting of:
26. - The method according to claim 22, further characterized in that a cell is selected from a non-small cell lung carcinoma, a breast cancer cell, an ovarian cancer cell, a colorectal cancer cell, a prostate cancer, a pediatric cancer cell and a pancreatic cancer cell.
27. The method according to claim 26, further characterized in that a cell is an NCI-H322 cell, an A2780 cell or an MCF7 cell.
28. A kit comprising: (a) one or more binding compositions comprising a member selected from the group consisting of: an isolated light chain amino acid sequence comprising CDR-L1 defined by SEQ ID NO: 5, CDR-L2 defined by SEQ ID NO: 6 and CDR-L3 defined by SEQ ID NO: 7; and an isolated heavy chain amino acid sequence comprising CDR-H1 defined by SEQ ID NO: 8 or 12, CDR-H2 defined by SEQ ID NO: 9 and CDR-H3 defined by SEQ ID NO: 10; in association with (b) one or more chemotherapeutic agents.
29. The equipment according to claim 28, further characterized in that said binding compositions and said chemotherapeutic agents are in separate containers.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/524,732 | 2003-11-21 |
Publications (1)
Publication Number | Publication Date |
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MXPA06005779A true MXPA06005779A (en) | 2006-10-17 |
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