Preclinical Safety Evaluation of rhuMAbVEGF, an Antiangiogenic Humanized Monoclonal Antibody

Abstract

Recombinant humanized antivascular endothelial growth factor (rhuMAbVEGF) is a monoclonal IgG1 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.

AZD2171: A Highly Potent, Orally Bioavailable, Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for the Treatment of Cancer

“…This is the first study to report the effects of a VEGF receptor kinase inhibitor on follicular development, although a soluble VEGF receptor construct has been previously found to have inhibitory effects on corpora luteal angiogenesis and development in mice (55) and a KDR blocking antibody shown to significantly delay follicular development in rhesus monkey (56). Analogous changes in bone growth plate and ovary have also been observed in primate following treatment with the VEGF-neutralizing antibody, bevacizumab (57). AZD2171 (1.5 and 6 mg per kg per day) completely abolished VEGF-dependent angiogenesis in vivo, in a s.c. Matrigel plug assay, suggesting that it might also inhibit tumor growth at comparatively small doses.…”

Osteogenesis and angiogenesis: The potential for engineering bone

“…(Tammela et al, 2005;Ferrara and Gerber, 2001;Carmeliet and Collen, 2000;Yancopoulos et al, 2000;Rossant and Howard, 2002). Although VEGF is a critical regulator in physiological angiogenesis it also plays a significant role in skeletal growth (Zelzer et al, 2002;Gerber et al, 1999;Haigh et al, 2000;Ryan et al, 1999) and repair (Street et al, 2002;Chu et al, 2002;Peng et al, 2002).…”

“…In the bone remodelling sequence Niida et al, (1999) showed VEGF can act with sRANKL to promote osteoclastogenesis and that a single injection of recombinant human VEGF can similarly induce osteoclast recruitment in op/op mice, suggesting that VEGF can act as a substitute for M-CSF in osteoclastogenesis. Street and colleagues (Street et al, 2000;Street et al, 2002;Ryan et al, 1999;Gerber et al, 1999) have demonstrated that the inhibition of VEGF in fractured mouse femurs results in a decrease in blood vessel invasion with a reduction in osteoclastic bone remodelling, impaired callus mineralization and reduced trabecular bone healing.…”

The Expanding Role of Vascular Endothelial Growth Factor Inhibitors in Ophthalmology

“…7 Postnatal VEGF blockade results in stunted growth, increased mortality due to renal failure, and impaired organ development, 8,9 while experimental blockade in juvenile primates causes ovarian failure and stunted growth due to chondrocyte failure within the epiphyseal growth plates. 10 In adults, VEGF infusion stimulates microvascular perfusion in patients with severe coronary artery disease and ischemic limbs. 11,12 Although new blood vessel growth in response to ischemic myocardium may be lifesaving, 13 pathologic neovascularization and hyperpermeability in other organs, such as the eye, cause blindness from retinal detachment, uncontrollable glaucoma, and untreatable retinal edema.…”