Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1998-04-09
2001-02-27
Eyler, Yvonne (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S141100, C530S350000, C530S388100
Reexamination Certificate
active
06193968
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to antibodies which are useful as &agr;
v
&bgr;
3
integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by &agr;
v
&bgr;
3
by inhibiting or antagonizing &agr;
v
&bgr;
3
integrins.
2. Background of the Invention
Integrins are a group of cell surface glycoproteins that mediate cell adhesion and therefore are mediators of cell adhesion interactions that occur in various biological processes. Integrins are heterodimers composed of noncovalently linked &agr; and &bgr; polypeptide subunits. Currently at least eleven different &agr; subunits have been identified and at least six different &bgr; subunits have been identified. The various &agr; subunits can combine with various &bgr; subunits to form distinct integrins.
The integrin identified as &agr;
v
&bgr;
3
(also known as the vitronectin receptor) has been identified as an integrin that plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, angiogenesis, including tumor angiogenesis, retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis). Additionally, it has been found that such integrin inhibiting agents would be useful as antivirals, antifungals and antimicrobials. Thus, antibodies that selectively inhibit or antagonize &agr;
v
&bgr;
3
would be beneficial for treating such conditions.
It has been shown that the &agr;
v
&bgr;
3
integrin binds to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules, such as fibrinogen (Bennett et al., Proc. Natl. Acad. Sci. USA, Vol. 80 (1983) 2417), fibronectin (Ginsberg et al., J. Clin. Invest., Vol. 71 (1983) 619-624), and von Willebrand factor (Ruggeri et al., Proc. Natl. Acad. Sci. USA, Vol. 79 (1982) 6038-6041). Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides that bind to &agr;
v
&bgr;
3
also bind to &agr;
v
&bgr;
5
, &agr;
v
&bgr;
1
, and &agr;
IIb
&bgr;
IIIa
. Antagonism of platelet &agr;
IIb
&bgr;
IIIa
(also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions of disease states associated with the integrin &agr;
v
&bgr;
3
, it would be beneficial to develop selective antagonists of &agr;
v
&bgr;
3
as opposed to &agr;
IIb
&bgr;
IIIa
. Antibodies selective for &agr;
v
&bgr;
3
offer such an advantage.
SUMMARY OF THE INVENTION
The present invention provides methods for treating tumor metastasis, comprising administering to a mammal in need of such treatment an anti-&agr;
v
&bgr;
3
integrin monoclonal antibody. In a preferred embodiment, the monoclonal antibody is complex-specific. Also provided is a method for inhibiting or preventing tumor metastasis from a tumor containing human tumor cells.
The monoclonal antibodies employed in the present methods are produced from hybridomas generated from mice immunized with human integrin &agr;
v
&bgr;
3
, and or cells expressing &agr;
v
&bgr;
3
, that block the functional activity of &agr;
v
&bgr;
3
. More specifically, the murine monoclonal antibodies involve, P113-7D6, P112-4C1, P113-12A6, P112-11D2, P112-10D4 and P113-1F3, which are complex specific for &agr;
v
&bgr;
3
in the sense that they immunoreact with an integrin &agr;
v
&bgr;
3
complex and do not react with either of the integrin &agr;
v
or &bgr;
3
subunits individually. In addition, the inventive monoclonal antibodies do not significantly bind to &agr;
IIb
&bgr;
IIIa
. The monoclonal antibodies used in the present methods may also be used in treating &agr;
v
&bgr;
3
integrin-mediated diseases or conditions by administering to a mammal in need of treatment an effective amount of an &agr;
v
&bgr;
3
integrin antibody that acts as an &agr;
v
&bgr;
3
integrin antagonist or inhibitor.
REFERENCES:
patent: 4659839 (1987-04-01), Nicolotti et al.
patent: 4816567 (1989-03-01), Cabilly et al.
patent: 5057604 (1991-10-01), Brown
patent: 5130118 (1992-07-01), Johnson et al.
patent: 5149780 (1992-09-01), Plow et al.
patent: 5252748 (1993-10-01), Yamauchi et al.
patent: 5306620 (1994-04-01), Ginsberg et al.
patent: 5591829 (1997-01-01), Matsushita
patent: 5631236 (1997-05-01), Woo et al.
patent: 5679318 (1997-10-01), Vanderheyden et al.
patent: 5681927 (1997-10-01), Fritzberg et al.
patent: 5693761 (1997-12-01), Queen et al.
patent: WO 89/05155 (1989-06-01), None
patent: WO 93/20229 (1993-10-01), None
patent: 95/25543 (1995-09-01), None
E. Aboud-Pirak, et al., “Inhibition of Human Tumor Growth in Nude Mice by a Conjugate of Doxorubicin With Monoclonal Antibodies to Epidermal Growth Factor Receptor”, Proc. Natl. Acad. Science, vol. 86, pp. 3778-3781, (1989).
A. Adamis, et al., “Increased Vascular Endothelial Growth Factor Levels in the Vitreous of Eyes With Proliferative Diabetic Retinopathy”, Amer. Journal of Ophthalmology vol. 118, pp. 445-450, (1994).
L. Apelgren, et al., “Antitumor Activity of the Monoclonal Antibody-Vinca Alkaloid Immunoconjgate LY203725 (KS1/4-4-Desacetylvinblastine-3-carboxhydrazide) in a Nude Mouse Model of Human Ovarian Cancer”, Cancer Research, vol. 50, 3540-3544, (1990).
A. Bachmann et al., “Integrin receptor-targeted transfer peptides for efficient delivery of antisense oligodeoxynucleotides”, Journal of Molecular Medicine, vol. 76, No. 2, pp. 126-132 (1998).
J. Bennett, et al., “Inhibition of fibrinogen binding to stimulated human platelets by a monoclonal antibody”, Proc. Natl. Acad. Science, vol. 80, pp. 2417-2421, (1983).
S. Bodary et al., “The Integrin &bgr;1 Submit Associates with the Vitronectin Receptor &agr;v Subunit to Form a Novel Vitronectin Receptor in a Human Embryonic Kidney Cell Line”, J. Biolog. Chem., vol. 265, pp. 5938-5941, (1990).
P. Brooks, et al.,“Antiintegrin &agr;v&bgr;3blocks human breast cancer growth and angiogenesis in human skin”, J. Clin. Invest., vol. 96, pp. 1815-1822, (1995).
P. Brooks, et al., “Integrin &agr;v&bgr;3Antagonists Promote Tumor Regression by Inducing Apoptosis of Angiogenic Blood Vessels”, Cell Press, vol. 79, pp. 1157-1164, (1994).
P. Brooks, et al., “Requirement of Vascular Integrin &agr;v&bgr;3for Angioenesis”, Science, vol. 264, (1994).
D. Cheresh, “Human endothelial cells synthesize and express an Arg-Gly-Asp-directed adhesion receptor involved in attachment to fibrinogen and von Willebrand factor”, Proceedings of the National Academy of Sciences, vol. 84, No. 18, pp. 6471-6475, (1987).
E. Choi, et al., “Inhibition of neointimal hyperplasia by blocking &agr;v&bgr;3integrin with a small peptide antagonist Gpen GRGDSPCA”, J. of Vascular Surgery, vol. 19, No. 1, pp. 125-134, (1994).
A. Chuntharapai, et al., “Blocking Monoclonal Antibodies to &agr;V&bgr;3Integrin Ia Present on Human Osteoclasts”,Cell Research, vol. 205, No. 2, (1993).
S. Crooke, “Therapeutic Applications of Oligonucleotides”, Bio/Technology, vol. 10, pp. 882-886, (1992).
R. Dillman, et al., “Superiority of an Acid-Labile Daunorubicin-Monoclonal Antibody Immunoconjugate Compared to Free Drug”, Cancer Research, vol. 48, pp. 6097-6102, (1988).
M. Doerr, et al., “The Roles of Integrins and Extracellular Matrix Proteins in the Insulin-like Growth I-stimulated Chemotaxis of Human Breast Cancer Cells”, J. Biological Chemistry, vol. 271, No. 5, pp. 2443-2447, (1996).
J. Fisher, et al., “Inhibition of Osteoclastic Bone Resorption in Vivo by Eshistatin, an Arginyl-Glycyl-Aspartyl (RGD)—Containing Protein”, Endocrinology, vol. 132, pp. 1411-1413, (1983).
G. Fuller et al., “Fibrinogen”, Methods in Enzymol, vol. 163, pp. 474-485, (1988).
G. Galfre et al., “Immunochemical Techniques”, Methods in Enzymology, vol. 73, pp. 3-46, (1981).
M. Ginsberg, et al., “Reduced Surface Expression and Binding
Carron Christopher P.
Meyer Debra M.
Nickols George A.
Smith Jeffrey W.
Davis Minh-Tam
Eyler Yvonne
Fitzpatrick ,Cella, Harper & Scinto
The Burnham Institute
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