Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody

Recombinant humanized antivascular endothelial growth factor (rhuMAbVEGF) i s a monoclonal IgG(1) antibody that is being developed as an antiangiogenic agent for use in treating a variety of solid tumors. Preclinical safety st udies included an immunohistochemical tissue cross-reactivity study, in vit ro hemolytic potential and blood compatibility studies, and multiple dose t oxicity studies. Toxicity studies were conducted in cynomolgus monkey becau se rhuMAbVEGF is pharmacologically active in this species and does not bind rat or mouse vascular endothelial growth factor (VEGF). Following twice we ekly administration of rhuMAbVEGF for 4 or 13 wk, young adult cynomolgus mo nkeys exhibited physeal dysplasia characterized by a dose-related increase in hypertrophied chondrocytes, subchondral bony plate formation, and inhibi tion of vascular invasion of the growth plate. In addition, decreased ovari an and uterine weights and an absence of corpora lutea were observed in fem ales receiving 10 and 50 mg/kg/dose in the 13-wk study. Both the physeal an d ovarian changes were reversible with cessation of treatment. No other tre atment-related effects were observed following rhuMAbVEGF administration at doses up to 50 mg/kg. These findings indicate that VEGF is required for lo ngitudinal bone growth and corpora lutea formation and that rhuMAbVEGF can reversibly inhibit physiologic neovascularization at these sites.