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...
Reexamination Certificate
1999-04-01
2004-03-02
Helms, Larry R. (Department: 1642)
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...
C530S387100, C424S130100, C424S156100
Reexamination Certificate
active
06699974
ABSTRACT:
This application is the national phase of PCT application PCT/JP97/03553 filed Oct. 3, 1997 which claims priority from Japanese application 8-264756 filed Oct. 4, 1996.
1. Field of the Invention
The present invention relates to reshaped human anti-HM 1.24 antibodies and chimeric anti-HM 1.24 antibodies, genes encoding them, methods for producing said antibodies, and the use of said antibodies. The reshaped human antibodies and the chimeric antibodies of the present invention are useful as a therapeutic agent, etc. for myeloma.
2. Background Art
Human B cells go through a variety of processes that are classified based on the kind of surface antigens being expressed, and finally mature into antibody-producing plasma cells. At the final stage of their differentiation, B cells, on one hand, acquire the ability of producing cytoplasmic immunoglobulins and, on the other, B cell-associated antigens such as cell surface immunoglobulins, HLA-DR, CD20, Fc receptors, complement C3 receptors and the like disappear (Ling, N. R. et al., Leucocyte Typing III (1986) p320, Oxford, UK, Oxford).
So far, there have been reports on monoclonal antiboies such as anti-PCA-1 (Anderson, K. C. et al., J. Immunol. (1983) 130, 1132), anti-PC-1 (Anderson, K. C. et al., J. Immunol. (1983) 132, 3172), anti-MM4 (Tong, A. W. et al., Blood (1987) 69, 238) and the like that recognize antigens on the cell membrane of the plasma cells. However, anti-CD38 monoclonal antibody is still being used for detection of plasma cells and myeloma cells (Epstein, J. et al., N. Engl. J. Med. (1990) 322, 664, Terstappen, L. W. M. M. et al., Blood (1990) 76, 1739, Leo, R. et al., Ann. Hematol. (1992) 64, 132, Shimazaki, C. et al., Am J. Hematol. (1992) 39, 159, Hata, H. et al., Blood (1993) 81, 3357, Harada, H. et al., Blood (1993). 81, 2658, Billadeau, D. et al., J. Exp. Med. (1993) 178, 1023).
However, anti-CD38 monoclonal antibody is an antigen associated with activation of T cells rather than an antigen associated with differentiation of B cells, and is expressed on various cells in addition to B cells. Furthermore, although CD38 is not expressed on some of the lymphoplasmacytoid, it is strongly expressed on the hemopoietic precursor cells. For these reasons, it is believed that anti-CD38 monoclonal antibody is not suitable for research on differentiation and maturation of human B cells or for treatment of diseases of plasma cells.
Goto, T. et al. have reported mouse anti-HM 1.24 monoclonal antibody that recognizes an antigen having a molecular weight of 29 to 33 kDa which is specifically expressed on B cell lines (Blood (1994) 84, 1922-1930). From the fact that the antigen recognized by anti-HM 1.24 monoclonal antibody is believed to be associated with the terminal differentiation of B cells (Goto, T. et al., Jpn. J. Clin. Immun. (1992) 16, 688-691) and that the administration of anti-HM 1.24 monoclonal antibody to a plasmacytoma-transplanted mouse resulted in specific accumulation of the antibody at the tumor (Shuji Ozaki et al., The Program of General Assembly of the 19th Japan Myeloma Study Meeting, general presentation 3), it has been suggested that anti-HM 1.24 monoclonal antibody, by labelling with a radioisotope, may be used for diagnosis of tumor localization, the missile therapy such as radioimmunotherapy, and the like.
Furthermore, the above-mentioned Blood describes that the anti-HM 1.24 monoclonal antibody has the complement-dependent cytotoxicity activity to the human myeloma cell line RPMI8226.
Myeloma is a neoplastic disease characterized by the accumulation of monoclonal plasma cells (myeloma cells) in the bone marrow. Myeloma is a disease in which terminally differentiated B cells that produce and secrete immunoglobulins, or plasma cells, are monoclonally increased mainly in the bone marrow, and accordingly monoclonal immunoglobulins or the constituting components thereof, L chains or H chains, are detected in the serum (Masaaki Kosaka et al., Nippon Rinsho (1995) 53, 91-99).
Conventionally chemotherapeutic agents have been used for treatment of myeloma, but there have been found no effective therapeutic agents that can lead to remission of myeloma and elongation of the survival period of patients with myeloma. There is, therefore, a long-awaited need for the advent of drugs that have a therapeutic effect on myeloma.
Mouse monoclonal antiboies have high immunogenicity (sometimes referred to as “antigenicity”) in humans. Accordingly, the medical therapeutic value of mouse monoclonal antibodies in humans is limited. For example, a mouse antibody administered into a human may be metabolized as a foreign substance so that the half life of the mouse antibody in the human is relatively short and thereby it cannot fully exhibit its expected effects. Furthermore, human anti-mouse antibodies that are raised against the administered mouse antibody may trigger immunological responses that are unfavorable and dangerous to the patients, such as serum disease, other allergic reactions, or the like. Therefore, mouse monoclonal antibody cannot be frequently administered into humans.
In order to resolve these problems, a method was developed for reducing the immunogenicity of non-human-derived antibodies such as mouse-derived monoclonal antibodies. As one such example, there is a method of producing a chimeric antibody in which the variable region (V region) of the antibody is derived from the original mouse and the constant region (C region) thereof is derived from an appropriate human antibody.
Since the chimeric antibody thus obtained contains the variable region of the original mouse antibody in the intact form, it is expected to bind to the antigen with a specificity identical to that of the original mouse antibody. Furthermore, in a chimeric antibody the ratio of the amino acid sequences derived from non-humans is substantially reduced, and so the antibody is expected to have a low immunogenicity compared to the original mouse antibody. A chimeric antibody may bind to the antigen in an equal manner to the original mouse monoclonal antibody, and may include immunological responses against the mouse variable region though the immunogenicity is reduced (LoBuglio, A. F. et al., Proc. Natl. Acad. Sci. USA, 86, 4220-4224, 1989).
The second method for reducing the immunogenicity of mouse antibody, though much more complicated, can reduce the potential immunogenicity of mouse antibody further greatly. In this method, only the complementarity determining region (CDR) of the variable region of a mouse antibody is grafted to the variable region of a human antibody to prepare a “reshaped” human antibody variable region.
However, In order to make the structure of the CDR of a reshaped human antibody variable region as much close as possible to that of the original mouse antibody, if necessary, part of the amino acid sequence of the framework region (FR) that supports the CDR may be grafted from the variable region of the mouse antibody to the variable region of the human antibody. Subsequently, this V region of the humanized reshaped human antibody is linked to the constant region of a human antibody. The part that is derived from the non-human amino acid sequence in the finally reshaped humanized antibody is the CDR, and only part of the FR. A CDR is composed of hypervariable amino acid sequences which do not exhibit species-specific sequences. Therefore, the humanized antibody carrying the mouse CDR should not have an immunogenicity stronger than the natural human antibody having the human antibody CDR.
For the humanized antibody, see Riechmann, L. et al., Nature, 332, 323-327, 1988; Verhoeye, M. et al., Science, 239, 1534-1536, 1988; Kettleborough, C. A. et al., Protein Engng., 4, 773-783, 1991; Meada, H. et al., Human Antibodies and Hybridoma, 2, 124-134, 1991; Groman, S. D. et al., Proc. Natl. Acad. Sci. USA, 88, 4181-4185, 1991; Tempest, P. R. et al., Bio/Technology, 9, 266-271; 1991; Co, M. S. et al., Proc. Natl. Acad. Sci. USA, 88, 2869-2873, 1991; Carter, P. et al., Proc. Natl. Acad. Sci. USA, 89, 4285-4289, 1992; Co, M.
Koishihara Yasuo
Kosaka Masaaki
Ohtomo Toshihiko
Ono Koichiro
Tsuchiya Masayuki
Chugai Seiyaku Kabushiki Kaisha
Helms Larry R.
Morrison & Foerster / LLP
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