Polynucleotides which encode reshaped IL-8-specific antibodies a

Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives

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435 691, 435 696, 435 697, 435 7021, 435455, 435471, 435326, 435335, 5303873, 53038823, 536 231, 536 234, 536 235, C12N 1513, C12N 510, C07K 2104, C07K 1624

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059945249

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BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to the complementarity determining regions (CDRs) and the variable regions (V regions) of mouse monoclonal antibody against human interleukin-8 (IL-8), to human/mouse chimeric antibody against human IL-8, as well as to a reshaped human antibody wherein the complementarity determining regions of the human light chain (L chain) variable region and the human heavy chain (H chain) variable region are substituted with the CDR of mouse monoclonal antibody against human IL-8. Moreover, the present invention provides DNAs that code for the above-mentioned antibody and its portions. The present invention also relates to a vector that contains the above-mentioned DNA, and more particularly, to an expression vector and a host transformed with said vector. Moreover, the present invention provides a process for producing reshaped human antibody against human IL-8 as well as a process for producing a chimeric antibody against human IL-8.


BACKGROUND ART

Interleukin-8 (IL-8) was discovered in the culture supernatant of monocytes stimulated with lipopolysaccharide (LPS), and is a chemokine known also as monocyte-derived neutrophil chemotactic factor (MDNCF) or neutrophil activating protein-1 (NAP-1). IL-8 is produced by various cells, acts on polymorphonuclear leukocytes and lymphocytes, and possesses activity that causes chemotaxis along its concentration gradient. In addition, not only does it induce chemotaxis in neutrophils, but it also activates neutrophilic functions such as degranulation, the release of superoxide, and the promotion of adhesion to endothelial cells.
In inflammatory diseases, and more specifically in respiratory diseases such as pulmonary cystic fibrosis, idiopathic pulmonary fibrosis, adult respiratory distress syndrome, sarcoidosis and empyema, as well as in skin diseases such as psoriasis, and in chronic rheumatoid arthritis, Crohn's disease and ulcerative colitis, leukocyte infiltration is observed pathologically at the inflamed site of these diseases. In addition, IL-8 is detected in test samples from patients with these diseases, suggesting that IL-8 may play a central role in inflammation. (McElvaney, N. G. et al., J. Clin. Invest., 90, 1296-1301, 1992; Lynch III, J. P. et al., Am. Rev. Respir. Dis., 145, 1433-1439, 1992; Donnelly, S. C. et al., Lancet, 341, 643-647, 1993; Car, B. D. et al., Am. J. Respir. Crit. Care Med., 149, 655-659, 1994; Antony, V. B. et al., J. Immunol., 151, 7216-7223, 1993; Takematsu, H. et al., Arch. Dermatol., 129, 74-80, 1993; Brennan, F. M. et al., Eur. J. Immunol., 20, 2141-2144, 1990; Izzo, R. S. et al., Scand. J. Gastroenterol., 28, 296-300, 1993; Izzo, R. S. et al., Am. J. Gastroenterol., 87, 1447-1452, 1992).
Subsequence to immunizing mice with human IL-8 as antigen, Ko, Y-C. et al. prepared the mouse monoclonal antibody WS-4 that binds to human IL-8 and inhibits the binding of human IL-8 to neutrophils as a result of that binding, namely that neutralizes the biological activity possessed by human IL-8. It has been clearly shown that the isotypes of mouse monoclonal antibody WS-4 consist of a .kappa.-type L chain and a C.gamma.l-type H chain (J. Immunol. Methods, 149, 227-235, 1992).
Known examples of antibodies against human IL-8 other than WS-4 include A.5.12.14 (Boylan, A. M. et al., J. Clin. Invest., 89, 1257-1267, 1992), the anti-Pep-1 antibody and anti-Pep-3 antibody disclosed in International Patent Application No. W092-04372, and DM/C7 (Mulligan, M. S. et al., J. Immunol., 150, 5585-5595, 1993).
It was also found by administration of the mouse monoclonal antibody WS-4 into experimental models using rabbits that neutrophil infiltration is inhibited in pulmonary ischemic and reperfusion injury (Sekido, N. et al., Nature, 365, 654-657, 1993), LPS-induced dermatitis (Harada, A. et al., Internatl. Immunol., 5, 681-690, 1993) and LPS- or interleukin-1 (IL-1)-induced arthritis (Akahoshi, T. et al., Lymphokine Cytokine Res., 13, 113-116, 1994).
A homologue of human IL-8 exists in rabbits, and is referred to as

REFERENCES:
patent: 5530101 (1996-06-01), Queen et al.
Ko, Yue-chau, et al., "A Sensitive enzyme-linked immunosorbent assay for human interleukin-8"J Immunol Methods, 149:227-235 (1992).
Osamu Kanemitsu, "Antibody Engineering" 1st. Edit (Tokyo) Chijin Shokan K..K. pp. 195-234 (1995).
Riechmann, L. et al., "Reshaping Human antibodies for therapy" Nature 332:323-327 (1988).
Buluwela, L. et al., "The use of chromosomal translocations to study human immunoglobulin gene organization: mapping D.sub.H segments within 35kb of C.mu. gene and identification of a new D.sub.H locus" The EMBO Journal, 7:2003-2010 (1988).
Sanz, I. et al., "V.sub.H Sequence of a human anti-Sm autoantibody", J. Immunol. 142:883-887 (1989).

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