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Preclinical Safety Evaluation of rhuMAbVEGF, an Antiangiogenic Humanized Monoclonal Antibody

Departement of Pathology, Genentech, Inc., South San Francisco, Department of Pathology, MS 72 B, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, ryan.anne{at}gene.com.

Dorothy Bates Eppler

Department of Toxicology, Genentech, Inc., South San Francisco, California

Kelly E. Hagler

Departement of Pathology, Genentech, Inc., South San Francisco

Richard H. Bruner

Pathology Associates International, West Chester, Ohio

Peter J. Thomford

Covance Laboratories, Inc., Madison Wisconsin

Robert L. Hall

Covance Laboratories, Inc., Madison Wisconsin

George M. Shopp

Department of Toxicology, Genentech, Inc., South San Francisco, California, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080.

Charles A. O'Neill

Department of Toxicology, Genentech, Inc., South San Francisco, California

Recombinant humanized antivascular endothelial growth factor (rhuMAbVEGF) is a monoclonal IgG, antibody that is being developed as an antiangiogenic agent for use in treating a variety of solid tumors. Preclinical safety studies included an immunohistochemical tissue cross-reactivity study, in vitro hemolytic potential and blood compatibility studies, and multiple dose toxicity studies. Toxicity studies were conducted in cynomolgus monkey because rhuMAbVEGF is pharmacologically active in this species and does not bind rat or mouse vascular endothelial growth factor (VEGF). Following twice weekly administration of rhuMAbVEGF for 4 or 13 wk, young adult cynomolgus monkeys exhibited physeal dysplasia characterized by a dose-related increase in hypertrophied chondrocytes, subchondral bony plate formation, and inhibition of vascular invasion of the growth plate. In addition, decreased ovarian and uterine weights and an absence of corpora lutea were observed in females receiving 10 and 50 mg/kg/dose in the 13-wk study. Both the physeal and ovarian changes were reversible with cessation of treatment. No other treatment-related effects were observed following rhuMAbVEGF administration at doses up to 50 mg/kg. These findings indicate that VEGF is required for longitudinal bone growth and corpora lutea formation and that rhuMAbVEGF can reversibly inhibit physiologic neovascularization at these sites.

Key Words: Growth plate • physis • vascular endothelial growth factor • angiogenesis • monoclonal antibody

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