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 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.
Egan
R W
RW
Department of Allergy and Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey, USA.
Athwal
D
D
Bodmer
M W
MW
Carter
J M
JM
Chapman
R W
RW
Chou
C C
CC
Cox
M A
MA
Emtage
J S
JS
Fernandez
X
X
Genatt
N
N
Indelicato
S R
SR
Jenh
C H
CH
Kreutner
W
W
Kung
T T
TT
Mauser
P J
PJ
Minnicozzi
M
M
Murgolo
N J
NJ
Narula
S K
SK
Petro
M E
ME
Schilling
A
A
Sehring
S
S
Stelts
D
D
Stephens
S
S
Taremi
S S
SS
Zurcher
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000494:pharmacology*; D001667:Binding, Competitive; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003001:Cloning, Molecular; D004802:Eosinophilia / Q000276:immunology / Q000473:pathology; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology* / Q000378:metabolism; D007700:Kinetics; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000473:pathology; D008252:Macaca fascicularis; D051379:Mice; D008815:Mice, Inbred Strains; D009504:Neutrophils / Q000473:pathology; D011817:Rabbits; D051381:Rats; D012867:Skin / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D015848:Interleukin-5