Abstract 2046: Structural analysis of VEGFR2 function blocking antibodies

Abstract

The vascular endothelial growth factor receptor-2 (VEGFR2) is a receptor tyrosine kinase that is expressed highly in endothelial cells (ECs). By binding to VEGF165 (VEGF-A) VEGFR2 signals in ECs mediate the formation of new blood vessels, a process known as angiogenesis. Growth of tumor and metastasis depends on angiogenic activities of ECs. Thus, an agent that blocks VEGFR2 signaling specifically in tumor ECs could inhibit tumor growth and metastasis. The IMC-1121B is an antiangiogenic agent that inhibits the VEGFR2 signaling. Here we modeled the structure of the 1121B Fab fragment in complex with domain-3 of VEGFR2, and the structure of a different neutralizing anti-VEGFR2 antibody, 6.64, also in complex with VEGFR2 domain-3. The two Fab fragments interact at opposite ends of VEGFR2 domain-3; 1121B blocks VEGF binding, whereas 6.64 appears to prevent receptor dimerization by perturbing the domain-3:domain-4 interface. Blocking of VEGFR2 signaling activities by two different antibodies could be a powerful approach to block angiogenesis, thereby inhibiting growth of tumor and metastasis. Key reference: Franklin MC et al., Structure 2011;19:1097-1107. Citation Format: Anita Wary. Structural analysis of VEGFR2 function blocking antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2046.