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VEGF kinoid vaccine, a therapeutic approach against tumor angiogenesis and metastases

Rad, Farhad Haghighi, Le Buanec, Hélène, Paturance, Sébastien, Larcier, Patrick, Genne, Philippe, Ryffel, Bernhard, Bensussan, Armand, Bizzini, Bernard, Gallo, Robert C., Zagury, Daniel, Uzan, Georges
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.8 pp. 2837-2842
adverse effects, angiogenesis, antigens, blood serum, cell growth, clinical trials, colorectal neoplasms, cultured cells, growth retardation, hemocyanin, human umbilical vein endothelial cells, humans, immune response, immunoglobulin G, metastasis, mice, neoplasm cells, severe combined immunodeficiency, vaccines, vascular endothelial growth factors
Tumor growth depends on blood supply, requiring the development of new vessels, and vascular endothelial growth factor (VEGF) plays a central role in neoangiogenic processes. For this reason, VEGF represents a target for the development of new therapeutic antiangiogenic molecules. Clinical trials using anti-VEGF mAbs such as bevacizumab have validated the efficacy of this therapeutic approach but have also revealed adverse effects. Here we report that a VEGF-derived immunogen, consisting of a heterocomplex of a murine (m)VEGF and keyhole limpet hemocyanin, called "mVEGF kinoid," triggered a strong Ab immune response in mice. The anti-VEGF Abs inhibited both the proliferation of human umbilical vein endothelial cells cultured in the presence of mVEGF and the binding of mVEGF to its receptor-2 Flk-1. In mVEGF kinoid-immunized BALB/c mice challenged with syngeneic CT26 colorectal tumor cells, the number and size of lung metastases were significantly decreased. In human (h)VEGF kinoid-immunized BALB/c mice, high levels of serum Abs to hVEGF were present, and purified IgG from these mice decreased by >=50% the tumor growth of human A673 rhabdomyosarcoma cells and HT29 colon carcinoma xenografted in Swiss nude and NOD/SCID mice, respectively. Tumor cell growth inhibition was similar to that observed in mice receiving therapeutic doses of bevacizumab. These experiments suggest that a therapeutic vaccine containing VEGF kinoid may represent a strategy for safely combating VEGF-dependent neovascularization and metastases occurring in malignant tumors.