Abstract 4590: Anti-angiogenic mAb, anti-human VEGFR2(Cyramza) retards tumor growth in KDR (VEGFR2) humanized mice engrafted with syngeneic vs. xenograft solid tumors
Authors: He Daniel 
Published: April 2023

Abstract
Blood vessels is required for the growth of solid tumors and cutting off the blood supply to tumor is a potential novel strategy to retard tumor growth, although which may consequently result in pan-hypoxia and metastasis paradoxically. VEGFA is identified as the major angiogenic factor and VEGFR2 binds to all VEGFA isoforms and VEGFR2 (KDR) is a dominant mediator in regulating the angiogenic and permeability-enhancing effects of VEGFA. Importantly, in numerous solid tumors, VEGFA and VEGFR2 are overexpressed to promote intratumoral angiogenesis to support local tumor survival, tumor growth and distant metastasis. Given that VEGFA/VEGFR2 interaction plays a crucial role in promoting intratumoral angiogenesis and tumor growth, it is appealing to develop novel potent anti-angiogenic agents for cancer treatment by direct against VEGFA-VEGFR2 interaction. However, the preclinical assessment of anti-angiogenesis agents are limited due to lack of suitable preclinical models for human-specific therapeutic antibodies which usually don’t cross-bind to mouse targets. To this end, we developed the KDR (VEGFR2) humanized mouse model (hKDR model), in which the extracellular regions of mouse VEGFR2 corresponding to exons 4-15 are replaced by human counterparts via ES cell-based homologous recombination. As a result, hKDR humanized mouse expresses a chimeric VEGFR2 receptor containing the human extracellular domain plus mouse trans-membrane and intracellular domains. Firstly, we characterized the chimeric h/m KDR expression on the endothelial cells as well as in intratumoral blood vessels derived from hKDR knockin mice. Subsequently, we investigated the anti-tumor responses of anti-human VEGFR2 antibody (Cyramza, Ramucirumab) in hKDR mice bearing B16-F1 and MC38 syngenic solid tumors and we observed that Cyramza inhibited the tumor growth in vivo remarkably in a dose-dependent way, indicating the binding of anti-human VEGFR2 antibody to the chimeric h/m KDR receptor. Notably, we further generated hKDR knockin model in Rag2 knockout background (hKDR/Rag2KO) by crossbreeding which lack mature T cells and B cells. The female hKDR/Rag2KO mice were subcutaneously inoculated with human hepatocellular carcinoma LI0612 PDX model and human gastric cancer GA2419 PDX model to assess the anti-tumor effects of anti-angiogenic agents in xenograft solid tumors. The data suggested that Cyramza displayed moderate tumor growth inhibition (TGI) in LI0612 model at 10 mg/kg and weak TGI in GA2419 model at 10 mg/kg, respectively. Our findings support the notion that normalization of tumor vasculature is critical for tumor inhibition based on anti-angiogenic therapy and may synergize the anti-tumor effects with the immune checkpoint blockade or promote the cancer immunotherapy of immunomodulators in the future trials.
Citation Format: Daniel He. Anti-angiogenic mAb, anti-human VEGFR2(Cyramza) retards tumor growth in KDR (VEGFR2) humanized mice engrafted with syngeneic vs. xenograft solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4590.