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  Pharmaceutical Patents  

 

Title:  Insulin-like growth factor antibodies and uses thereof
United States Patent: 
7,939,637
Issued: 
May 10, 2011

Inventors: 
Raeber; Olivia (Redwood City, CA), Gazit-Bornstein; Gadi (Cambridge, MA), Yang; Xiaodong (Palo Alto, CA), Cartlidge; Susan Ann (Macclesfield, GB), Tonge; David William (Macclesfield, GB)
Assignee: 
MedImmune Limited (Cambridge, GB)
Appl. No.: 
11/608,705
Filed: 
December 8, 2006


 

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Abstract

Binding proteins, such as antibodies directed to IGF-II with cross-reactivity to IGF-I and uses of such antibodies are described. In particular, fully human monoclonal antibodies directed to the IGF-II with cross-reactivity to IGF-I are disclosed. Also discussed are nucleotide sequences encoding, and amino acid sequences comprising, heavy and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences spanning the framework regions and/or complementarity determining regions (CDR's), specifically from FR1 through FR4 or CDR1 through CDR3.

Description of the Invention

REFERENCE TO SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled ABXAZ.004A.TXT, created Dec. 8, 2006, which is 65 Kb in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety:

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to binding proteins that bind to insulin-like growth factor-2 (IGF-II) with cross-reactivity to insulin-like growth factor-1 (IGF-I) and uses of such binding proteins. More specifically, the invention relates to monoclonal antibodies directed to IGF-II with cross-reactivity to IGF-I and uses of these antibodies. Aspects of the invention also relate to hybridomas or other cell lines expressing such antibodies.

2. Description of the Related Art

Insulin-like growth factor IGF-I and IGF-II are small polypeptides involved in regulating cell proliferation, survival, differentiation and transformation. IGFs exert their various actions by primarily interacting with a specific cell surface receptor, the IGF-I receptor (IGF-IR) and activating various intracellular signaling cascades. IGFs circulate in serum mostly bound to IGF-binding proteins (IGFBP-1 to 6). The interaction of IGFs with the IGF-IR is regulated by the IGFBPs, and IGFs can only bind to the IGF-IR once released from the IGFBPs (mostly by proteolysis of the IGFBPs). IGF-I can also bind to a hybrid receptor comprised of IGF-IR and insulin receptor (IR) subunits. IGF-II has been shown to bind to the "A" isoform of the insulin receptor.

Malignant transformation involves the imbalance of diverse processes such as cell growth, differentiation, apoptosis, and transformation. IGF-I and IGF-II have been implicated in the pathophysiology of a wide range of conditions, and are thought to play a role in tumorigenesis due to the mitogenic and antiapoptotic properties mediated by the receptor IGF-IR. LeRoith and Roberts, Cancer Lett. 195:127-137 (2003).

IGF-I was discovered as a growth factor produced by the liver under the regulatory control of pituitary growth hormone and was originally designated somatomedin-C. Salmon et al., J. Lab. Clin. Med. 49:825-826 (1957). Both IGF-I and IGF-II are expressed ubiquitously and act as endocrine, paracrine, and autocrine growth factors, through their interaction with the IGF-IR, a trans-membrane tyrosine kinase that is structurally and functionally related to the insulin receptor (IR). IGF-I functions primarily by activating the IGF-IR, whereas IGF-II can act through either the IGF-IR or through the IR-A isoform. LeRoith and Roberts, Cancer Lett. 195:127-137 (2003). Additionally, the interaction of both IGF-I and IGF-II with the IGF-binding proteins may affect the half-life and bioavailability of the IGFs, as well as their direct interaction with receptors in some cases. Rajaram et al., Endocr. Rev. 18:801-831 (1997).

IGF-I has a long-term impact on cell proliferation, differentiation, and apoptosis. Experiments in cultured osteosarcoma and breast cancer cells suggested that IGF-I is a potent mitogen and exerts its mitogenic action by increasing DNA synthesis and by stimulating the expression of cyclin DI, which accelerates progression of the cell cycle from G.sub.1 to S phase. Furlanetto et al., Mol. Endocrinol. 8:510-517 (1994); Dufourny et al., J. Biol. Chem. 272:311663-31171 (1997). Suppression of cyclin D1 expression in pancreatic cancer cells abolished the mitogenic effect of IGF-I. Kornmann et al., J. Clin. Invest. 101:344-352 (1998). In addition to stimulating cell cycle progression, IGF-I also inhibits apoptosis. IGF-I was shown to stimulate the expression of Bcl proteins and to suppress expression of Bax, which results in an increase in the relative amount of the Bcl/Bax heterodimer, thereby blocking initiation of the apoptotic pathway. Minshall et al., J. Immunol. 159:1225-1232 (1997); Parrizas et al., Endocrinology 138:1355-1358 (1997); Wang et al., Endocrinology 139:1354-1360 (1998).

Like IGF-I, IGF-II also has mitogenic and antiapoptotic actions and regulates cell proliferation and differentiation. Compared with IGF-I, high concentrations of IGF-II circulate in serum. High serum IGF-II concentrations have been found in patients with colorectal cancer, with a trend towards higher concentrations in advanced disease. Renehan et al., Br. J. Cancer 83:1344-1350. Additionally, most primary tumors and transformed cell lines overexpress IGF-II MRNA and protein. Werner and LeRoith Adv. Cancer Res. 68:183-223 (1996). Overexpression of IGF-II in colon cancer is associated with an aggressive phenotype, and the loss of imprinting (loss of allele-specific expression) of the IGF-II gene may be important in colorectal carcinogenesis. Michell et al., Br. J. Cancer 76:60-66 (1997); Takano et al., Oncology 59:210-216 (2000). Cancer cells with a strong tendency to metastasize have four-fold higher levels of IGF-II expression than those cells with a low ability to metastasize. Guerra et al., Int. J. Cancer 65:812-820 (1996).

Research and clinical studies have highlighted the role of the IGF family members in the development, maintenance and progression of cancer. Many cancer cells have been shown to overexpress the IGF-IR and/or the IGF ligands. For example, IGF-I and IGF-II are strong mitogens for a wide variety of cancer cell lines, including sarcoma, leukemia, and cancers of the prostate, breast, lung, colon, stomach, esophagus, liver, pancreas, kidney, thyroid, brain, ovary, and uterus. Macaulay et al., Br. J. Cancer 65:311-320 (1992); Oku et al., Anticancer Res. 11: 1591-1595 (1991); LeRoith et al., Ann. Intern. Med. 122:54-59 (1995); Yaginuma et al., Oncology 54:502-507 (1997); Singh et al., Endocrinology 137:1764-1774 (1996); Frostad et al., Eur. J. Haematol 62:191-198 (1999). When IGF-I was administered to malignant colon cancer cells, they became resistant to cytokine-induced apoptosis. Remacle-Bonnet et al., Cancer Res. 60:2007-2017 (2000).

The role of IGFs in cancer is also supported by epidemiologic studies, which showed that high levels of circulating IGF-I and low levels of IGFBP-3 are associated with an increased risk for development of several common cancers (prostate, breast, colorectal and lung). Mantzoros et al., Br. J. Cancer 76:1115-1118 (1997); Hankinson et al., Lancet 351:1393-1396 (1998); Ma et al., J. Natl. Cancer Inst. 91:620-625 (1999); Karasik et al., J. Clin. Endocrinol Metab. 78:271-276 (1994). These results suggest that IGF-I and IGF-II act as powerful mitogenic and anti-apoptotic signals, and that their overexpression correlates with poor prognosis in patients with several types of cancer.

Using knockout mouse models, several studies have further established the role of IGFs in tumor growth. With the development of the technology for tissue specific, conditional gene deletion, a mouse model of liver IGF-I deficiency (LID) was developed. Liver-specific deletion of the igf1 gene abrogated expression of IGF-I mRNA and caused a dramatic reduction in circulating IGF-I levels. Yakar. et al., Proc. Natl. Acad. Sci. USA 96:7324-7329 (1999). When mammary tumors were induced in the LID mouse, reduced circulating IGF-1 levels resulted in significant reductions in cancer development, growth, and metastases, whereas increased circulating IGF-1 levels were associated with enhanced tumor growth. Wu et al., Cancer Res. 63:4384-4388 (2003).

Several papers have reported that inhibition of IGF-IR expression and/or signaling leads to inhibition of tumor growth, both in vitro and in vivo. Inhibition of IGF signaling has also been shown to increase the susceptibility of tumor cells to chemotherapeutic agents. A variety of strategies (antisense oligonucleotides, soluble receptor, inhibitory peptides, dominant negative receptor mutants, small molecules inhibiting the kinase activity and anti-hIGF-IR antibodies) have been developed to inhibit the IGF-IR signaling pathway in tumor cells. One approach has been to target the kinase activity of IGF-IR with small molecule inhibitors. Two compounds were recently identified as small molecule kinase inhibitors capable of selectively inhibiting the IGF-IR. Garcia-Echeverria et al., Cancer Cell 5:231-239 (2004); Mitsiades et al., Cancer Cell 5:221-230 (2004). Inhibition of IGF-IR kinase activity abrogated IGF-I-mediated survival and colony formation in soft agar of MCF-7 human breast cancer cells. Garcia-Echeverria et al., Cancer Cell 5:231-239 (2004). When an IGF-IR kinase inhibitor was administered to mice bearing tumor xenografts, IGF-IR signaling in tumor xenografts was inhibited and the growth of IGF-IR-driven fibrosarcomas was significantly reduced. Garcia-Echeverria et al., Cancer Cell 5:231-239 (2004). A similar effect was observed on hematologic malignancies, especially multiple myeloma. In multiple myeloma cells, a small molecule IGF-IR kinase inhibitor demonstrated a >16-fold greater potency against the IGF-1R, as compared to the insulin receptor, and was similarly effective in inhibiting cell growth and survival. Mitsiades et al., Cancer Cell 5:221-230 (2004). The same compound was injected intraperitoneally into mice and inhibited multiple myeloma cell growth and enhanced survival of the mice. Mitsiades et al., Cancer Cell 5:221-230 (2004). When combined with other chemotherapeutics at subtherapeutic doses, inhibition of IGF-IR kinase activity synergistically reduced tumor burden. Mitsiades et al., Cancer Cell 5:221-230 (2004).

Another approach to inhibit IGF signaling has been the development of neutralizing antibodies directed against the receptor IGF-IR. Various groups have developed antibodies to IGF-IR that inhibit receptor IGF-I-stimulated autophosphorylation, induce receptor internalization and degradation, and reduce proliferation and survival of diverse human cancer cell lines. Hailey et al., Mol Cancer Ther. 1:1349-1353 (2002); Maloney et al., Cancer Res. 63:5073-5083 (2003); Benini et al., Clin. Cancer Res. 7:1790-1797 (2001); Burtrum et al., Cancer Res. 63:8912-8921 (2003). Additionally, in xenograft tumor models, IGF-IR blockade resulted in significant growth inhibition of breast, renal and pancreatic tumors in vivo. Burtrum et al., Cancer Res. 63:8912-8921 (2003); Maloney et al., Cancer Res. 63:5073-5083 (2003). Experiments utilizing chimeric humanized IGF-IR antibodies yielded similar results, inhibiting growth of breast cancer cells in vitro and in tumor xenografts. Sachdev et al., Cancer Res. 63:627-635 (2003). Other humanized IGF-IR antibodies blocked IGF-I-induced tyrosine phosphorylation and growth inhibition in breast and non small cell lung tumors, as well as in vivo. Cohen et al., Clin. Cancer Res. 11:2063-2073 (2005); Goetsch et al., Int. J. Cancer 113:316-328 (2005).

Increased IGF-I levels have also been associated with several non-cancerous pathological conditions, including acromegaly and gigantism (Barkan, Cleveland Clin. J. Med. 65: 343, 347-349, 1998), while abnormal IGF-I/IGF-II receptor function has been implicated in psoriasis (Wraight et al., Nat. Biotech. 18: 521-526, 2000), atherosclerosis and smooth muscle restenosis of blood vessels following angioplasty (Bayes-Genis et al., Circ. Res. 86: 125-130, 2000). Increased IGF-I levels have been implicated in diabetes or in complications associated with diabetes, such as microvascular proliferation (Smith et al., Nat. Med. 5: 1390-1395, 1999).

Antibodies to IGF-I and IGF-II have been disclosed in the art. See, for example, Goya et al., Cancer Res. 64:6252-6258 (2004); Miyamoto et al., Clin. Cancer Res. 11:3494-3502 (2005). Additionally, see WO 05/18671, WO 05/28515 and WO 03/93317.

SUMMARY

Embodiments of the invention relate to binding proteins that specifically bind to insulin-like growth factors and reduce tumor growth. In one embodiment, the binding proteins are fully human monoclonal antibodies, or binding fragments thereof that specifically bind to insulin-like growth factors and reduce tumor growth. Mechanisms by which this can be achieved can include and are not limited to either inhibition of binding of IGF-I/II to its receptor IGF-IR, inhibition of IGF-I/II-induced IGF-IR signaling, or increased clearance of IGF-I/II, therein reducing the effective concentration of IGF-I/II.

Thus, some embodiments provide a fully human isolated specific binding protein that preferentially binds to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor I (IGF-I) and neutralizes IGF-I and IGF-II activity. In certain aspects, the binding protein binds to IGF-II with at least 2.5 times greater affinity than to IGF-I. In other aspects, the binding protein binds to IGF-II with at least 3, at least 4, at least 5, at least 7, at least 10, at least 50, at least 60, at least 100 or at least 150 times greater affinity than to IGF-I.

In some embodiments, the specific binding protein has an EC.sub.50 of no more than 15 nM for inhibiting IGF-I-dependent IGF-I receptor phosphorylation in NIH3T3 cells expressing IGF-IR ectopically. In some aspects, the specific binding protein has an EC.sub.50 of no more than 15 nM, no more than 10 nM, or no more than 8 nM for inhibiting IGF-I-dependent IGF-I receptor phosphorylation in NIH3T3 cells expressing IGF-1R ectopically.

In some embodiments, the specific binding protein has an EC.sub.50 of no more than 5 WM, no more than 4 nM, or no more than 3 nM for inhibiting IGF-II-dependent IGF-I receptor phosphorylation in NIH3T3 cells expressing IGF-1R ectopically.

In other embodiments, the specific binding protein inhibits greater than 70% of IGF-IL dependent proliferation of NIH3T3 cells that express recombinant hIGF-IR with an EC.sub.50 of no more than 25 nM, no more than 20 nM, no more than 15 nM, or no more than 10 nM.

In other embodiments, the specific binding protein inhibits greater than 70% of IGF-I dependent proliferation of NIH3T3 cells that express recombinant hIGF-IR with an EC.sub.50 of no more than 40 nM, no more than 30 nM, or no more than 25 nM.

In certain embodiments, the specific binding protein competes for binding with a monoclonal antibody comprising a variable heavy chain sequence selected from the group consisting of SEQ ID NO.: 2, SEQ ID NO.: 6, SEQ ID NO.: 10, SEQ ID NO.: 14 and SEQ ID NO.: 18, and comprising a variable light chain sequence selected from the group consisting of SEQ ID NO.: 4, SEQ ID NO.: 8, SEQ ID NO.: 12 and SEQ ID NO.: 16.

One embodiment of the invention is a fully human antibody that binds to IGF-I with a Kd less than 500 picomolar (pM). More preferably, the antibody binds with a Kd less than 450 picomolar (pM). More preferably, the antibody binds with a Kd less than 410 picomolar (pM). More preferably, the antibody binds with a K.sub.d of less than 350 pM. Even more preferably, the antibody binds with a K.sub.d of less than 300 pM. Affinity and/or avidity measurements can be measured by BIACORE.RTM., as described herein.

Yet another embodiment of the invention is a fully human monoclonal antibody that binds to IGF-II with a K.sub.d of less than 175 picomolar (pM). More preferably, the antibody binds with a Kd less than 100 picomolar (pM). More preferably, the antibody binds with a Kd less than 50 picomolar (pM). More preferably, the antibody binds with a Kd less than 5 picomolar (pM). Even more preferably, the antibody binds with a K.sub.d of less than 2 pM.

In certain embodiments, the specific binding protein is a fully human monoclonal antibody or a binding fragment of a fully human monoclonal antibody. The binding fragments can include fragments such as Fab, Fab' or F(ab').sub.2 and Fv.

One embodiment of the invention comprises fully human monoclonal antibodies 7.251.3 (ATCC Accession Number PTA-7422), 7.34.1 (ATCC Accession Number PTA-7423) and 7.159.2 (ATCC Accession Number PTA-7424) which specifically bind to IGF-I/II, as discussed in more detail below. The hybridoma producing monoclonal antibody 7.159.2 was deposited on Mar. 7, 2006 at the American Type Culture Collection, 10801 University Boulevard, Manassas, Va. 20110-2209, U.S.A. and has been assigned a deposit number PTA-7424.

In some embodiments the specific binding protein that binds to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), or binding fragment thereof can include a heavy chain polypeptide having the sequence of SEQ ID NO.: 6, and a light chain polypeptide having the sequence of SEQ ID NO.: 8.

The specific binding protein can include a heavy chain polypeptide having the sequence of SEQ ID NO.: 10, and a light chain polypeptide having the sequence of SEQ IDNO.: 12.

The specific binding protein of the invention can include heavy chain polypeptide having the sequence of SEQ ID NO.: 14 and a light chain polypeptide having the sequence of SEQ ID NO.: 16.

In certain embodiments, .the specific binding protein can be in a mixture with a pharmaceutically acceptable carrier.

Another embodiment includes isolated nucleic acid molecules encoding any of the specific binding proteins described herein, vectors having isolated nucleic acid molecules encoding the specific binding proteins, or a host cell transformed with any of such nucleic acid molecules and vectors.

In certain embodiments the specific binding protein that binds to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), or binding fragment thereof does not bind specifically to IGF-II or IGF-I proteins when said proteins are bound to Insulin Growth Factor Binding Proteins.

Further embodiments include methods of determining the level of insulin-like growth factor-II (IGF-II) and insulin-like growth factor I (IGF-I) in a patient sample. These methods can include providing a patient sample; contacting the sample with a specific binding protein that binds to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), or binding fragment thereof; and determining the level of IGF-I and IGF-II in said sample. In some aspects, the patient sample is blood.

Additional embodiments include methods of treating a malignant tumor in a mammal. These methods can include selecting a mammal in need of treatment for a malignant tumor; and administering to the mammal a therapeutically effective dose of a specific binding protein that binds to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), or binding fragment thereof. In some aspects the animal is human. In some aspects the binding protein is a fully human monoclonal antibody, and is selected from the group consisting of mAb 7.251.3 (ATCC Accession Number PTA-7422), mAb 7.34.1 (ATCC Accession Number PTA-7423), and mAb 7.159.2 (ATCC Accession Number PTA-7424).

Treatable diseases can include melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, thyroid tumor, gastric (stomach) cancer, prostrate cancer, breast cancer, ovarian cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, colon cancer, pancreatic cancer, and epidermoid carcinoma.

Additional embodiments include methods of treating a growth factor-dependent disease in a mammal. These methods include selecting a mammal in need of treatment for a growth factor-dependent disease; and administering to said mammal a therapeutically effective dose of a specific binding protein that binds to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), or binding fragment thereof In some aspects, the mammal can be human. In some aspects the binding protein is a fully human monoclonal antibody, and is selected from the group consisting of mAb 7.251.3 (ATCC Accession Number PTA-7422), mAb 7.34.1 (ATCC Accession Number PTA-7423), and mAb 7.159.2 (ATCC Accession Number PTA-7424).

Treatable growth factor-dependent diseases can include osteoporosis, diabetes, and cardiovascular diseases. Other treatable disease conditions include acromegaly and gigantism, psoriasis, atherosclerosis and smooth muscle restenosis of blood vessels, as well as diabetes.

Additional embodiments include a conjugate comprising a fully human monoclonal antibody that binds to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), or a binding fragment thereof and a therapeutic agent. In some aspects the therapeutic agent can be a toxin, a radioisotope, or a pharmaceutical composition.

In other embodiments, the invention provides fully human monoclonal antibodies, or binding fragment thereof, that bind to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), and comprise a heavy chain complementarity determining region 1 (CDR1) having the amino acid sequence of "Ser Tyr Tyr Trp Ser" (SEQ ID NO: 21); a heavy chain complementarity determining region 2 (CDR2) having the amino acid sequence of "Tyr Phe Phe Tyr Ser Gly Tyr Thr Asn Tyr Asn Pro Ser Leu Lys Ser" (SEQ ID NO: 22); and a heavy chain complementarity determining region 3 (CDR3) having the amino acid sequence. of "Ile Thr Gly Thr Thr Lys Gly Gly Met Asp Val" (SEQ ID NO: 23).

Further embodiments include fully human monoclonal antibodies, or binding fragment thereof, having a light chain complementarity determining region 1 (CDR1) having the amino acid sequence of "Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His" (SEQ ID NO: 24). Antibodies herein can also include a light chain complementarity determining region 2 (CDR2) having the amino acid sequence of "Gly Asn Asn Asn Arg Pro Ser" (SEQ ID NO: 25); and a light chain complementarity determining region 3 (CDR3) having the amino acid sequence of "Gln Ser Phe Asp Ser Ser Leu Ser Gly Ser Val" (SEQ ID NO: 26).

In other embodiments, the invention provides fully human monoclonal antibodies, or binding fragment thereof, that bind to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), and comprise a heavy chain complementarity determining region 1 (CDR1) having the amino acid sequence of "Ser Tyr Tyr Trp Ser" (SEQ ID NO: 27); a heavy chain complementarity determining region 2 (CDR2) having the amino acid sequence of "Tyr Phe Phe Tyr Ser Gly Tyr Thr Asn Tyr Asn Pro Ser Leu Lys Ser" (SEQ ID NO: 28); and a heavy chain complementarity determining region 3 (CDR3) having the amino acid sequence of "Ile Thr Gly Thr Thr Lys Gly Gly Met Asp Val" (SEQ ID NO: 29).

Further embodiments include fully human monoclonal antibodies, or binding fragment thereof, having a light chain complementarity determining region 1 (CDR1) having the amino acid sequence of "Thr Gly Arg Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His" (SEQ ID NO: 30); a light chain complementarity determining region 2 (CDR2) having the amino acid sequence of "Gly Asn Ser Asn Arg Pro Ser" (SEQ ID NO: 31); and a light chain complementarity determining region 3 (CDR3) having the amino acid sequence of "Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser Val" (SEQ ID NO: 32).

In other embodiments, the invention provides fully human monoclonal antibodies, or binding fragment thereof, that bind to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), and comprise a heavy chain complementarity determining region 1 (CDR1) having the amino acid sequence of "Ser Tyr Asp Ile Asn" (SEQ ID NO: 33); a heavy chain complementarity determining region 2 (CDR2) having the amino acid sequence of "Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe Gln Gly" (SEQ ID NO: 34); and a heavy chain complementarity determining region 3 (CDR3) having the amino acid sequence of "Asp Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val" (SEQ ID NO: 35).

Further embodiments include fully human monoclonal antibodies, or binding fragment thereof, having a light chain complementarity determining region 1 (CDR1) having the amino acid sequence of "Ser Gly Ser Ser Ser Asn Ile Glu Asn Asn His Val Ser" (SEQ ID NO: 36); a light chain complementarity determining region 2 (CDR2) having the amino acid sequence of "Asp Asn Asn Lys Arg Pro Ser" (SEQ ID NO: 37); and a light chain complementarity determining region 3 (CDR3) having the amino acid sequence of "Glu Thr Trp Asp Thr Ser Leu Ser Ala Gly Arg Val" (SEQ ID NO: 38).

In other embodiments, the invention provides fully human monoclonal antibodies, or binding fragment thereof, that bind to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), and comprise a heavy chain complementarity determining region I (CDR1) having the amino acid sequence of "Ser Ser Ser Tyr Tyr Trp Gly" (SEQ ID NO: 81); a heavy chain complementarity determining region 2 (CDR2) having the amino acid sequence of "Gly Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser" (SEQ ID NO: 82); and a heavy chain complementarity determining region 3 (CDR3) having the amino acid sequence of "Gln Arg Gly His Ser Ser Gly Trp Trp Tyr Phe Asp Leu" (SEQ ID NO: 83).

Further embodiments include fully human monoclonal antibodies, or binding fragment thereof, having a light chain complementarity determining region 1 (CDR1) having the amino acid sequence of "Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala" (SEQ ID NO: 84); a light chain complementarity determining region 2 (CDR2) having the amino acid sequence of "Ala Ala Ser Ser Leu Gln Ser" (SEQ ID NO: 85); and a light chain complementarity determining region 3 (CDR3) having the amino acid sequence of "Gln Gln Ala Asn Asn Phe Pro Phe Thr" (SEQ ID NO: 86).

In other embodiments, the invention provides fully human monoclonal antibodies, or binding fragment thereof, that bind to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor-I (IGF-I), and comprise a heavy chain complementarity determining region 1 (CDR1) having the amino acid sequence of "Ser Ser Ser Asn Tyr Trp Gly" (SEQ ID NO: 87); a heavy chain complementarity determining region 2 (CDR2) having the amino acid sequence of "Gly Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Ser" (SEQ ID NO: 88); and a heavy chain complementarity determining region 3 (CDR3) having the amino acid sequence of "Gln Arg Gly His Ser Ser Gly Trp Trp Tyr Phe Asp Leu" (SEQ ID NO: 89).

Further embodiments include fully human monoclonal antibodies, or binding fragment thereof, having a light chain complementarity determining region 1 (CDR1) having the amino acid sequence of "Arg Ala Ser Arg Gly Ile Ser Ser Trp Leu Ala" (SEQ ID NO: 90); a light chain complementarity determining region 2 (CDR2) having the amino acid sequence of "Thr Ala Ser Ser Leu Gln Ser" (SEQ ID NO: 91); and a light chain complementarity determining region 3 (CDR3) having the amino acid sequence of "Gln Gln Ala Asn Ser Phe Pro Phe Thr" (SEQ ID NO: 92).

Some embodiments provide the use of the specific binding proteins described herein in the preparation of a medicament for the treatment of a malignant tumor. In some aspects, the specific binding protein can be a fully human monoclonal antibody. In certain aspects, the binding protein is mAb 7.251.3 (ATCC Accession Number PTA-7422) or mAb 7.34.1 (ATCC Accession Number PTA-7423) or mAb 7.159.2 (ATCC Accession Number PTA-7424). In some aspects, the medicament is for use in combination with a second anti-neoplastic agent selected from the group consisting of an antibody, a chemotherapeutic agent, and a radioactive drug. In some aspects, the medicament is for use in conjunction with or following a conventional surgery, a bone marrow stem cell transplantation or a peripheral stem cell transplantation.

The malignant tumor can be melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, thyroid tumor, gastric (stomach) cancer, prostrate cancer, breast cancer, ovarian cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, colon cancer, pancreatic cancer, and epidermoid carcinoma, for example.

Other embodiments provide the use of the specific binding proteins described herein in the preparation of a medicament for the treatment of a growth factor-dependent disease. In some aspects, the specific binding protein is a fully human monoclonal antibody and can be selected from the group consisting of mAb 7.251.3 (ATCC Accession Number PTA-7422), mAb 7.34.1 (ATCC Accession Number PTA-7423), and mAb 7.159.2 (ATCC Accession Number PTA-7424).

The growth factor-dependent disease can be osteoporosis, diabetes, and cardiovascular diseases, for example.

Preferably, the antibody comprises a heavy chain amino acid sequence having a complementarity determining region (CDR) with one or more of the sequences shown in Table 11 (see Original Patent). For example, the antibody can comprise a heavy chain amino acid sequence having the CDR1, CDR2, or CDR3 of one or more of the sequences shown in Table 11, or a combination thereof It is noted that those of ordinary skill in the art can readily accomplish CDR determinations. See for example, Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda Md. (1991), vols. 1-3.

Embodiments of the invention described herein relate to monoclonal antibodies that bind IGF-I/II and affect IGF-I/II function. Other embodiments relate to fully human anti-IGF-I/II antibodies and anti-IGF-I/II antibody preparations with desirable properties from a therapeutic perspective, including high binding affinity for IGF-I/II, the ability to neutralize IGF-I/II in vitro and in vivo, and the ability to inhibit IGF-I/II induced cell proliferation.

Claim 1 of 18 Claims

1. An isolated antibody, or binding fragment thereof, that preferentially binds to insulin-like growth factor-II (IGF-II) with cross-reactivity to insulin-like growth factor I (IGF-I), wherein said antibody has the amino acid sequence of the antibody produced by hybridoma cell line 7.159.2 (ATCC Accession Number PTA-7424).

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