Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1998-04-09
2001-01-09
Gambel, Philip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S141100, C424S143100, C424S152100, C424S172100, C435S070210, C435S326000, C435S332000, C435S334000, C435S346000, C530S387100, C530S388100, C530S388200, C530S388220
Reexamination Certificate
active
06171588
ABSTRACT:
BACKGROUND OF THE INVENTION
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.
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). 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 involves murine monoclonal antibodies produced by hybridomas generated from mice immunized with human integrin &agr;
v
&bgr;
3
, or cells expressing &agr;
v
&bgr;
3
, that block the functional activity of &agr;
v
&bgr;
3
. More specifically, the present invention involves murine monoclonal antibodies, P113-7D6, P112-4C1, P113-12A6, P112-llD2, P112-10D4 and P113-lF3, 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
, or other RGD recognizing integrins. The monoclonal antibodies of this invention may also be used in a method of 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.
The monoclonal antibodies of the present invention can also be used in methods for delivering either cytotoxic or cytostatic compounds, nucleic and deoxynucleic acids or radioisotopes to cells having &agr;
v
&bgr;
3
-integrin. For example, the monoclonal antibodies of the present invention (or a Fab, Fab′, F(ab′)2 and F(v) fragments thereof containing a paratope for &agr;
v
&bgr;
3
-integrin) can be conjugated to the cytotoxic or cytostatic compounds, nucleic acids or radioisotopes and then contacted with tissue or cells in vivo or in vitro.
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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).
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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).
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M. Doerr, et al., “The Ro
Carron Christopher P.
Meyer Debra M.
Nickols George A.
Fitzpatrick ,Cella, Harper & Scinto
G. D. Searle & Company
Gambel Philip
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