M200 (volociximab), a chimeric antibody against integrin alpha5 beta1, inhibits tumor growth by multiple mechanisms

Proc Amer Assoc Cancer Res, Volume 46, 2005 4497 Interactions between cells and extracellular matrix (ECM) proteins in the tumor microenvironment are mediated by heterodimeric integrins. One such integrin, alpha5 beta1, mediates adhesion and migration towards fibronectin via a highly conserved RGD sequence. We have found, through immunohistochemical analysis of human tumor tissue, that integrin alpha5 beta1 is highly expressed on the surface of tumor epithelial cells, as well as endothelial cells that make up the invading neovasculature. In vitro , a high-affinity function-blocking antibody against alpha5 beta1, M200, was found to inhibit the proliferation of human endothelial cells by a mechanism that involves cell death. A significant proportion of cancer cell lines tested retained a high level of surface alpha5 beta1 in vitro . In proliferation assays, a subset of these cell lines was particularly sensitive to M200. In affected cell lines, M200 was found to inhibit proliferation on fibronectin, as well as other ECM proteins, even when added 24 hours after plating. The effects on proliferation were due, at least in part, to the ability of M200 to induce cell death in these cell lines. M200 cross-reacts with rabbit, but not rodent, alpha5 beta1, therefore, a rabbit neovascularization model was chosen to evaluate the potency of M200 in vivo . M200 was found to exert a statistically significant effect in inhibiting angiogenesis in this setting. We are currently assessing possible anti-tumor effects using the rabbit VX2 carcinoma model. These data suggest that M200 inhibits tumor growth by targeting cancer cells directly, in addition to endothelial cells in the tumor neovasculature.