Antibodies directed to PDGFD and uses thereof Number:7,135,174 from the United States Patent and Trademark Office (PTO) owispatent The present invention is related to antibodies directed to the antigen PDGFD and uses of such antibodies. In particular, in accordance with the present invention, there are provided fully human monoclonal antibodies directed to the antigen PDGFD. Nucelotide 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, are provided. Hybridomas or other cell lines expressing such immunoglobulin molecules and monoclonal antibodies are also provided.<H Antibodies, directed, Antibodies, dire, 7135174.html, Patent, pto, 7135174

Title: Antibodies directed to PDGFD and uses thereof

Abstract: The present invention is related to antibodies directed to the antigen PDGFD and uses of such antibodies. In particular, in accordance with the present invention, there are provided fully human monoclonal antibodies directed to the antigen PDGFD. Nucelotide 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, are provided. Hybridomas or other cell lines expressing such immunoglobulin molecules and monoclonal antibodies are also provided.

Patent Number: 7,135,174 Issued on 11/14/2006 to Corvalan, et al.

Inventors: Corvalan; Jose R. F. (Foster City, CA), Jia; Xiao-Chi (San Mateo, CA), Feng; Xiao (Union City, CA), Yang; Xiao-dong (Palo Alto, CA), Chen; Francine (San Francisco, CA), Gazit; Gadi (Mountain View, CA), Weber; Richard (San Francisco, CA), Bezabeh; Binyam (Oakland, CA)
Assignee: Amgen Fremont, Inc. (Fremont, CA)

Appl. No.: 10/041,860

Filed: January 7, 2002

Current U.S. Class: 424/130.1 ; 424/133.1; 424/145.1; 530/387.1; 530/387.3; 530/388.23

Current International Class: A61K 39/395 (20060101); C07K 16/22 (20060101)

Field of Search: 530/388.15,388.24,391.3,388.23 424/133.1,134.1,145.1,178.1,13,130.1

References Cited [Referenced By]

U.S. Patent Documents


4683195	July 1987	Mullis et al.
4683202	July 1987	Mullis
4816397	March 1989	Boss et al.
5151510	September 1992	Stec et al.
5194594	March 1993	Khawli et al.
5733743	March 1998	Johnson et al.
5916771	June 1999	Hori et al.
6207418	March 2001	Hori et al.
6432673	August 2002	Gao et al.
6468543	October 2002	Gilbertson et al.
6495668	December 2002	Gilbert et al.
6528050	March 2003	Gao et al.
6630142	October 2003	Hart et al.
6706687	March 2004	Eriksson et al.
6814965	November 2004	Gao et al.
6827938	December 2004	Hart et al.
6866991	March 2005	Gilbertson et al.
6887982	May 2005	Gao et al.
6893637	May 2005	Gilbertson
6962802	November 2005	Gilbert et al.

Foreign Patent Documents


WO 94/29444	Dec., 1994	WO
WO 97/38137	Oct., 1997	WO
WO 01/25433	Apr., 2001	WO

Other References

Ngo et al., 1994, The Protein Folding Problem and Tertiary Structure Prediction, pp. 492-495. cited by examiner .
Kuby et al., 1994, Immunology, second edition, pp. 85-96. cited by examine- r .
Janway et al, p. 3:1-3:3, in Immunobiology, 1994. cited by examiner .
Merriam-Webster's Online Dictionary, 10th Edition. cited by examiner .
Green et al, Nature Genetics 7: 13-21, May 4, 1994. cited by examiner .
Alon et al. Nat. Med., 1(10):1024-1028 (1995). cited by other .
Athanassiades et al. Placenta, 19(7): 465-473 (1998). cited by other .
Baldrick, Regul. Toxicol. Pharmacol., 32(2):210-218 (2000). cited by other .
Bellamy et al. Cancer Res., 59(3):728-733 (1999). cited by other .
Blake et al. BioConjugate Chem., Abstract only, 3:510-513 (1992). cited by other .
Bowie et al. Science, Abstract only, 253:164-170 (1991). cited by other .
Carmeliet et al. Cell, 98(2):147-157 (1999). cited by other .
Charman, J. Pharm. Sci., 89(8):967-978 (2000). cited by other .
Chen et al Hum. Gene Ther., Abstract only, 5(5):595-601 (1994). cited by other .
Chiswell et al. Trends Biotechnol., Abstract only, 10(3):80-84 (1992). cit- ed by other .
Chothia et al. J. Mol. Biol., Abstract only, 196(4):901-917 (1987). cited by other .
Chothia et al. Nature, 342:878-883 (1989). cited by other .
Crossen et al. Cancer Genet. Cytogenet., 112:144-148 (1999). cited by othe- r .
Cwirla et al. Proc. Natl. Acad. Sci. USA, 87:6378-6382 (1990). cited by other .
Deo et al. Immunol. Today, 18:127-135 (1997). cited by other .
Evans et al. J. Med. Chem., Abstract only, 30(7):1229-1239 (1987). cited by other .
Fanger et al. Immunomethods., Abstract only, 4(1):72-81 (1994). cited by other .
Ferrara, Curr. Top Microbiol. Immunol., 237:1-30 (1999). cited by other .
Ferti-Passantonopoulou et al. Cancer Genet. Cytogenet., Abstract only, 51(2):183-188 (1991). cited by other .
Gerber et al. J. Biol. Chem., 273(46):30336-30343 (1998). cited by other .
Gorman et al. Proc. Natl. Acad. Sci. USA, 79:6777-6781 (1982). cited by other .
Green et al. J. Exp. Med., 188(3):483-495 (1998). cited by other .
Green et al. Nature Genetics, 7:13-21 (1994). cited by other .
Grosschedl et al. Cell, Abstract only, 41(3):885-897 (1985). cited by othe- r .
Hanes et al. Proc. Natl. Acad. Sci. USA, 94:4937-4942 (1997). cited by oth- er .
Hoogenboom et al. Immunol. Rev., Abstract only, 130:41-68 (1992). cited by other .
Houghten et al. Biotechniques, 13(3):412-421 (1992). cited by other .
Houghten Proc. Natl. Acad. Sci. USA, 82:5131-5135 (1985). cited by other .
Ike et al. Nucl. Acid Res., 11(2):477-488 (1983). cited by other .
Itakura et al. Annu. Rev. Biochem., Abstract only,53:323-356 (1984). cited by other .
Katoh et al. J. Gastroenterol., 31(1):137-139 (1996). cited by other .
Kessler et al. Science, 271:360-362 (1996). cited by other .
Kostelny et al. J. Immunol., 148:1547-1553 (1992). cited by other .
Kurahashi et al. Hum. Mol. Genet., 9(11):1665-1670 (2000). cited by other .
LaPlanche et al. Nucl. Acids Res., 14(22):9081-9093 (1986). cited by other .
LaRochelle et al. Nat. Cell Biol., 3:517-521 (2001). cited by other .
Li et al. Cell Res., 9:11-25 (1999). cited by other .
Liu et al. Proc. Natl. Acad. Sci. USA, 84:3439-3443 (1987). cited by other .
Liu et al. J. Immunol., Abstract only,139(10):3521-3526 (1987). cited by other .
Marasco, Gene Ther., Abstract only, 4(1): 11-15 (1997). cited by other .
Masood et al., Proc. Natl. Acad. Sci. USA, 94(3):979-984 (1997). cited by other .
Mendez et al. Nat. Genet., 15:146-156 (1997). cited by other .
Michaux et al. Genes, Chromosomes & Cancer, 29:40-47 (2000). cited by othe- r .
Narang, Tetrahedron, Abstract only, 39(1):3-22 (1983). cited by other .
Needleman et al. J. Mol. Biol., 48:443-453 (1970). cited by other .
Okayama et al. Mol. Cell. Biol., 3(2):280-289 (1983). cited by other .
Parmley et al. Gene, Abstract only, 73(2):305-318 (1988). cited by other .
Pearson et al. Proc. Natl. Acad. Sci. USA, 85:2444-2448 (1988). cited by other .
Pinilla et al. Biotechniques, Abstract only, 13(6):901-905 (1992). cited by other .
Pivnick et al. J. Med. Genet., Abstract only, 33(9):772-778 (1996). cited by other .
Powell et al. PDA J. Pharm. Sci. Technol., Abstract only, 52(5):238-311 (1998). cited by other .
Risau et al., Annu. Rev. Cell Dev. Biol., 11:73-91 (1995). cited by other .
Risau, FASEB J., 9(10):926-933 (1995). cited by other .
Rizo et al. Annu. Rev. Biochem., Abstract only 61:387-418(1992). cited by other .
Russell et al. Nucl. Acids Res., 21(5):1081-1085 (1993). cited by other .
Scott, Trends Biochem. Sci., Abstract only, 17(7):241-245 (1992). cited by other .
Shen et al. J. Surg. Oncol., Abstract only, 74(2):100-107 (2000). cited by other .
Smith et al. Adv. Appl. Math., Abstract only, 2(4):482-489 (1981). cited by other .
Songsivilai et al. Clin. Exp. Immunol., Abstract only, 79(3):315-321 (1990). cited by other .
Speirs et al. Br. J. Cancer, 80(5/6):898-903(1999). cited by other .
Stec et al. J. Am. Chem. Soc., Abstract only, 106:6077-6079 (1984). cited by other .
Stein et al. Nucl. Acids Res., 16:3209-3221 (1988). cited by other .
Tarkkanen et al. Genes, Chromosomes & Cancer, 25:323-331 (1999). cited by other .
Thornton et al. Nature, 354:105-106 (1991). cited by other .
Traunecker et al. Int. J. Cancer (Suppl.), Abstract only,7:51-52 (1992). cited by other .
Uhlmann et al. Chem. Rev., Abstract only, 90(4):543 (1990). cited by other .
Valerius et al. Blood, 90(11):4485-4492 (1997). cited by other .
Veber et al. Trends in Neurosci., Abstract only, 8:392-396 (1985). cited by other .
Vitetta et al. Immunol. Today, Abstract only,14(6):252-259 (1993). cited by other .
Wang, Int. J. Pharm., 203(1-2):1-60 (2000). cited by other .
Warren et al. J. Clin. Invest., 95:1789-1797 (1995). cited by other .
Winter et al. Immunol. Today, Abstract only,14(6):243-246 (1993). cited by other .
Wozney et al. Science, 242:1528-1534 (1988). cited by other .
Wright et al. Crit. Rev. Immunol., Abstract only, 12(3-4):125-168 (1992). cited by other .
Yoshikawa et al. Cancer, 56:1682-1687 (1985). cited by other .
Yuan et al. Proc. Natl. Acad. Sci. USA, 93:14765-14770 (1996). cited by other .
Zon et al. Anti-Cancer Drug Des., Abstract only,6(6):539-568 (1991). cited by other.

Primary Examiner: Chan; Christina
Assistant Examiner: Huynh; Phuong N
Attorney, Agent or Firm: Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, P.C. Elrifi; Ivor R.

Claims

What we claim is:

1. A human monoclonal antibody that binds to Platelet Derived Growth Factor D (PDGFD) and comprises a heavy chain amino acid sequence comprising SEQ ID NO: 48 and a light chain amino acid sequence comprising SEQ ID NO: 49.

2. A human monoclonal antibody or antigen-binding portion thereof that specifically binds to Platelet Derived Growth Factor D (PDGFD) and is encoded by human V.sub.H1-8 gene and J.sub.H6B gene, wherein said monoclonal antibody comprises a heavy chain polypeptide comprising the sequence of SEQ ID NO:48 and a light chain polypeptide comprising the sequence of SEQ ID NO:49.

3. A human monoclonal antibody that binds to Platelet Derived Growth Factor D (PDGFD) and is derived from V.sub.H1-8 and J.sub.H6B, wherein said monoclonal antibody comprises a heavy chain polypeptide comprising the sequence of SEQ ID NO:48 and a light chain polypeptide comprising the sequence of SEQ ID NO:49.

4. A composition comprising a human monoclonal antibody or antigen-binding portion thereof that specifically binds to Platelet Derived Growth Factor D (PDGFD) and is encoded by human V.sub.H1-8 gene and J.sub.H6B gene, wherein said human monoclonal antibody or antigen-binding portion thereof comprises a heavy chain polypeptide comprising the sequence of SEQ ID NO:48 and a light chain polypeptide comprising the sequence of SEQ ID NO:49 in association with a pharmaceutically acceptable carrier.

Description

BACKGROUND OF THE INVENTION

1. Summary of the Invention

The present invention is related to antibodies directed to the antigen PDGFD and uses of such antibodies. In particular, in accordance with the present invention, there are provided fully human monoclonal antibodies directed to the antigen PDGFD. Nucelotide 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, are provided. Hybridomas or other cell lines expressing such immunoglobulin molecules and monoclonal antibodies are also provided.

2. Background of the Technology

Polypeptide growth factors exerting effects in a variety of tissues have been described. Such growth factors include platelet-derived growth factor (PDGF).

The platelet derived growth factor (PDGF) family currently consists of at least 3 distinct genes, PDGF A, PDGF B, and PDGF C whose gene products selectively signal through two PDGFRs to regulate diverse cellular functions. PDGF A, PDGF B, and PDGF C dimerize in solution to form homodimers, as well as the heterodimer.

Expression of RNA encoding the PDGF A and PDGF B subunits of has been reported in vascular tissues involved in atherosclerosis. PDGF A and PDGF B mRNA have been reported to be present in mesenchymal-appearing intimal cells and endothelial cells, respectively, of atherosclerotic plaques. In addition, PDGF receptor mRNA has also been localized predominantly in plaque intimal cells.

The PDGF B is related to the transforming gene (v-sis) of simian sarcoma virus. The PDGF B has also been reported to be mitogen for cells of mesenchymal origin. The PDGF B has in addition been implicated in autocrine growth stimulation in the pathologic proliferation of endothelial cells characteristically found in glioblastomas. PDGF has also been reported to promote cellular proliferation and inhibits apoptosis.

A novel PDGF, PDGF-D, has recently been cloned and characterized. See LaRochelle et al. Nature Cell Biology 3:517 (2001), GenBank Accession No. AF335584, International Patent Application No. WO 01/25433, U.S. Ser. No. 60/158,083, filed Oct. 7, 1999; U.S. Ser. No. 60/159,231, filed Oct. 13, 1999; U.S. Ser. No. 60/174,485 filed Jan. 4, 2000; U.S. Ser. No. 60/186,707 filed Mar. 3, 2000; U.S. Ser. No. 60/188,250, filed Mar. 10, 2000; U.S. Ser. No. 60/223,879, filed Aug. 8, 2000; U.S. Ser. No. 60/234,082, filed on Sep. 20, 2000; U.S. Ser. No. 09/685,330, filed on Oct. 5, 2000; PCT Application US00/27671, filed Oct. 6, 2000; U.S. Ser. No. 09/688,312, filed Oct. 13, 2000 and U.S. Ser. No. 09/715,332, filed Nov. 16, 2000. Each of these applications is incorporated by reference in its entirety., the disclosures of which are hereby incorporated by reference. Because of its expression profile and sequence homology and/or similarity to the above-discussed genes and gene products, antibodies to the PDGF-D antigen could be useful therapeutically.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 is a representation of the nucleotide sequence of the human PDGFD gene (SEQ ID NO:50).

FIG. 2 is a representation of the nucleotide (SEQ ID NO:50) and deduced amino acid (SEQ ID NO:12) sequence of the human PDGF D gene.

FIG. 3 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.6 of the invention, with FIG. 3A representing the nucleotide sequence encoding the variable region of the heavy chain (SEQ.ID.NO: 55), FIG. 3B (SEQ.ID.NO: 13) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 3A, FIG. 3C (SEQ.ID.NO: 56) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 3D (SEQ.ID.NO: 14) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 3C.

FIG. 4 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.11 of the invention, with FIG. 4A representing the nucleotide sequence encoding the variable region of the heavy chain (SEQ.ID.NO: 57) FIG. 4B (SEQ.ID.NO: 15) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 4A, FIG. 4C (SEQ.ID.NO: 58) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 4D (SEQ.ID.NO: 16) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 4C.

FIG. 5 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.17 of the invention, with FIG. 5A (SEQ.ID.NO: 59) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 5B (SEQ.ID.NO: 17) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 5A, FIG. 5C (SEQ.ID.NO: 60) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 5D (SEQ.ID.NO: 18) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 5C.

FIG. 6 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.18 of the invention, with FIG. 6A (SEQ.ID.NO: 61) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 6B (SEQ.ID.NO: 19) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 6A, FIG. 6C (SEQ.ID.NO: 62) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 6D (SEQ.ID.NO: 20) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 6C.

FIG. 7 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.19 of the invention, with FIG. 7A (SEQ.ID.NO: 63) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 7B (SEQ.ID.NO: 21) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 7A, FIG. 7C (SEQ.ID.NO: 64) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 7D (SEQ.ID.NO: 22) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 7C.

FIG. 8 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.23 of the invention, with FIG. 8A (SEQ.ID.NO: 65) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 8B (SEQ.ID.NO: 23) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 8A, FIG. 8C (SEQ.ID.NO: 66) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 8D (SEQ.ID.NO: 24) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 8C.

FIG. 9 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.24 of the invention, with FIG. 9A (SEQ.ID.NO: 67) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 9B (SEQ.ID.NO: 25) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 9A, FIG. 9C (SEQ.ID.NO: 68) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 9D (SEQ.ID.NO: 26) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 9C.

FIG. 10 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.25 of the invention, with FIG. 10A (SEQ.ID.NO: 69) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 10B (SEQ.ID.NO: 27) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 10A, FIG. 10C (SEQ.ID.NO: 70) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 10D (SEQ.ID.NO: 28) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 10C.

FIG. 11 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.29 of the invention, with FIG. 11A (SEQ.ID.NO: 71) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 11B (SEQ.ID.NO: 29) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 11A, FIG. 11C (SEQ.ID.NO: 72) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 11D (SEQ.ID.NO: 30) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 11C.

FIG. 12 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.33 of the invention, with FIG. 12A (SEQ.ID.NO: 73) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 12B (SEQ.ID.NO: 31) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 12A, FIG. 12C (SEQ.ID.NO: 74) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 12D (SEQ.ID.NO: 32) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 12C.

FIG. 13 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.38 of the invention, with FIG. 13A (SEQ.ID.NO: 75) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 13B (SEQ.ID.NO: 33) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 13A, FIG. 13C (SEQ.ID.NO: 76) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 13D (SEQ.ID.NO: 34) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 13C.

FIG. 14 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.39 of the invention, with FIG. 14A (SEQ.ID.NO: 77) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 14B (SEQ.ID.NO: 35) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 14A, FIG. 14C (SEQ.ID.NO: 78) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 14D (SEQ.ID.NO: 36) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 14C.

FIG. 15 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.40 of the invention, with FIG. 15A (SEQ.ID.NO: 79) representing the nucleotide sequence encoding the variable region of the heavy chain and FIG. 15B (SEQ.ID.NO: 37) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 15A.

FIG. 16 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.45 of the invention, with FIG. 16A (SEQ.ID.NO: 80) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 16B (SEQ.ID.NO: 38) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 16A, FIG. 16C (SEQ.ID.NO: 81) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 16D (SEQ.ID.NO: 39) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 16C.

FIG. 17 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.46 of the invention, with FIG. 17A (SEQ.ID.NO: 82) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 17B (SEQ.ID.NO: 40) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 17A, FIG. 17C (SEQ.ID.NO: 83) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 17D (SEQ.ID.NO: 41) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 17C.

FIG. 18 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.48 of the invention, with FIG. 18A (SEQ.ID.NO: 84) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 18B (SEQ.ID.NO: 42) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 18A, FIG. 18C (SEQ.ID.NO: 85) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 18D (SEQ.ID.NO: 43) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 18C.

FIG. 19 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.49 of the invention, with FIG. 19A (SEQ.ID.NO: 86) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 19B (SEQ.ID.NO: 44) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 19A, FIG. 19C (SEQ.ID.NO: 87) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 19D (SEQ.ID.NO: 45) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 19C.

FIG. 20 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.51 of the invention, with FIG. 20A (SEQ.ID.NO: 88) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 20B (SEQ.ID.NO: 46) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 20A, FIG. 20C (SEQ.ID.NO: 89) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 20D (SEQ.ID.NO: 47) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 20C.

FIG. 21 is a series of representations of the heavy chain and light chain variable region nucleotide and amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-6.4 of the invention, with FIG. 21A (SEQ.ID.NO: 90) representing the nucleotide sequence encoding the variable region of the heavy chain, FIG. 21B (SEQ.ID.NO: 48) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 21A, FIG. 21C (SEQ.ID.NO: 91) representing the nucleotide sequence encoding the variable region of the light chain, and FIG. 21D (SEQ.ID.NO: 49) representing the amino acid sequence encoded by the nucleotide sequence shown in FIG. 21C.

FIG. 22 is a table showing VDJ gene utilization of antibodies of the invention and indicating nucleotide/amino acid changes between the antibodies and the V, D, or J genes from which they are derived in the antibodies FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 regions.

FIG. 23 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.6 of the invention and the V gene from which it is derived. FIG. 23A representing the alignment of the heavy chain amino acid sequence CUR2.1.6.1. HC (SEQ. ID. NO: 270) and VH2-21 (SEQ. ID. NO: 271), the consensus being shown below (SEQ. ID. NO: 272). FIG. 23B representing the alignment of the light chain amino acid sequence of .CUR2.1.6.1 LC (SEQ. ID. NO: 273) and A30 (SEQ. ID. NO: 274), with the consensus sequence being shown below (SEQ. ID. NO: 275).

FIG. 24 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.11 of the invention and the V gene from which it is derived. FIG. 24A represents the alignment of the heavy chain amino acid sequence CUR2.1.11.1 HC (SEQ. ID. NO: 276) and VH3-53 (SEQ. ID. NO: 277), the consensus being shown below (SEQ. ID. NO: 278). FIG. 24B represents the alignment of the light chain amino acid sequence of CUR2.1.11.1 LC (SEQ. ID. NO: 279) and A19 (SEQ. ID. NO: 280), with the consensus sequence shown below (SEQ. ID. NO: 281).

FIG. 25 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.17 of the invention and the V gene from which it is derived. FIG. 25A represents the alignment of the heavy chain amino acid sequence CR 2-1.17.1 HC (SEQ. ID. NO: 282) and VH3-53 (SEQ. ID. NO: 283), the consensus being shown below (SEQ. ID. NO: 284). FIG. 25B represents the alignment of the light chain amino acid sequence of CR 2-1.17.1 LC (SEQ. ID. NO: 285) and A30 (SEQ. ID. NO: 286), with the consensus sequence being shown below (SEQ. ID. NO: 287).

FIG. 26 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.18 of the invention and the V gene from which it is derived. FIG. 26A represents the alignment of the heavy chain amino acid sequence CR2-1.18 HC (SEQ. ID. NO: 288) and VH1-8 (SEQ. ID. NO: 289), the consensus being shown below (SEQ. ID. NO: 290). FIG. 26B represents the alignment of the light chain amino acid sequence of CR2-1.18 LC (SEQ. ID. NO: 291) and A30 (SEQ. ID. NO: 292), with the consensus sequence being shown below (SEQ. ID. NO: 293).

FIG. 27 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.19 of the invention and the V gene from which it is derived FIG. 27A represents the alignment of the heavy chain amino acid sequence CUR2.1.19.1 HC (SEQ. ID. NO: 294) and VH1-8 (SEQ. ID. NO: 295), the consensus being shown below (SEQ. ID. NO: 296). FIG. 27B represents the alignment of the light chain amino acid sequence of CUR2.1.19.1 LC (SEQ. ID. NO: 297) and A30 (SEQ. ID. NO: 298), with the consensus sequence begin shown below (SEQ. ID. NO: 299).

FIG. 28 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.23 of the invention and the V gene from which it is derived. FIG. 28A represents the alignment of the heavy chain amino acid sequence CUR2.1.23.1 HC (SEQ. ID. NO: 300) and VH5-51 (SEQ. ID. NO: 301), the consensus being shown below (SEQ. ID. NO: 302). FIG. 28B represents the alignment of the light chain amino acid sequence of CUR2.1.23.1 LC (SEQ. ID. NO: 303) and A30 (SEQ. ID. NO: 304), with the consensus sequence being shown below (SEQ. ID. NO: 305).

FIG. 29 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.24 of the invention and the V gene from which it is derived, with FIG. 29A represents the alignment of the heavy chain amino acid sequence CUR2.1.24.1 HC (SEQ. ID. NO: 306) and VH3-33 (SEQ. ID. NO: 307), the consensus being shown below (SEQ. ID. NO: 308). FIG. 29B represents the alignment of the light chain amino acid sequence of CUR2.1.24.1 LC (SEQ. ID. NO: 309) and A30 (SEQ. ID. NO: 310), with the consensus sequence being shown below (SEQ. ID. NO: 311).

FIG. 30 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.25 of the invention and the V gene from which it is derived. FIG. 30A represents the alignment of the heavy chain amino acid sequence VH5-51 (SEQ. ID. NO: 312) and CUR2.1.25.1 HC (SEQ. ID. NO: 313), the consensus being shown below (SEQ. ID. NO: 314). FIG. 30B represents the alignment of the light chain amino acid sequence of A30 (SEQ. ID. NO: 315) and CUR2.1.25.1 LC (SEQ. ID. NO: 316), with the consensus sequence shown below (SEQ. ID. NO: 317).

FIG. 31 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.29 of the invention and the V gene from which it is derived. FIG. 31A represents the alignment of the heavy chain amino acid sequence VH5-51 (SEQ. ID. NO: 318) and CUR2.1.29 HC (SEQ. ID. NO: 319), the consensus being shown below (SEQ. ID. NO: 320). FIG. 31B represents the alignment of the light chain amino acid sequence of A19 (SEQ. ID. NO: 321) and CUR2.1.29 LC (SEQ. ID. NO: 322), with the consensus sequence being shown below.

FIG. 32 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.33 of the invention and the V gene from which it is derived. FIG. 32A represents the alignment of the heavy chain amino acid sequence VH1-18 (SEQ. ID. NO: 324) and CR2.1.33 HC (SEQ. ID. NO: 325), the consensus being shown below (SEQ. ID. NO: 326). FIG. 32B represents the alignment of the light chain amino to acid sequence of A20 (SEQ. ID. NO: 327) and CR2.1.33 LC (SEQ. ID. NO: 328), with the consensus sequence being shown below (SEQ. ID. NO: 329).

FIG. 33 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.38 of the invention and the V gene from which it is derived. FIG. 33A represents the alignment of the heavy chain amino acid sequence VH3-33 (SEQ. ID. NO: 330) and CR2.1.38.1 HC (SEQ. ID. NO: 331), the consensus being shown below (SEQ. ID. NO: 322). FIG. 33B represents the alignment of the light chain amino acid sequence of A20 (SEQ. ID. NO: 334) and CUR2.1.38.1 LC (SEQ. ID. NO: 335), with the consensus sequence begin shown below (SEQ. ID. NO: 336).

FIG. 34 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.39 of the invention and the V gene from which it is derived. FIG. 34A represents the alignment of the heavy chain amino acid sequence VH5-51 (SEQ. ID. NO: 336) and CR2.1.39.1 HC (SEQ. ID. NO: 337), the consensus being shown below (SEQ. ID. NO: 338). FIG. 34B represents the alignment of the light chain amino acid sequence of A30 (SEQ. ID. NO: 339) and CR2.1.39.1 LC (SEQ. ID. NO: 340), with the consensus sequence being shown below (SEQ. ID. NO: 341).

FIG. 35 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.45 of the invention and the V gene from which it is derived. FIG. 35A represents the alignment of the heavy chain amino acid sequence VH1-8 (SEQ. ID. NO: 342) and CR2.1.45.1 HC (SEQ. ID. NO: 343), the consensus being shown below (SEQ. ID. NO: 344). FIG. 35B represents the alignment of the light chain amino acid sequence of A20 (SEQ. ID. NO: 345) and CUR2.1.45.1 LC (SEQ. ID. NO: 346), with the consensus sequence being shown below (SEQ. ID. NO: 347).

FIG. 36 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.46 of the invention and the V gene from which it is derived. FIG. 36A represents the alignment of the heavy chain amino acid sequence VH1-8 (SEQ. ID. NO: 348) and CR2.1.46.1 HC (SEQ. ID. NO: 349), the consensus being shown below (SEQ. ID. NO: 350). FIG. 36B represents the alignment of the light chain amino acid sequence of A30 (SEQ. ID. NO: 351) and CR2.1.46.1 LC (SEQ. ID. NO: 352), with the consensus sequence being shown below (SEQ. ID. NO: 353).

FIG. 37 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.48 of the invention and the V gene from which it is derived. FIG. 37A represents the alignment of the heavy chain amino acid sequence CR2.1.48.1 HC (SEQ. ID. NO: 354) and VH1-18 (SEQ. ID. NO: 355), the consensus being shown below (SEQ. ID. NO: 356). FIG. 37B represents the alignment of the light chain amino acid sequence of CR2.1.48.1 LC (SEQ. ID. NO: 357) and L5 (SEQ. ID. NO: 358), with the consensus sequence being shown below (SEQ. ID. NO: 359).

FIG. 38 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.49 of the invention and the V gene from which it is derived. FIG. 38A represents the alignment of the heavy chain amino acid sequence CR2.1.49.1 HC (SEQ. ID. NO: 360) and VH1-8 (SEQ. ID. NO: 361), the consensus being shown below (SEQ. ID. NO: 362). FIG. 38B representing the alignment of the light chain amino acid sequence of CUR2.1.49.1 LC (SEQ. ID. NO: 363) and A19 (SEQ. ID. NO: 364), with the consensus sequence being shown below (SEQ. ID. NO: 365).

FIG. 39 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-1.51 of the invention and the V gene from which it is derived. FIG. 39A represents the alignment of the heavy chain amino acid sequence CR2.1.51.1 HC (SEQ. ID. NO: 366) and VH5-51 (SEQ. ID. NO: 367), the consensus being shown below (SEQ. ID. NO: 368). FIG. 39B representing the alignment of the light chain amino acid sequence of CR2.1.51.1 LC (SEQ. ID. NO: 369) and A27 (SEQ. ID. NO: 370), with the consensus sequence being below (SEQ. ID. NO: 371).

FIG. 40 is a series of alignments of the heavy chain and light chain variable region amino acid sequences of the human anti-PDGFD antibody expressed by the hybridoma cell line designated Cur 2-6.4 of the invention and the V gene from which it is derived. FIG. 40A represents the alignment of the heavy chain amino acid sequence CUR2.6.4.1 HC (SEQ. ID. NO: 372) and VH1-8 (SEQ. ID. NO: 373), the consensus being shown below (SEQ. ID. NO: 374). FIG. 40B representing the alignment of the light chain amino acid sequence of CUR2.6.4.1 LC (SEQ. ID. NO: 375) and A27 (SEQ. ID. NO: 376), with the consensus sequence being shown below (SEQ. ID. NO: 377).

FIG. 41 is a table showing VDJ gene utilization of the 1.19.1 and 6.4.1 antibodies of the invention and indicating nucleotide changes between the antibodies and the VH, DH, and JH and VK and JK genes from which they are derived.

FIG. 42 is a table showing VDJ gene utilization of the 1.6.1, 1.11.1, and 1.23.1 antibodies of the invention and indicating nucleotide changes between the antibodies and the VH, DH, and JH and VK and JK genes from which they are derived.

FIG. 43 is a table showing VDJ gene utilization of the 1.19.1, 6.4.1, 1.6.1, 1.11.1, 1.23.1, 1.17.1, 1.18, 1.24.1, 1.25.1, 1.29, 1.33, 1.38.1, 1.39.1, 1.40.1, 1.45, 1.46.1, 1.46.2, 1.48.1, 1.49.1, and 1.51.1 antibodies of the invention and indicating nucleotide changes between the antibodies and the VH, DH, and JH and VK and JK genes from which they are derived.

FIG. 44 is a bar graphic representation comparing the levels of BrdU incorporation in NIH 3T3 cells upon exposure to various human anti-PDGFD monoclonal antibodies of the invention.

FIG. 45 is a bar graphic representation comparing the levels of BrdU incorporation in NIH 3T3 cells upon exposure to various human anti-PDGFD monoclonal antibodies of the invention at varying doses as compared to a control run utilizing PDGFBB at varying concentrations.

FIG. 46 is a bar graphic representation comparing the levels of BrdU incorporation in NIH 3T3 cells upon exposure to various human anti-PDGFD monoclonal antibodies of the invention at varying doses as compared to a control run utilizing PDGFBB at varying concentrations.

FIG. 47 is a bar graphic representation comparing the levels of BrdU incorporation in NIH 3T3 cells upon exposure to various human anti-PDGFD monoclonal antibodies of the invention at varying doses as compared to a control run utilizing PDGFBB at varying concentrations.

FIG. 48 is a representation of a ClustalW sequence alignment between the heavy chain amino acid sequences of antibodies of the invention indicating locations of the CDRs of the antibodies. Heavy chain sequences shown are: 1.19H (SEQ. ID. NO: 199); 6.4H (SEQ. ID. NO: 200); 1.18H (SEQ. ID. NO: 201); 1.40H (SEQ. ID. NO: 202); 1.45H (SEQ. ID. NO: 203); 1.46H (SEQ. ID. NO: 204); 1.49H (SEQ. ID. NO: 205); 1.33H (SEQ. ID. NO: 206); 1.48H (SEQ. ID. NO: 207); 1.6H (SEQ. ID. NO: 208); 1.17H (SEQ. ID. NO: 209); 1.24H (SEQ. ID. NO: 210); 1.38H (SEQ. ID. NO: 211); 1.11H (SEQ. ID. NO: 212); 1.23H (SEQ. ID. NO: 213); 1.25H (SEQ. ID. NO: 214); 1.29H (SEQ. ID. NO: 215); 1.39H (SEQ. ID. NO: 216); and 1.51H (SEQ. ID. NO: 217).

FIG. 49 is a representation of a ClustalW sequence alignment between the light chain amino acid sequences of antibodies of the invention indicating locations of the CDRs of the antibodies. Light chain sequences shown are: 1.48L (SEQ. ID. NO: 218); 1.49L (SEQ. ID. NO: 219); 1.11L (SEQ. ID. NO: 220); 1.29L (SEQ. ID. NO: 221); 1.45L (SEQ. ID. NO: 222); 1.33L (SEQ. ID. NO: 223); 1.38L (SEQ. ID. NO: 224); 6.4L (SEQ. ID. NO: 225); 1.51L (SEQ. ID. NO: 226); 1.19L (SEQ. ID. NO: 227); 1.18L (SEQ. ID. NO: 228); 1.16L (SEQ. ID. NO: 229); 1.23L (SEQ. ID. NO: 230); 1.25L (SEQ. ID. NO: 231); 1.39L (SEQ. ID. NO: 232); 1.17L (SEQ. ID. NO: 233); 1.24L (SEQ. ID. NO: 234); and 1.46L (SEQ. ID. NO: 235).

FIG. 50 is a representation of a ClustalW sequence alignment between the heavy chain amino acid sequences of antibodies of the invention that possess heavy chains derived from the VH 1-8 gene with CDRs indicated. Heavy chains sequences shown are: 1.19H (SEQ. ID. NO: 236); 6.4H (SEQ. ID. NO: 237); 1.18H (SEQ. ID. NO: 238); 1.40H (SEQ. ID. NO: 239); 1.45H (SEQ. ID. NO: 240); 1.46H (SEQ. ID. NO: 241); and 1.49H (SEQ. ID. NO: 242);

FIG. 51 is a representation of a ClustalW sequence alignment between the heavy chain amino acid sequences of antibodies of the invention that possess heavy chains derived from the VH 1-18 gene with CDRs indicated. Heavy chain sequences shown are: 1.33H (SEQ. ID. NO: 243); and 1.48H (SEQ. ID. NO: 244).

FIG. 52 is a representation of a ClustalW sequence alignment between the heavy chain amino acid sequences of antibodies of the invention that possess heavy chains derived from the VH 3-33 gene with CDRs indicated. Heavy chain sequences shown are: 1.17H (SEQ. ID. NO: 245); 1.24H (SEQ. ID. NO: 246); and 1.38H (SEQ. ID. NO: 247).

FIG. 53 is a representation of a ClustalW sequence alignment between the heavy chain amino acid sequences of antibodies of the invention that possess heavy chains derived from the VH 5-51 gene with CDRs indicated. Heavy chain sequences shown are: 1.23H (SEQ. ID. NO: 248); 1.25H (SEQ. ID. NO: 249); 1.29H (SEQ. ID. NO: 250); 1.39H (SEQ. ID. NO: 251); and 1.51H (SEQ. ID. NO: 252).

FIG. 54 is a representation of a ClustalW sequence alignment between the light chain amino acid sequences of antibodies of the invention that possess light chains derived from the VK A19 gene with CDRs indicated. Light chain sequences shown are: 1.49L (SEQ. ID. NO: 253); 1.11L (SEQ. ID. NO: 254); and 1.29L (SEQ. ID. NO: 255).

FIG. 55 is a representation of a ClustalW sequence alignment between the light chain amino acid sequences of antibodies of the invention that possess light chains derived from the VK A20 gene with CDRs indicated. Light chain sequences are shown are: 1.45L (SEQ. ID. NO: 256); 1.33L (SEQ. ID. NO: 257); and 1.38L (SEQ. ID. NO: 258).

FIG. 56 is a representation of a ClustalW sequence alignment between the light chain amino acid sequences of antibodies of the invention that possess light chains derived from the VK A27 gene with CDRs indicated. Light chain sequences shown are: 6.4L (SEQ. ID. NO: 259) and 1.5L (SEQ. ID. NO: 260).

FIG. 57 is a representation of a ClustalW sequence alignment between the light chain amino acid sequences of antibodies of the invention that possess light chains derived from the VK A30 gene with CDRs indicated. Light chain sequences shown are: 1.19L (SEQ. ID. NO: 261); 1.18L (SEQ. ID. NO: 262); 1.16L (SEQ. ID. NO: 263); 1.23L (SEQ. ID. NO: 264); 1.25L (SEQ. ID. NO: 265); 1.39L (SEQ. ID. NO: 266); 1.17L (SEQ. ID. NO: 267); 1.24L (SEQ. ID. NO: 268); and 1.46L (SEQ. ID. NO: 269).

SUMMARY OF THE INVENTION

In accordance with a first aspect of the present invention, there is provided a human monoclonal antibody that binds to PDGFD and has a heavy chain amino acid sequence selected from the group consisting of SEQ ID NOS: 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 38, 40, 42, 44, 46, and 48. In one embodiment, the antibody further comprises a light chain amino acid sequence selected from the group consisting of SEQ ID NOS: 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 39, 41, 43, 45, 47, and 49.

In accordance with a second aspect of the present invention there is provided a human antibody that binds to PDGFD that comprises a heavy chain amino acid sequence corresponding substantially to the amino acid sequence encoded by the VH 1-8 gene and any of the amino acid differences shown in FIG. 50 and comprising a CDR3 sequence selected from the group consisting of the CDR3 sequences shown in FIG. 50.

In accordance with a third aspect of the present invention there is provided a human antibody that binds to PDGFD that comprises a heavy chain amino acid sequence corresponding substantially to the amino acid sequence encoded by the VH 1-18 gene and any of the amino acid differences shown in FIG. 51 and comprising a CDR3 sequence selected from the group consisting of the CDR3 sequences shown in FIG. 51.

In accordance with a fourth aspect of the present invention there is provided a human antibody that binds to PDGFD that comprises a heavy chain amino acid sequence corresponding substantially to the amino acid sequence encoded by the VH 3-33 gene and any of the amino acid differences shown in FIG. 52 and comprising a CDR3 sequence selected from the group consisting of the CDR3 sequences shown in FIG. 52.

In accordance with a fifth aspect of the present invention there is provided a human antibody that binds to PDGFD that comprises a heavy chain amino acid sequence corresponding substantially to the amino acid sequence encoded by the VH 5-51 gene and any of the amino acid differences shown in FIG. 53 and comprising a CDR3 sequence selected from the group consisting of the CDR3 sequences shown in FIG. 53.

In accordance with a sixth aspect of the present invention there is provided a human antibody that binds to PDGFD that comprises a light chain amino acid sequence corresponding substantially to the amino acid sequence encoded by the VK A19 gene and any of the amino acid differences shown in FIG. 54 and comprising a CDR3 sequence selected from the group consisting of the CDR3 sequences shown in FIG. 54.

In accordance with a seventh aspect of the present invention there is provided a human antibody that binds to PDGFD that comprises a light chain amino acid sequence corresponding substantially to the amino acid sequence encoded by the VK A20 gene and any of the amino acid differences shown in FIG. 55 and comprising a CDR3 sequence selected from the group consisting of the CDR3 sequences shown in FIG. 55.

In accordance with an eighth aspect of the present invention there is provided a human antibody that binds to PDGFD that comprises a light chain amino acid sequence corresponding substantially to the amino acid sequence encoded by the VK A27 gene and any of the amino acid differences shown in FIG. 56 and comprising a CDR3 sequence selected from the group consisting of the CDR3 sequences shown in FIG. 56.

In accordance with a ninth aspect of the present invention there is provided a human antibody that binds to PDGFD that comprises a light chain amino acid sequence corresponding substantially to the amino acid sequence encoded by the VK A30 gene and any of the amino acid differences shown in FIG. 57 and comprising a CDR3 sequence selected from the group consisting of the CDR3 sequences shown in FIG. 57.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A novel PDGF, PDGF-D, has recently been cloned and characterized. See LaRochelle et al. Nature Cell Biology 3:517 (2001), GenBank Accession No. AF335584, International Patent Application No. WO 01/25433, U.S. Ser. No. 60/158,083, filed Oct. 7, 1999; U.S. Ser. No. 60/159,231, filed Oct. 13, 1999; U.S. Ser. No. 60/174,485 filed Jan. 4, 2000; U.S. Ser. No. 60/186,707 filed Mar. 3, 2000; U.S. Ser. No. 60/188,250, filed Mar. 10, 2000; U.S. Ser. No. 60/223,879, filed Aug. 8, 2000; U.S. Ser. No. 60/234,082, filed on Sep. 20, 2000; U.S. Ser. No. 09/685,330, filed on Oct. 5, 2000; PCT Application US00/27671, filed Oct. 6, 2000; U.S. Ser. No. 09/688,312, filed Oct. 13, 2000 and U.S. Ser. No. 09/715,332, filed Nov. 16, 2000. Each of these applications is incorporated by reference in its entirety., the disclosures of which are hereby incorporated by reference. Because of its expression profile and sequence homology and/or similarity to the above-discussed genes and gene products, antibodies to the PDGF-D antigen could be useful therapeutically. Because of its expression profile and sequence homology and/or similarity to the above-discussed genes and gene products, antibodies to the PDGF-D antigen could be useful therapeutically.

The nucleotide and translated amino acid sequence, respectively, of PDGF-D is set forth in FIGS. 1 and 2.

The similarities of the disclosed PDGFD polypeptides to previously described BMP-1 VEGF-E and PDGF polypeptides indicate a similarity of functions by the PDGFD nucleic acids and polypeptides of the invention. These utilities are described in more detail below.

PDGFD nucleic acids and polypeptides may be use to induce formation of cartilage, as BMP-1 is also capable of inducing formation of cartilage in vivo (Wozney et al., Science 242: 1528 1534 (1988)).

An additional use for the PDGFD nucleic acids and polypeptides is in the modulation of collagen formation. Recombinantly expressed BMP1 and purified procollagen C proteinase (PCP), a secreted metalloprotease requiring calcium and needed for cartilage and bone formation, are, in fact, identical. See, Kessler et al., Science 271:360 62 (1996). BMP-1 cleaves the C-terminal propeptides of procollagen I, II, and III and its activity is increased by the procollagen C-endopeptidase enhancer protein. PDGFD nucleic acids and polypeptides may play similar roles in collagen modulation pathways.

PDGFD nucleic acids and polypeptides can also be used to stage various cancers. For example, bone metastases can almost universally be correlated to the morbidity and mortality of certain prostate cancers. For example, bone morphogenetic proteins are implicated as having important roles in various cancers. Overexpression of bone morphogenetic protein-4 ("BMP-4") and BMP-2 mRNA has been reported in gastric cancer cell lines of poorly differentiated type. See, Katoh et al., J. Gastroenterol 31(1):137 9 (1996). This observation may have implications regarding the poor prognosis of patients with diffuse osteoplastic bone metastasis of gastric cancer. Additionally, osteosarcomas producing bone morphogenetic protein ("BMP") differed in clinical features from those not producing BMP. See, Yoshikawa et al Cancer 56: 1682 7 (1985) They were characterized radiologically by perpendicular spicules, histologically by osteoblastic type cells, and clinically by an increased serum alkaline phosphatase level, relative resistance to preoperative chemotherapy with Adriamycin (doxorubicin) plus high-dose methotrexate, and a tendency to metastasize to other bones and the lungs.

The relatedness of PDGFD polypeptides to VEGF--reveals uses for PDGFD nucleic acids and polypeptides in modulating angiogenesis. Angiogenesis is a process which contributes to the development of new blood vessels. During angiogenesis, new capillaries sprout from existing vessels. See, Risau FASEB J. 9(10): 926 33 (1995); Risau et al., Ann.Rev. Cell Dev Biol. 11: 73 91 (1995). In adult mammals, new blood vessels are produced through angiogenesis. Pathological states in which angiogenesis contributes to the appearance and maintenance of the pathology include tumor development and growth vascular endothelial growth factor F has been reported to be involved in angiogenesis.

Vascular endothelial growth factor ("VEGF") is a multifunctional cytokine expressed and secreted at high levels by many tumor cells in both nonhumans and humans. See review in Ferrara, Curr Top Microbiol Immunol 237: 1 30 (1999). VEGF exerts its effects on the vascular endothelium through at least two receptors that are expressed on the cell surface. The first is kinase insert domain-containing receptor ("KDR")/fetal liver kinase 1 ("Flk-1"), and the second is FLT-1 (Warren et al., J Clin Invest 95: 1789 97 (1995)). These two receptors have different affinities for VEGF and appear to have different cellular responses. See, Athanassiades et al., Placenta 19(7): 465 73 (1998); Li et al. Cell Res 9: 11 25 (1999). FLT-1 null mice die in the embryonic stage, at about day 8.5, whereas KDR null mice survive through birth and retain endothelial and hematopoietic cell development. Activation of KDR leads to mitogenesis and to up-regulation of e-nitric oxide synthase (eNOS) and inducible NOS, enzymes in the nitric oxide pathway that contribute to regulation of vasodilation and that play a role in vascular tumor development.

It has been also been reported that VEGF acts as a survival factor for newly formed blood vessels. In the developing retina, for example, vascular regression in response to hyperoxia has been correlated with inhibition of VEGF release by glial cells. See, Alon et al, Nat Med 1: 1024 8(1995). Furthermore, administration of anti-VEGF monoclonal antibodies results in regression of already established tumor-associated vasculature in xenograft models. See, Yuan, et al., Proc Natl Acad Sci U S A 93: 14765 70 (1996). Therefore, antibodies to PDGFD polypeptides may also be used to induce or promote regression of newly formed blood vessels.

Tumor cells additionally respond to hypoxia by secreting VEGF. This response promotes neovascularization and consequently permits tumor growth. Furthermore, it has been found that several tumor cells, including hematopoietic cells (Bellamy et al., Cancer Res 59(3): 728 33 (1999)), breast cancer cells (Speirs et al., Br J Cancer 80(5 6): 898 903(1999)), and Kaposi's sarcoma (Masood et al., Proc Natl Acad Sci U S A 94(3): 979 84 (1997)), express the KDR receptor. Such results suggest that in these tumors VEGF is acting not only in a paracrine fashion to stimulate angiogenesis, but also via an autocrine mechanism as well to stimulate proliferation and/or survival of endothelial cells, and/or promoting survival of tumor cells. Accordingly, modulation of angiogenesis by PDGFD antibodies, or other antagonists of PDGFD nucleic acid or polypeptide function, can be used in anoxia-associated conditions to inhibit endothelial cell proliferation, and/or tumor cells such as hematopoietic cells, breast cancer cells, and Kaposi's sarcoma cells.

The similarity between PDGFD polypeptides and VEGF polypeptides suggests that PDGFD nucleic acids and their encoded polypeptides can be used to modulate cell survival. It has been reported that VEGF signaling is important for cell survival. Binding of VEGF to its receptor, VEGF receptor-2 (VEGFR-2/Flk1/KDR), is reported to induce the formation of a complex of VE-cadherin, .beta.-catenin, phosphoinositide-3-OH kinase (PI3-K), and KDR. PI3-K in this complex activates the serine/threonine protein kinase Akt (protein kinase B) by phosphorylation. See, Carmeliet et al., 1999 Cell 98(2): 147 57. Activated Akt is then thought to be necessary and sufficient to mediate the VE