Effect of Sch 55700, a humanized monoclonal antibody to human interleukin-5, on eosinophilic responses and bronchial hyperreactivity

This report describes the development and the biology of Sch 55700, a humanized monoclonal antibody to human IL-5 (hIL-5). Sch 55700 was synthesized using CDR (complementarity determining regions) grafting technology by incorporating the antigen recognition sites for hIL-5 onto consensus regions of...

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Published in:	Arzneimittel-Forschung Vol. 49; no. 9; pp. 779 - 790
Main Authors:	EGAN, R. W, ATHWAL, D, INDELICATO, S. R, JENH, C.-H, KREUTNER, W, KUNG, T. T, MAUSER, P. J, MINNICOZZI, M, MURGOLO, N. J, NARULA, S. K, PETRO, M. E, SCHILLING, A, BODMER, M. W, SEHRING, S, STELTS, D, STEPHENS, S, TAREMI, S. S, WEINER, S. H, ZAVODNY, P. J, ZURCHER, J, CARTER, J. M, CHAPMAN, R. W, CHOU, C.-C, COX, M. A, EMTAGE, J. S, FERNANDEZ, X, GENATT, N
Format:	Journal Article
Language:	English
Published:	Aulendorf Cantor 01-09-1999
Subjects:	Animals Antibodies, Monoclonal - biosynthesis Antibodies, Monoclonal - pharmacology Binding, Competitive Biological and medical sciences Bronchial Hyperreactivity - immunology Bronchial Hyperreactivity - pathology Cell Division - drug effects Cell Line Cloning, Molecular Eosinophilia - immunology Eosinophilia - pathology Eosinophils - drug effects Eosinophils - immunology Eosinophils - pathology Humans Immunoglobulin G - immunology Interleukin-5 - immunology Interleukin-5 - metabolism Kinetics Leukocyte Count Lung - immunology Lung - pathology Macaca fascicularis Medical sciences Mice Mice, Inbred Strains Neutrophils - pathology Pharmacology. Drug treatments Rabbits Rats Respiratory system Skin - immunology Skin - pathology Human origin Intraperitoneal administration Intravenous administration Monkey Rabbit Monoclonal antibody Antiasthma agent Intramuscular administration Antiallergic Research and development Guinea pig Interleukin 5 Established cell line Primates Cytokine Rodentia Antiinflammatory agent Antigen antibody reaction Lagomorpha In vitro Biological activity In vivo Vertebrata Biological fixation Mammalia Mouse Animal
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Summary:	This report describes the development and the biology of Sch 55700, a humanized monoclonal antibody to human IL-5 (hIL-5). Sch 55700 was synthesized using CDR (complementarity determining regions) grafting technology by incorporating the antigen recognition sites for hIL-5 onto consensus regions of a human IgG4 framework. In vitro, Sch 55700 displays high affinity (Kd = 20 pmol/l) binding to hIL-5, inhibits the binding of hIL-5 to Ba/F3 cells (IC50 = 0.5 nmol/l) and blocks IL-5 mediated proliferation of human erythroleukemic TF-1 cells. In allergic mice, Sch 55700 (0.1-10 mg/kg, i.p. or i.m.) inhibits the influx of eosinophils in the lungs, demonstrates long duration of activity and the anti-inflammatory activity of this compound is additive with oral prednisolone. In allergic guinea pigs, Sch 55700 (0.03-30 mg/kg i.p.) inhibits both the pulmonary eosinophilia and airway hyperresponsiveness and at 30 mg/kg, i.p. inhibited allergic, but not histamine-induced bronchoconstriction. In allergic rabbits, Sch 55700 blocks cutaneous eosinophilia. Sch 55700 (0.1-1 mg/kg i.p.) also blocks the pulmonary eosinophilia and neutrophilia caused by tracheal injection of hIL-5 in guinea pigs. In allergic cynomolgus monkeys, a single dose of Sch 55700 (0.3 mg/kg i.v.) blocks the pulmonary eosinophilia caused by antigen challenge for up to six months. Sch 55700 is, therefore, a potent antibody against IL-5 in vitro and in a variety of species in vivo that could be used to establish the role of IL-5 in human eosinophilic diseases such as asthma.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0004-4172 1616-7066
DOI:	10.1055/s-0031-1300502