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
1993-12-20
1998-08-18
Feisee, Lila
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...
53038824, 53038873, C07K 1600
Patent
active
057959650
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to variable regions (V region) of a mouse monoclonal antibody to the human interleukin-6 receptor (IL-6R), human/mouse chimeric antibody to the human IL-6R, and reshaped human antibody comprising a human antibody wherein the complementarity determining regions (CDRs) of the human light chain (L chain) V region and of the human heavy chain (H chain) V region are grafted with the CDRs of a mouse monoclonal antibody to the human IL-6R. Moreover, the present invention provides DNA coding for the above-mentioned antibodies or part thereof. The present invention further provides vectors, especially expression vectors comprising said DNA, and host cells transformed or transfected with said vector. The present invention still more provides a process for production of a chimeric antibody to the human IL-6R, and process for production of a reshaped human antibody to the human IL-6R.
BACKGROUND ART
Interleukin-6 (IL-6) is a multi-function cytokine that is produced by a range of cells. It regulates immune responses, acute phase reactions, and hematopoiesis, and may play a central role in host defense mechanisms. It acts on a wide range of tissues, exerting growth-inducing, growth inhibitory, and differentiation-inducing effects, depending on the nature of the target cells. The specific receptor for IL-6 (IL-6R) is expressed on lymphoid as well as non-lymphoid cells in accordance with the multifunctional properties of IL-6. Abnormal expression of the IL-6 gene has been suggested to be involved in the pathogenesis of a variety of diseases, especially autoimmune diseases, mesangial proliferative glomerulonephritis, and plasmacytoma/myeloma (see review by Hirano et al., Immunol. Today 11, 443-449, 1990). Human myeloma cells are observed to produce IL-6 and express IL-6R. In experiments, antibody against IL-6 inhibited the in vitro growth of myeloma cells thus indicating that an autocrine regulatory loop is operating in oncogenesis of human myelomas (Kawano et al., Nature, 332, 83, 1988).
The IL-6R is present on the surface of various animal cells, and specifically binds to IL-6, and the number of IL-6R molecules on the cell surface has been reported (Taga et al., J. Exp. Med. 196, 967, 1987). Further, cDNA coding for a human IL-6R was cloned and a primary structure of the IL-6R was reported (Yamasaki et al., Science, 241, 825, 1988).
Mouse antibodies are highly immunogenic in humans and, for this reason, their therapeutic value in humans is limited. The half-life of mouse antibodies in vivo in human is relatively short. In addition, mouse antibodies can not be administered in multiple doses without generating an immune response which not only interferes with the planned efficacy but also risks an adverse allergic response in the patient.
To resolve these problems methods of producing humanized mouse antibodies were developed. Mouse antibodies can be humanized in two ways. The more simple method is to construct chimeric antibodies where the V regions are derived from the original mouse monoclonal antibody and the C regions are derived from suitable human antibodies. The resulting chimeric antibody contains the entire V domains of the original mouse antibody and can be expected to bind antigen with the same specificity as the original mouse antibody. In addition, chimeric antibodies have a substantial reduction in the percent of the protein sequence derived from a non-human source and, therefore, are expected to be less immunogenic than the original mouse antibody. Although chimeric antibodies are predicted to bind antigen well and to be less immunogenic, an immune response to the mouse V regions can still occur (LoBuglio et al., Proc. Natl. Acad. Sci. USA 84, 4220-4224, 1989).
The second method for humanizing mouse antibodies is more complicated but more extensively reduces the potential immunogenicity of the mouse antibody. In this method, the complementarity determining regions (CDRs) from the V regions of the mouse antibody are grafted into human V regions to create "res
REFERENCES:
Oi et al. Biotechniques. vol. 4, No. 3, 1986 p. 214.
Morrison Hospital Practice Oct. 15, 1989, 65.
Kitani et al. Clin. Exp. Immunol. 88, 75-83 1992.
Suzuki et al. Immunology letters 30(1991) 17-22.
Bendig Mary Margaret
Jones Steven Tarran
Saldanha Jose William
Sato Koh
Tsuchiya Masayuki
Bansal Geetha P.
Chugai Seiyaku Kabushiki Kaisha
Feisee Lila
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