Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1996-02-20
1999-01-05
Hutzell, Paula K.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
435 696, 435 7021, 4353201, 435326, 435328, 435332, 435335, 536 2353, C12P 2104, C12N 1500, C07H 2104
Patent
active
058561358
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/JP94/00859, filed May 30, 1994.
The present invention relates to a human/mouse chimeric antibody comprising variable regions (V regions) of mouse monoclonal antibody SK2 to human interleukin-6 (IL-6) and constant regions (C regions) of human antibody; a reshaped human antibody wherein the complementarity determining regions (CDRs) of a human light chain (L chain) V region and a human heavy chain (H chain) V region are replaced with CDRs of the mouse monoclonal antibody to human IL-6 (SK2); as well as L chains and H chains comprising said antibody.
The present invention further provides DNA coding for said antibody, especially the V regions thereof. The present invention also provides vectors especially expression vectors, comprising said DNA, and hosts transformed with said vectors. The present invention further provides a process for the production of a chimeric antibody to human IL-6, and a process for the production of a reshaped human antibody to human IL-6.
BACKGROUND ART
Interleukin-6 is a multifunctional cytokine produced by a variety of cells. This cytokine controls immune responses, the acute phase reaction and hematopoiesis, and plays a central role in the host defense mechanisms (Kishimoto et al., Blood, 74, 1-10, 1989). This cytokin acts on various tissues, and exhibits growth induction effects, growth inhibitory effects and differentiation induction effects, depending on the nature of the target cell.
It has been suggested that an abnormal expression of the IL-6 gene is related to the generation of various diseases, particularly autoimmune disease, mesangial proliferative glomerulonephritis and plasmacytoma/myeloma (Hirano et al., Immunol. Today, 11, 443-449, 1990; Clein, B. et al., Eur. Cytokine Net. 1, 193-201, 1990). Accordingly, antibodies which inhibit the function of IL-6 are expected to be useful as therapeutic agents in human patients.
In fact, in clinical research wherein mouse monoclonal antibody to human IL-6 was used to treat terminal patients with plasmacytoma, inhibition of the growth of the plasmacytoma, as well as decreases in the levels of circulating M protein, serum calcium, serum IgG and C-reactive protein were shown (Klein, B. et al., Blood, 78, 1198-1204, 1991; Klein, B. et al., Res. Immunol., 143, 774-776, 1992).
Mouse monoclonal antibodies are highly immunogenic n(in other words, "antigenic") in humans, and therefore their therapeutic value in humans is limited. In addition, although mouse monoclonal antibodies may block target activities, they cannot be administered frequently without causing an immune response which results in the danger of an undesirable allergic response.
To solve these problems, processes for the production of humanized antibodies have been developed. Mouse antibodies can be humanized by two processes. The simpler method provides a chimeric antibody comprising variable regions derived from a mouse monoclonal antibody and constant regions derived from a human antibody. The resulting chimeric antibody comprises the entire variable regions of a mouse antibody and would be expected to bind to an antigen with the same specificity as the mouse antibody.
In addition, in a chimeric antibody, the proportion of protein sequence derived from a source other than human is decreased, and therefore its immunogenicity would be expected to be lower than that of a mouse antibody. Although chimeric antibodies bind well to antigens and have a lower antigenicity, there is still a possibility that an immune response to the mouse variable regions will occur (LoBuglio et al., Proc. Natl. Acad. Sci. USA, 86, 4220-4224, 1989).
Although the second process for humanizing a mouse antibody is more complicated, it further Lowers the potential immunogenicity of the mouse antibody. In this process, complementarity determining regions (CDRs) from the variable regions of a mouse antibody are transplanted into the variable regions of a human antibody to construct reshaped human antibody variable regions.
Next, these reshaped human vari
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Hirata Yuichi
Sato Koh
Tsuchiya Masayuki
Chugai Seiyaku Kabushiki Kaisha
Hutzell Paula K.
Vavarro Mark
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