A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b

Huiling Wang; Yiming Li; Gang Shi; Yuan Wang; Yi Lin; Qin Wang; Yujing Zhang; Qianmei Yang; Lei Dai; Lin Cheng; Xiaolan Su; Yang Yang; Shuang Zhang; Zhi Li; Jia Li; Yuquan Wei; Dechao Yu; Hongxin Deng

doi:10.1016/j.omto.2019.12.004

A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b

Mol Ther Oncolytics. 2019 Dec 14:16:20-29. doi: 10.1016/j.omto.2019.12.004. eCollection 2020 Mar 27.

Authors

Huiling Wang¹, Yiming Li^{1

2}, Gang Shi¹, Yuan Wang¹, Yi Lin¹, Qin Wang¹, Yujing Zhang¹, Qianmei Yang¹, Lei Dai¹, Lin Cheng¹, Xiaolan Su¹, Yang Yang¹, Shuang Zhang³, Zhi Li², Jia Li², Yuquan Wei^{1

3}, Dechao Yu^{1

3}, Hongxin Deng¹

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
² Innovent Biologics (Suzhou) Co., Ltd., Suzhou, Jiangsu 215000, China.
³ Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.

Abstract

Therapeutic antibodies targeting vascular endothelial growth factor (VEGF) have become a critical regimen for tumor therapy, but the efficacy of monotherapy is usually limited by drug resistance and multiple angiogenic mechanisms. Complement proteins are becoming potential candidates for cancer-targeted therapy based on their role in promoting cancer progression and angiogenesis. However, the antitumor abilities of simultaneous VEGF and complement blockade were unknown. We generated a humanized soluble VEGFR-Fc fusion protein (VID) binding VEGFA/PIGF and a CR1-Fc fusion protein (CID) targeting C3b/C4b. Both VID and CID had good affinities to their ligands and showed effective bioactivities. In vitro, angiogenesis effects induced by VEGF and hemolysis induced by complement were inhibited by VID and CID, respectively. Further, VID and CID confer a synergetic therapeutic effect in a colitis-associated colorectal cancer (CAC) model and an orthotopic 4T1 breast cancer model. Mechanically, combination therapy inhibited tumor angiogenesis, cell proliferation, and MDSC infiltration in the tumor microenvironment and promoted tumor cell apoptosis. Our study offers a novel therapeutic strategy for anti-VEGF-resistant tumors and chronic-inflammation-associated tumors.

Keywords: CR1-Fc fusion protein; MDSCs; VEGFR-Fc fusion protein; angiogenesis; combination therapy.