Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1994-09-30
1996-11-26
Parr, Margaret
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
5303882, 5303871, 5303913, 5303911, 435 7021, 43524027, 4241411, 4241431, 4241521, C07K 1628, C12P 2108, C12N 520
Patent
active
055787045
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This application relates to hybrid cell lines (lymphocyte hybridomas) for the production of monoclonal antibodies to .alpha.v.beta.3 integrin, to such homogeneous antibodies, and to the use of such antibodies for diagnostic and therapeutic purposes.
BACKGROUND OF THE INVENTION
.alpha.v.beta.3 is a member of the integrin supergene family of cell-surface glycoprotein receptors that promote cellular adhesion. Each cell has a specific repertoire of receptors that define its adhesive capabilities. The integrins are expressed as heterodimers of noncovalently associated .alpha. and .beta. subunits. According to the nomenclature proposed by Hynes, R. O. [Cell 48, 875-886 (1987)], the integrins can be divided into families each with a common .beta.-subunit and a set of variable .alpha.-subunits known to associate with the common .beta.-subunit. The different .alpha. chains are denoted by the original cell type, by a subscript used by the original discoverer, or, as in the case of the .alpha.v.beta.3 receptor, by the nature of the ligand (i.e. .alpha.v stands for a vitronectin receptor .alpha.-chain). Many, but not all, integrin receptors have been shown to interact with proteins via a tripeptide sequence, Arg-Gly-Asp (or RGD using the single letter amino acid code), originally defined from studies of the cell binding domains of fibronectin [Ruoslahti, E. and Pierschbachter, M. D., Cell 44, 5170518 (1986); Ruoslahti, E. and Pierschbachter, M.D., Science 238, 491-497 (1987)].
.alpha.v.beta.3 (also referred to as vitronectin receptor or VNR) is a member of the .beta.3 integrin subfamily and is expressed on a variety of cells, including endothelial, melanoma, smooth muscle cells and, along with another integrin .alpha.2.beta.1 (VLA-2) (the receptor for Type I collagen and laminin), on the surface of osteoclasts [Horton, M. A. and Davies, J., J. Bone Min. Res. 4, 803-808 (1989); Davies, J. et al., J. Cell. Biol. 109, 1817-1826(1989); Horton, M., Int. J. Exp. Pathol. 71 741-759 (1990)]. .alpha.v.beta.3 mediates cell adhesion to vitronectin, fibrinogen, fibronectin, thrombospondin, osteopontin, bone sialo protein II and von Willebrand factor.
Osteoclasts are the main type of bone cells involved in the resorption of bone tissues. The resorption process involves the proliferation and chemotaxis of developing osteoclasts to the skeleton from hematopoietic sites migration of mature cells to sites of subsequent resorption, attachment of osteoclasts to bone substrate and the eventual formation of the polarized, functional mature end cells which are directly involved in bone resorption. The .alpha.v.beta.3 integrin mediates adhesion of osteoclasts to RGD sequence-containing bone matrix proteins.
Antibodies to .alpha.v.beta.3 are expected to be valuable diagnostic and therapeutic tools in studying the biological role and the structural/functional relationships of this integrin with its various ligands. In particular, monoclonal antibodies (Mabs) detecting unique epitopes on osteoclasts would be of great value in understanding of the development of osteoclasts. Even more importantly, neutralizing Mabs specific for .alpha.v.beta.3 that inhibit the osteoclast binding to the bone matrix proteins have great potential as therapeutic agents useful in the treatment of conditions associated with excessive bone resorption.
There are several monoclonal antibodies known in the art that bind to various epitopes on .alpha.v.beta.3. Immunizing with osteoclasts from osteoclastomas (giant cell tumors of bone), Horton, M. A. et al. [Cancer Res. 45, 5663-5669 (1985)] produced eleven mouse hybridomas secreting monoclonal antibodies which bind to osteoclasts in normal human fetal bone and a variety of neoplastic and non-neoplastic bone lesions. One of these, designated 23C6, was subsequently shown to bind the .alpha.v.beta.3 complex, and was demonstrated to be able to disrupt osteoclast function [Horton, M. A. et al., Exp. Cell. Res. 195 368-375 (1991)]. Another monoclonal antibody, LM609 (produced in hybridoma LM609 ATCC H
REFERENCES:
patent: 4707352 (1987-11-01), Stavrianpoulos
patent: 5057604 (1991-10-01), Brown
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Bodary Sarah C.
Chuntharapai Anan
Horton Michael A.
Kim Kyung J.
Genentech Inc.
Hasak Janet E.
Krikorian Jacqueline G.
Lee Wendy M.
Parr Margaret
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