title: Safety and kinetic properties of a humanized antibody to human interleukin-6 receptor in healthy non-human primates.
abstract: A monoclonal antibody, hPM-1, was constructed by grafting the complementarity determining regions to human interleukin-6 (IL-6) receptor, raised in mouse, onto a human antibody backbone (humanized antibody). It is expected to be useful as a therapeutic agent for IL-6-related diseases such as multiple myeloma. To investigate the toxicological and kinetic properties of hPM-1 preliminarily, normal cynomolgus monkeys, which showed cross-reactivity with hPM-1, were intravenously administered with hPM-1 at doses of 0 (vehicle), 4 or 40 mg/kg once a week for 13 weeks. Upon toxicological examination, there were no changes in clinical signs, food consumption, body weights, urinalyses, body temperatures, electrocardiograms, hematological and biochemical parameters including blood platelet counts, serum levels of immunoglobulin G and C-reactive protein, and pathological findings. In a kinetic study, serum concentrations of hPM-1 showed a linearity between doses of 4 and 40 mg/kg. The serum concentrations, even at a dose of 4 mg/kg, were maintained at a high enough level to inhibit the IL-6 functions throughout the period of the study. Concentrations of hPM-1 in bone marrow were almost equal to those in serum. The antibodies against hPM-1 were detected only in one of four monkeys receiving hPM-1. This study suggests that blockage of the IL-6 receptor by hPM-1 does not induce any influence on a healthy living body, and hPM-1 is not toxic under the conditions of this investigation.
authors.affiliation: Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Shizuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shinkura
authors.forename: I
authors.initials: I
authors.lastname: Imazeki
authors.forename: N
authors.initials: N
authors.lastname: Fukushima
authors.forename: N
authors.initials: N
authors.lastname: Chiba
authors.forename: F
authors.initials: F
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Aikawa
authors.forename: H
authors.initials: H
authors.lastname: Kitamura
authors.forename: T
authors.initials: T
authors.lastname: Furuichi
authors.forename: N
authors.initials: N
authors.lastname: Horiba
authors.forename: Y
authors.initials: Y
authors.lastname: Ohsugi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000633:toxicity*; D015703:Antigens, CD / Q000276:immunology*; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000737:chemistry; D006131:Growth Inhibitors / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000032:analysis; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D010976:Platelet Count; D018123:Receptors, Interleukin / Q000276:immunology*; D019947:Receptors, Interleukin-6; D012449:Safety
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D006131:Growth Inhibitors; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6