Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Animal cell – per se – expressing immunoglobulin – antibody – or...
Reexamination Certificate
1997-10-15
2003-06-24
Gambel, Phillip (Department: 1644)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Animal cell, per se, expressing immunoglobulin, antibody, or...
C435S326000, C435S332000, C435S346000, C530S387100, C530S388100, C530S388200, C530S388240
Reexamination Certificate
active
06582959
ABSTRACT:
FIELD OF THE INVENTION
This application relates to hybrid cell lines (lymphocyte hybridomas) for the production of monoclonal antibodies to human vascular endothelial growth factor (hVEGF), to such homogeneous monospecific antibodies, and to the use of such antibodies for diagnostic and therapeutic purposes.
BACKGROUND OF THE INVENTION
The two major cellular components of the vasculature are the endothelial and smooth muscle cells. The endothelial cells form the lining of the inner surface of all blood vessels, and constitute a nonthrombogenic interface between blood and tissue. In addition, endothelial cells are an important component for the development of new capillaries and blood vessels. Thus, endothelial cells proliferate during the neovascularization associated with tumor growth and a variety of diseases, including psoriasis, arthritis, and diabetic retinopathy.
Various naturally occurring polypeptides reportedly induce the proliferation of endothelial cells. Among those polypeptides are the basic and acidic fibroblast growth factors (FGF), Burgess and Maciag, Annual Rev. Biochem., 58:575 (1989), platelet-derived endothelial cell growth factor (PD-ECGF), Ishikawa, et al., Nature, 338:557 (1989), and vascular endothelial growth factor (VEGF), Leung, et al., Science 246:1306 (1989); Ferrara & Henzel, Biochem. Biophys. Res. Commun. 161:851 (1989); Tischer, et al., Biochem. Biophys. Res. Commun. 165:1198 (1989); Ferrara, et al., PCT Pat. Pub. No. WO 90/13649 (published Nov. 15, 1990); Ferrara, et al., U.S. patent application Ser. No. 07/360,229.
VEGF was first identified in media conditioned by bovine pituitary follicular or folliculostellate cells. Biochemical analyses indicate that bovine VEGF is a dimeric protein with an apparent molecular mass of approximately 45,000 Daltons, and with an apparent mitogenic specificity for vascular endothelial cells. DNA encoding bovine VEGF was isolated by screening a cDNA library prepared from such cells, using oligonucleotides based on the amino-terminal amino acid sequence of the protein as hybridization probes.
Human VEGF was obtained by first screening a cDNA library prepared from human cells, using bovine VEGF cDNA as a hybridization probe. One cDNA identified thereby encodes a 165-amino acid protein having greater than 95% homology to bovine VEGF, which protein is referred to as human VEGF (hVEGF). The mitogenic activity of human VEGF was confirmed by expressing the human VEGF cDNA in mammalian host cells. Media conditioned by cells transfected with the human VEGF cDNA promoted the proliferation of capillary endothelial cells, whereas control cells did not. Leung, et al., Science 246:1306 (1989).
Several additional cDNAs were identified in the human cDNA library that encode 121- and 189-amino acid hVEGF-related proteins. The 121-amino acid protein differs from hVEGF by virtue of the deletion of the 44 amino acids between residues 116 and 159 in hVEGF. The 189-amino acid protein differs from hVEGF by virtue of the insertion of 24 amino acids at residue 116 in hVEGF, and apparently is identical to human vascular permeability factor (hVPF). Keck, et al., Science 246:1309 (1989); Connolly, et al., J. Biol. Chem. 264:20017 (1989); Keck, et al., EPO Pat. Pub. No. 0 370 989 (published May 30, 1990).
In view of the fundamental role of vascular endothelial cell growth in many diseases, it is desirable to have a means of regulating the mitogenic effect of VEGF. It is also desirable to have a means of assaying for the presence of VEGF in normal and pathological conditions, and especially cancer.
SUMMARY OF THE INVENTION
The present invention is directed to monoclonal antibodies, and portions thereof, which are capable of specifically binding to hVEGF or hVEGF-related protein. The invention also is directed to hybridoma cell lines that produce such monoclonal antibodies. The monoclonal antibodies of the invention are useful as therapeutic agents, either by themselves or in conjunction with cytotoxic or other chemotherapeutic agents, to treat diseases that are characterized by excessive vascular endothelial cell proliferation. The monoclonal antibodies of the invention also are useful in diagnostic and analytical assays for determining the presence of hVEGF or hVEGF related-protein in a test sample.
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Leung, et al Science 246: 1306-1309 (1989).*
Voller, et al Diagnostic Horizons Z(1):1-6 (1978).*
Antibodies, a Laboratory Manual p. 72-77, 92-97, 128-135 & 141-157 1988 Cold Spring Harbor Press.*
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Connolly, et al., J. Biol. Chem. 264(33):20017-20024 (1989).
Ferrara & Henzel, Biochem. Biophys. Res. Commun. 161(2):851-858 (1989).
Keck, et al., Science 246:1309-1312 (1989).
Tischler, et al., Biochem. Biophys. Res. Commun. 165(3):1198-1206 (1989).
Connolly et al., “Human Vascular Permeability Factor”Journal of Biological Chemistry264 (33):20017-20024 (Nov. 1989).
Ferrara et al., “Pituitary Follicular Cells Secrete a Novel Heparin-binding Growth Factor Specific for Vascular Endothelial Cells”jBiochem.&Biophys. Res. Comm. 161(2) :851-858 (JUn. 15, 1989).
Folkman, J., “The Vascularization of Tumors”Scientific American234(5) :59-73 (May 1976).
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Leung et al., “Vascular Endothelial Growth Factor is a Secreted Angiogenic Mitogen”Science246:1306-1309 (Dec. 1989).
Oikawa et al., “A Novel Angiogenic Inhibitor Derived from Japanese Shark Cartilage (I). Extraction and Estimation of Inhibitory Activities Toward Tumor and Embryonic Angiogenesis”Cancer Letters51:181-186 (1990).
Tischler et al., “Vascular Endothelial Growth Factor: A New Member of the Platelet-Derived Growth Factor Gene Family”Biochem. & Biophys. Res. Comm. 165(3) :1198-1206 (1989).
Various authorsAntibodies, A Laboratory Manual, ex:Cold Spring Harbor Press pp. 72-77, 92-87, 128-135, 141-157 (1988).
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Cui Steven X.
Gambel Phillip
Genentech Inc.
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