Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1996-11-13
1999-07-27
Chan, Christina Y.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
435 7021, 435326, 435346, 5303873, 5303881, 53038875, C12P 2108, C12N 1513, C07K 1628
Patent
active
059288930
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a monoclonal antibody(MAb) having an immunosuppressive activity, which is specific for human 4-1BB; a polynucleotide encoding the variable region thereof; and a hybridoma cell line producing same. More specifically, it pertains to a monoclonal antibody specific for human 4-1BB which is selectively expressed on activated T cells; polynucleotides encoding the variable regions of the monoclonal antibody and amino acid sequences deduced therefrom; a hybridoma cell line producing the monoclonal antibody; a process for preparing the cell line; and an immunosuppressive agent comprising the monoclonal antibody or a variant thereof.
BACKGROUND OF THE INVENTION
An immune response in human body is induced by a cascade of various processes which may be described as follows. First, an antigen is internalized through, e.g., phagocytosis, by antigen-presenting cells and degraded by cellular lysozyme, and the remainder forms a complex with a major histocompatibility complex(MHC) class II molecule. The resulting complex, after migrating to the outer surfacts of the antigen-presenting cell, is recognized by an antigen receptor of a helper T cell, triggering an antigen-specific humoral immune response. On the other hand, when an antigen, e.g., a viral antigen, is produced within a cell, it is degraded in the cell and the remainder forms a complex with a MHC class I molecule. The resulting complex moves to the outer surface of the virus-producing cell and an antigen-specific cellular immune response is initiated by the recognition of the complex by an antigen receptor of a cytotoxic T cell.
Subsequently, the T and antigen-presenting cells enter the initial stage of activation wherein new molecules, called accessory molecules, are expressed on their surfaces. The accessory molecules on the T cell bind to the corresponding ligand on the antigen-presenting cell and this binding accelerates the activation of the T and antigen-presenting cells, thereby promoting various immune responses. Representative accessory molecules include B7-1, B7-2, CD28, CTLA4, CD40, CD40 ligand, 4-1BB and 4-1BB ligand molecules(Goodwin et al., Eur. J. Immunol., 23, 2631(1993)).
The above-mentioned binding of accessory molecule, is indispensable for the activation of immune cells and, hence, the induction of an immune response. Accordingly, blocking of such binding may be decisive in suppressing immune responses. Further, immune responses may also be suppressed by depleting only the activated T cells which express the accessory molecules.
4-1BB, one of the accessory molecules mentioned above, was originally described as a protein expressed by activated murine T cells(Kwon, B. S., et al., Proc. Natl. Acad. Sci. U.S.A., 84, 2896-2900(1987); and Kwon, B. S. and Weissman, S. M., Proc. Natl. Acad. Sci. U.S.A., 86, 1963-1967(1989)) and subsequently demonstrated to encode a member of the tumor necrosis factor(TNF) receptor family of integral membrane proteins(Mallett, S. and Barclay, A. N., Immunol. Today, 12, 220-222(1991)). This receptor family is characterized by the presence of cysteine-rich motifs in the extracellular domains. Other members of this family include NGFR, CD40, OX-40, CD27, TNFR-I, TNFR-II, Fas and CD30(Smith, C. A., et al., Cell, 76, 959-962(1994); and Beutler, B. and VanHuffel, C., Science, 264, 667-668(1994)). 4-1BB is a 55 kDa homodimer and is expressed on a variety of murine T cell lines, thymocytes and mature T cells upon activation with concanavalin A(Con A), phytohemagglutinin(PHA) and ionomycin, or anti-CD3i(Kwon, B. S., et al., Cell. Immunol., 121, 414-422(1989); and Pollok, K. E., et al., J. Immunol., 150, 771-781(1993)). 4-1BB was found to be specifically coimmunoprecipitated with p56.sup.lck and to upregulate its own expression in Con A-stimulated thymocytes(Kim, Y. J., et al., J. Immunol., 151, 1255-1262(1993)). These results suggest that 4-1BB plays a role in intracellular signalling.
Crosslinking of 4-1BB on the surface of mouse T cell with a monoclonal antibody(MAb)
REFERENCES:
patent: 5530101 (1996-06-01), Queen et al.
patent: 5674704 (1997-10-01), Goodwin et al.
Kahan, B. Cur. Opin. Immunol. 4: 553-560, 1992.
Pollok, K. et al. J. Immunol. 150: 771-781, Feb. 1993.
Lenschow, D. et al. J. Exp. Med. 181: 1145-1155, Mar. 1995.
Kang Chang-Yuil
Kim Joong-Gon
Chan Christina Y.
LG Chemical Ltd.
Rabin Evelyn
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