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Novel human antibody against VEGFR2 shows therapeutic potential for leukemia and prostate cancer.

Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed in tumor-associated endothelial cells, where it modulates tumor-promoting angiogenesis, and it is also found on the surface of tumor cells. Currently, there are no antibody therapeutics targeting VEGFR2 approvals for treatment of prostate cancer and leukemia. Therefore, development of novel efficacious anti-VEGFR2 antibodies will benefit cancer patients. We used ICOB human antibody library and affinity maturation to develop a fully human antibody, anti-VEGFR2-AF, which exhibits excellent VEGFR2 binding activity. Anti-VEGFR2-AF bound Ig-like domain 3 of VEGFR2 extracellular region to disrupt the interaction between VEGF-A and VEGFR2, neutralizing downstream signaling of the receptor. Moreover, anti-VEGFR2-AF inhibited capillary structure formation and exerted antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity in vitro. We found that VEGFR2 is expressed in PC-3 human prostate cancer cell line and associated with malignancy and metastasis of human prostate cancer. In a PC-3 xenograft mouse model, treatment with anti-VEGFR2-AF repressed tumor growth and angiogenesis as effectively and safely as U.S. FDA-approved anti-VEGFR2 therapeutic, ramucirumab. We also demonstrated for the first time that addition of anti-VEGFR2 antibody can enhance the efficacy of docetaxel in the treatment of a prostate cancer mouse model. In HL-60 human leukemia-xenografted mice, anti-VEGFR2-AF exhibited better efficacy than ramucirumab with prolonged survival and reduced metastasis of leukemia cells to ovaries and lymph nodes. Our findings suggest that anti-VEGFR2-AF has strong potential as a cancer therapy that may directly target VEGFR2-expressing tumor cells in addition to its anti-angiogenic action.