A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b
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-targ...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-03-01
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| Series: | Molecular Therapy: Oncolytics |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770519301056 |
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doaj-596fab35f34d45ff86f3fede4515621c |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b Molecular Therapy: Oncolytics |
| author_facet |
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 |
| author_sort |
Huiling Wang |
| title |
A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b |
| title_short |
A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b |
| title_full |
A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b |
| title_fullStr |
A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b |
| title_full_unstemmed |
A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b |
| title_sort |
novel antitumor strategy: simultaneously inhibiting angiogenesis and complement by targeting vegfa/pigf and c3b/c4b |
| publisher |
Elsevier |
| series |
Molecular Therapy: Oncolytics |
| issn |
2372-7705 |
| publishDate |
2020-03-01 |
| description |
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: VEGFR-Fc fusion protein, CR1-Fc fusion protein, combination therapy, angiogenesis, MDSCs |
| url |
http://www.sciencedirect.com/science/article/pii/S2372770519301056 |
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doaj-596fab35f34d45ff86f3fede4515621c2020-11-25T02:25:36ZengElsevierMolecular Therapy: Oncolytics2372-77052020-03-01162029A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4bHuiling Wang0Yiming Li1Gang Shi2Yuan Wang3Yi Lin4Qin Wang5Yujing Zhang6Qianmei Yang7Lei Dai8Lin Cheng9Xiaolan Su10Yang Yang11Shuang Zhang12Zhi Li13Jia Li14Yuquan Wei15Dechao Yu16Hongxin Deng17State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China; Innovent Biologics (Suzhou) Co., Ltd., Suzhou, Jiangsu 215000, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaDepartment of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaInnovent Biologics (Suzhou) Co., Ltd., Suzhou, Jiangsu 215000, ChinaInnovent Biologics (Suzhou) Co., Ltd., Suzhou, Jiangsu 215000, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China; Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China; Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China; Corresponding author: Dechao Yu, Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou, Jiangsu, 215000, P.R. China.State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China; Corresponding author: Hongxin Deng, State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, Sichuan, 610041, P.R. China.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: VEGFR-Fc fusion protein, CR1-Fc fusion protein, combination therapy, angiogenesis, MDSCshttp://www.sciencedirect.com/science/article/pii/S2372770519301056 |