Characterization of therapeutic antibodies targeting lymphatic and vascular resistance factor for the treatment of hypervascularized and highly metastatic cancers.

Angiogenesis is a major driver of tumor progression and a validated therapeutic target in highly vascularized cancers such as clear cell renal cell carcinoma. However, the clinical benefit of antivascular endothelial growth factor therapies is limited by the emergence of resistance. We identified a vascular endothelial growth factor A splice variant, termed Lymphatic and Vascular Resistance Factor (LVRF), which promotes both angiogenesis and lymphangiogenesis and is upregulated following anti-angiogenic treatment. To therapeutically target this pathway, we generated fully human monoclonal antibodies against LVRF. Lead antibodies displayed high specificity and nanomolar affinity and effectively inhibited LVRF-driven biological activities. Anti-LVRF antibodies reduced renal carcinoma cell invasion, inhibited vascular and lymphatic endothelial responses, and suppressed lymphatic endothelial cell sprouting. In vivo, treatment significantly reduced the growth of bevacizumab-resistant renal carcinoma xenografts, induced regression of blood and lymphatic vessels, and decreased metastatic dissemination in zebrafish models. These findings identify LVRF as a mediator of resistance to anti-angiogenic therapy and support therapeutic targeting of LVRF as a novel strategy for vascularized tumors resistant to current antivascular endothelial growth factor treatments.