Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Patent
1995-11-06
1999-09-28
Chan, Christina Y.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
4241541, 4241791, 53038875, 5303917, A61K 39395, C07K 1628
Patent
active
059584106
DESCRIPTION:
BRIEF SUMMARY
1. INTRODUCTION
The present invention in the fields of immunology and medicine relates to methods for diagnosing and treating sarcoidosis based on the presence in the lungs of sarcoidosis patients of T lymphocytes expressing the V.sub.60 2.3 variant of the T cell receptor a chain. Monoclonal antibodies specific for an epitope of the variable region of the T cell receptor V.sub.60 2.3 chain, or epitope-binding fragments or derivatives of the antibody, are useful in diagnostic and therapeutic methods.
2. BACKGROUND OF THE INVENTION
2.1. Sarcoidosis
Sarcoidosis is a chronic inflammatory disorder with unknown etiology, characterized by non-caseating granulomas in affected organs, in particular, the lungs, lymph nodes, skin and eyes. The disorder is typically accompanied by nonspecific depression of cell-mediated as well as humoral immune responsiveness, and by polyclonal hypergamma-globulinemia (Siltzbach, L. E., Amer. Rev. Resp. Dis. 97:1-8 (1968); Roberts, C. R. et al., Ann. Intern. Med. 94:73 (1981)). At least 90% of the patients with this multisystem disease have pulmonary manifestations characterized by chronic inflammation, granuloma formation and some cases of pulmonary fibrosis. These processes affect the alveoli, airways and blood vessels resulting in an impairment of normal gas exchange. The inflammatory process precedes the other symptoms of sarcoidosis.
CD4.sup.+ T helper (Th) cells are believed to play a central role in the pathogenesis of sarcoidosis. Such activated cells accumulate in the alveolar space, spontaneously release IL2 and proliferate at high rates in vitro and express HLA-DR, a marker of T cell activation (Hunninghake, G. et al., N. Engl. J. Med. 305:429 (1981)). The T cells in the lung which spontaneously release IL2 are primarily of the CD4.sup.+ HLA-DR.sup.+ class (Saltini, C. et al., J. Clin. Invest. 77:1962-1970 (1986)). The release of cytokines results in modulation of granuloma formation and polyclonal activation of B cells to secrete immunoglobulin (Hunninghake et al., supra). A subset of Th cells identified by a mAb designated 5/9, which detects activated T cells, was shown to predominate in the lungs of sarcoidosis patients and was responsible for the release of lymphokines and the polyclonal B cell activation (Rossi, G. A. et al., Am. Rev. Respir. Dis. 133:1086-1090 (1986)). In sarcoidosis patients with high-intensity alveolitis, T lymphocytes from lung (but not those from peripheral blood) spontaneously release IL2 in vitro and replicate at a high rate (Pinkston, P. et al., N. Engl. J. Med. 308:793 (1983)).
2.2. The T Cell Antigen Receptor
T lymphocytes recognize and interact with antigens by means of a cell-surface molecular complex known as the T cell antigen receptor (TCR) complex. The TCR is a clone-specific heterodimeric protein on T cells, which recognizes its "target" antigen in association with a major histocompatibility complex (MHC)-encoded glycoprotein on the surface of antigen presenting cells (APC). CD4.sup.+ T cells recognize predominantly antigen associated with MHC class II molecules whereas CD8.sup.+ T cells recognize antigen associated with MHC class I molecules. The TCR is noncovalently associated with the CD3 complex of molecules. Approximately 90% of peripheral blood T cells express a TCR which is a heterodimer of an .alpha. and a .beta. chain. A small percentage of T cells express a TCR consisting of a heterodimer comprising a .gamma. and a .delta. polypeptide chain. (See, for example, Davis et al., 1988, Nature 334:395-402; Marrack et al., 1986, Sci. Amer. 254:36; Meuer et al., 1984, Ann. Rev. Immunol. 2:23-50; Brenner et al., 1986, Nature 322:145-159; Krangel et al., 1987, Science 237:1051-1055; Hata et al., 1987, Science 238:678-682; Hochstenbach et al., 1988, J. Exp. Med. 168:761-776).
In a given T cell or clone of T cells, each TCR chain is a unique (J), and constant (C) (Siu et al., 1984, Cell 37:393; Yanagi et al., 1985, Proc. Natl. Acad. Sci. USA 82:3430). Hypervariable regions have also been identified (Patten et al., 1984, Nature
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Grunewald Johan
Janson Carl Harald
Jones Nancy
Wigzell Hans
AVANT Immunotherapeutics, Inc.
Chan Christina Y.
Rabin Evelyn
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