Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Patent
1995-05-03
1998-04-21
Feisee, Lila
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
4241301, 4241411, 4241431, 4241441, 4241451, 4241531, 4241581, 4241731, A61K 39395
Patent
active
057414882
DESCRIPTION:
BRIEF SUMMARY
RELATED APPLICATIONS
This application is the U.S. National Phase Application of PCT/GB93/02070 having an International Filing Date of Oct. 6, 1993, which is a continuation-in-part of U.S. Ser. No. 07/958,248, filed Oct. 8, 1992 (now abandoned), the teachings of which are incorporated herein, in their entirety, by reference.
BACKGROUND OF THE INVENTION
The nature of autoantigens responsible for autoimmune disorders is not known, nor is the action which triggers the autoimmune response. One popular theory involves the similarity of a viral protein to a self antigen, which results in autoreactive T cells or B cells recognizing a self antigen. Whereas B-lymphocytes produce antibodies, thymus-derived or "T-cells" are associated with cell-mediated immune functions. T-cells recognize antigens presented on the surface of cells and carry out their functions with these "antigen-presenting" cells.
Various markers have been used to define human T cell populations. CD4 is a non-polymorphic surface glycoprotein receptor with partial sequence identity to immunoglobulins. CD4+ receptors define distinct subsets of mature peripheral T cells. In general, CD4 T cells expressing helper or regulatory functions interact with B cells in immune responses, while T cells expressing the CD8 surface antigen function as cytotoxic T cells and have regulatory effects on immune responses. Since T-cell receptors are the pathway through which stimuli augment or modulate T-cell responses, they present a potential target for immunological intervention.
Of the cellular interactions, that of CD4+ T cells with antigen presenting cells (APC) lies at the root of the immune response. Many aspects of the autoimmune response are essentially similar to that of normal immune responses. Thus CD4+ autoantigen reactive T cells are restimulated by APC expressing class II with autoantigen peptides in the binding groove. In certain human diseases the evidence that this occurs has been provided: in Graves' disease of the thyroid, in vivo activated T cells are present in the glands that are removed for refractory disease, and many of these cells after cloning can be shown to recognize autologous thyrocytes (as APC) not extrinsically supplied with any antigen, or APC supplied with the thyroid specific antigens thyroid peroxidase or thyroglobulin (Londei, M. et al., Science 228: 85-89 (1985); Dayan, C. M. et al., Proc. Natl. Acad. Sci. USA 88: 7415-7419 (1991)). Similarly, in rheumatoid arthritis (RA), in vivo activated T cells recognizing collagen type II have been isolated from joints of an RA patient in three consecutive operations during the course of three years (Londei, M. et al., Proc. Natl. Acad. Sci. 86: 636-640 (1989)). In other human diseases displaying autoimmune characteristics, CD4+ T cells from the blood have been cloned, including CD4+ cells recognizing the acetylcholine receptor in myasthenia gravis (Hohlfeld, R. et al., Nature 310: 224-246 (1984)); myelin basic protein in multiple sclerosis (Hafler, D. A. et al., J. Immunol. 139: 68-72 (1987)); or islet cell membranes in insulin dependent diabetes mellitus (De Berardinis, P. et al., Lancet II: 823-824 (1988); Kontiainen, S. et al., Autoimmunity 8: 193-197 (1991)).
Treatment with antibodies specific for CD4 is effective in preventing a wide range of both experimentally-induced and spontaneously-occurring autoimmune diseases. For example, treatment with either anti-CD4 or anti-MHC class II antibodies was found to effectively prevent murine collagen-induced arthritis as well as murine streptococcal cell wall-induced arthritis (Ranges, G. E. et al., J. Exp. Med. 162: 1105-1110 (1985); Hom, J. T. et al., Eur. J. Immunol. 18: 881-888 (1988); Wooley, P. H. et al., J. Immunol. 134: 2366-2374 (1985); Cooper, S. M. et al., J. Immunol. 141: 1958-1962 (1988); Van den Broek, M. F. et al., Eur. J. Immunol. 22: 57-61 (1992)). Anti-CD4 treatment also prevented systemic lupus erythematosus in NZB/NZW F1 (B/W) mice and BXSB mice (Wofsy, D. et al., J. Immunol. 134: 852-857 (1985); Wofsy, D. et al., J. Immunol
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Feldman Marc
Maini Ravinder N.
Williams Richard O.
Feisee Lila
Gambel Phillip
The Kennedy Institute for Rheumatology
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