Absence of adverse effects in cynomolgus macaques treated with CNTO 95, a fully human anti-alphav integrin monoclonal antibody, despite widespread tissue binding.
OBJECTIVE
CNTO 95 is a fully human anti-alphav integrin monoclonal antibody that inhibits macaque and rodent angiogenesis and inhibits human tumor growth in rodents. The purpose of these studies was to evaluate the preclinical safety of long-term administration of CNTO 95 in cynomolgus macaques.


METHODS
The in vitro binding profiles of CNTO 95 to human and macaque tissues and the in vivo binding to macaque tissues was evaluated by immunohistochemistry. The preclinical safety of CNTO 95 (10 and 50 mg/kg, i.v.) was evaluated in macaques treated once per week for up to 6 months. Safety was evaluated by clinical observations, ophthalmic and physical examinations (including heart rate, blood pressure, and electrocardiogram), clinical pathology (including coagulation parameters), and comprehensive anatomic pathology. The effect of CNTO 95 (50 mg/kg, i.v.) on incisional wound healing was evaluated in macaques.


RESULTS
The tissue binding studies showed that CNTO 95 bound with mild to moderate intensity to macaque and human endothelial cells, epithelial cells, and vascular smooth muscle cells in most normal tissues examined. CNTO 95 showed strong to intense staining to the positive control tissue, human placenta. Despite the widespread binding to normal tissues, treatment of cynomolgus macaques with CNTO 95 produced no signs of toxicity and no histopathologic changes in any of the tissues examined (including ovaries and bone growth plates). CNTO 95 did not impair wound healing.


CONCLUSIONS
These studies show that CNTO 95 is safe and, unlike some other angiogenesis inhibitors, does not seem to inhibit normal physiologic angiogenesis.
Martin
Pauline L
PL
Department of Toxicology and Investigational Pharmacology, Centocor, Inc., Radnor, Pennsylvania 19087, USA. Pmarti27@cntus.jnj.com
Jiao
Qun
Q
Cornacoff
Joel
J
Hall
William
W
Saville
Bradley
B
Nemeth
Jeffrey A
JA
Schantz
Allen
A
Mata
Marielena
M
Jang
Haishan
H
Fasanmade
Adedigbo A
AA
Anderson
Lisa
L
Graham
Martin A
MA
Davis
Hugh M
HM
Treacy
George
G
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001011:Aorta / Q000378:metabolism; D019540:Area Under Curve; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D007107:Immune System; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000737:chemistry*; D008252:Macaca fascicularis; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D009389:Neovascularization, Pathologic; D010920:Placenta / Q000378:metabolism; D011485:Protein Binding; D013997:Time Factors; D014945:Wound Healing
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039564:Integrin alphaV; C486839:intetumumab