Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1997-08-13
2001-07-17
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S139100, C424S141100, C424S142100, C514S907000, C514S921000, C530S387100, C530S387900, C530S388100, C530S388220
Reexamination Certificate
active
06261560
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a muscle protein proteolysis inhibiting agent comprising antibody (anti-IL-6R) to Interleukin-6 receptor (IL-6R)
BACKGROUND ART
IL-6 is a cytokine generically referred to as B cell stimulating factor 2 or Interferon &bgr;2. IL-6 was discovered to be a differentiation factor involved in activation of B lymphocytic cells (Hirano, T. et al., Nature 324, 73-76, 1986). Later, it was shown to have an effect on the functions of various cells (Akira, S. et al., Adv. in Immunology 54, 1-78, 1993).
IL-6 is a multi-functional cytokine that acts at various stages of immunity, hematopoiesis, acute phase reactions and so forth (Taga, T. et al., Critical Reviews in Immunol. 1992; 11: 265-280), and in addition to acting as a growth factor of multiple myeloma, has also been reported to be involved in various diseases such as illneses in which plasmacytosis is observed including rheumatism (Hirano, T. et al., Eur. J. Immunol. 1986; 18: 1797-1801; Houssiau, F. A. et al., Arth. Rheum. 1988; 31: 784-788) and Castleman's disease (Yoshizaki, K. et al., Blood 1989; 74: 1360-1367; Brant, S. J. et. al., Clin. Invest. 1990; 86: 592-599), or mesangial cell proliferative nephritis (Ohta, K. et al., Clin. Nephrol. (Germany) 1992; 38 185-189; Fukatsu, A. et al., Lab. Invest. 1991; 65: 61-66; Horii, Y. et al., J. Immunol. 1989; 143: 3949-3955) and cachexia accompanying tumor growth (Strassman, G. et al., J. Clin. Invest. 1992; 89: 1681-1684).
In H-2Ld hIL-6 transgenic mice (IL-6 Tgm), in which human IL-6 (hIL-6) was expressed in excess by genetic engineering, IgG1 plasmacytosis, mesangium proliferative nephritis, anemia, thrombocytopenia and the appearance of autoantibodies were observed (Miyai, T. et al., 21st Japan Immunol. Soc. Pres. “Hematological and Serological Changes Accompanying Aging in H-2Ld hIL-6 Transgenic Mice”: 1991), thereby suggesting that IL-6 is involved in various diseases.
In addition, IL-6 is also known to have the effect of promoting muscle protein proteolysis in myoblasts in vitro (Ebisui, T. et al., Clinical Science, 1995; 89: 431-439).
However, it has heretofore been unknown that antibody to interleukin-6 receptor is effective in inhibiting proteolysis of muscle proteins, and such attempts have yet to be made.
DISCLOSURE OF THE INVENTION
The present invention is intended to provide a drug that inhibits proteolysis of muscle proteins, and more particularly, provides a muscle protein proteolysis inhibiting agent comprising antibody to IL-6 receptor.
Following the occurrence of cancerous cachexnia, septicemia, serious trauma or muscular dystrophy and so forth, proteolysis of skeletal muscle protein proceeds so that a decrease in muscle mass is observed. Until now, only nosotropic measures were implemented for inhibiting agents of this muscle protein proteolysis in these diseases, and a fundamental method of treatment for these diseases has yet to be established.
As a result of conducting earnest studies on the effects of IL-6 receptor antibody on proteolysis of skeletal muscle proteins, the inventors of the present invention found that IL-6 receptor antibody inhibits the expression of proteolytic enzyme systems that promote muscle protein proteolysis as well as their activity, thereby leading to completion of the present invention.
Namely, the present invention relates to a muscle protein proteolysis inhibiting agent comprising IL-6 receptor antibody.
REFERENCES:
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Ebisui et al., “Interleukin-6 induces proteolysis by activating intracellular proteases (cathepsins B and L, proteasome) in C2C12 Myotubes”Clinical Science89:431-439 (1995.
Tsujinaka et al., “Interleukin 6 Receptor Antibody Inhibits Muscle Atrophy and Modulates Proteolytic Systems in Interleukin 6 Transgenic Mice”J. Clinic Invest.97:244-249 (1996).
Fujita et al., “Anti-Interleukin-6 Receptor Antibody Prevents Muscle Atrophy in Colon-26 Adenocarcinoma-Bearing Mice with Modulation of Lysosomal and ATP-Ubiquitin-Dependent Proteolytic Pathways”Int. J. Cancer68, pp. 637-643 (1996).
Miyai et al., Proc. Jpn. Soc. Immunol vol.21 (1991) (English Translation).
Fujita et al., “Official Journal of the European Society of Parenteral and Enteral Nutrition”Clinical NutritionSupplement 2 vol. 14 p. 15 (1995).
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Ebisui Chikara
Fujita Junya
Tsujinaka Toshimasa
Chugai Seiyaku Kabushiki Kaisha
Foley & Lardner
Mertz Prema
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