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Preliminary results from a phase 1 safety and tolerability study show no dose-limiting toxicity so far in patients treated with intravitreal injections of volociximab in combination with anti-VEGF therapy for neovascular age-related macular degeneration.
Volociximab is a chimeric monoclonal antibody that blocks the binding of the transmembrane receptor, α5β1 integrin, to its natural ligand, fibronectin. Potential limitations of monotherapy anti-VEGF strategies include persistent inflammation and continued proangiogenic signals via other growth factors besides VEGF.
The binding of endothelial integrin α5β1 to fibronectin plays a key role in the process of neovascularization by providing cell survival signals independent of VEGF and other proangiogenic factors. Interference of these downstream signals may reduce endothelial cell survival.
Interaction between activated and proliferating endothelial cells with extracellular matrix proteins via the α5β1 integrin-mediated mechanism regulates multiple key endothelial cellular processes involved in angiogenesis. Expression of α5β1 integrin is specifically up-regulated on the surface of the activated vascular endothelial cell after initiation of the angiogenesis cascade where it binds fibronectin, leading to endothelial cell proliferation and migration. By inhibiting binding between, α5β1 integrin and fibronectin, volociximab promotes apoptosis of the activated endothelial cell and inhibits angiogenesis.
"There is a huge portfolio of preclinical research showing that α5β1 is required for normal development of vascularization and demonstrating activity of volociximab for inhibiting new vessel growth independent of the inducing growth factor pathway," Dr. Kuppermann said. "Investigational new drug-enabling studies and this phase I study are underway with volociximab, and, so far, show no dose-limiting toxicity."
The preclinical studies include research showing that volociximab blocks human umbilical vein endothelial cell tube formation with high specificity, which is independent of the growth factor stimulus.
"The latter is a key message," he said. "Volociximab effectively inhibits tube formation whether induced by VEGF or other mediators of angiogenesis, such as basic fibroblast growth factor (bFGF), IL-1, and IL-8."
Volociximab also has been shown to induce apoptosis of endothelial cells and to block bFGF-induced angiogenesis in the chick chorioallantoic membrane model.
In addition, it has been shown to promote regression of new vessel growth in models of pathologic tumor angiogenesis and to inhibit vessel growth in cynomolgus monkey and rabbit models of ocular neovascularization.
"Volociximab has also been well tolerated in these animal studies," Dr. Kuppermann added.