Ocular inflammation in cynomolgus macaques following intravenous administration of a human monoclonal antibody.
Angiogenesis is a major component of the pathogenesis of various ocular diseases, including age-related macular degeneration (AMD). CNTO95 is a fully human monoclonal antibody against alpha(nu) integrins that has shown antiangiogenic properties in cynomolgus macaques and rats. Because angiogenesis inhibitors may have the potential to treat AMD, a proof-of-concept study was conducted in a macaque model of laser-induced choroidal neovascularization. In the course of this study, transient, intense anterior chamber ocular inflammation was observed within 24 hours following the first intravitreal or intravenous administration of the human monoclonal antibody. These animals had no outward signs of ocular toxicity or discomfort. Additional ocular safety studies demonstrated that the inflammation following intravenous administration of CNTO95 was not due to a contaminant in the vehicle, not due to endotoxin, and not a nonspecific reaction in the macaques from administration of a human monoclonal antibody. The anterior chamber ocular inflammation noted following the first dose did not recur with subsequent CNTO95 dosing. In repeated-dose toxicology studies, histopathological examination of the eyes revealed no ocular toxicity. The reason for the ocular inflammation following intravenous dosing remains unresolved but may be a secondary manifestation of a first-dose systemic infusion reaction.
Martin
Pauline L
PL
Department of Toxicology and Investigational Pharmacology, Centocor Research and Development, 145 King of Prussia Road, Radnor, PA 19087, USA. Pmarti27@cntus.jnj.com
Miller
Paul E
PE
Mata
Marielena
M
Christian
Brian J
BJ
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000867:Anterior Chamber / Q000187:drug effects* / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D020256:Choroidal Neovascularization / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D007275:Injections, Intravenous; D039001:Integrin alpha Chains / Q000276:immunology*; D008252:Macaca fascicularis; D008268:Macular Degeneration / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D018675:Toxicity Tests; D014605:Uveitis / Q000139:chemically induced* / Q000473:pathology; D014822:Vitreous Body / Q000187:drug effects / Q000473:pathology
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039001:Integrin alpha Chains; D000068258:Bevacizumab