Anti-VEGFR2 F(ab′)2 drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy

Di Liu, Yanling Song, Hui Chen, Yuchan You, Luwen Zhu, Jucong Zhang, Xinyi Xu, Jiahao Hu, Xiajie Huang, Xiaochuan Wu, Xiaoling Xu (), Saiping Jiang () and Yongzhong Du ()
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Di Liu: College of Pharmaceutical Sciences, Zhejiang University
Yanling Song: College of Pharmaceutical Sciences, Zhejiang University
Hui Chen: College of Pharmaceutical Sciences, Zhejiang University
Yuchan You: College of Pharmaceutical Sciences, Zhejiang University
Luwen Zhu: College of Pharmaceutical Sciences, Zhejiang University
Jucong Zhang: College of Pharmaceutical Sciences, Zhejiang University
Xinyi Xu: College of Pharmaceutical Sciences, Zhejiang University
Jiahao Hu: College of Pharmaceutical Sciences, Zhejiang University
Xiajie Huang: College of Pharmaceutical Sciences, Zhejiang University
Xiaochuan Wu: College of Pharmaceutical Sciences, Zhejiang University
Xiaoling Xu: Zhejiang Shuren University
Saiping Jiang: The First Affiliated Hospital, College of Medicine, Zhejiang University
Yongzhong Du: College of Pharmaceutical Sciences, Zhejiang University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Poor renal distribution of antibody-based drugs is the key factor contributing to low treatment efficiency for renal diseases and side effects. Here, we prepare F(ab′)2 fragmented vascular endothelial growth factor receptor 2 antibody (anti-VEGFR2 (F(ab′)2) to block VEGFR2 overactivation in diabetic nephropathy (DN). We find that the anti-VEGFR2 F(ab′)2 has a higher accumulation in DN male mice kidneys than the intact VEGFR2 antibody, and simultaneously preserves the binding ability to VEGFR2. Furthermore, we develop an antibody fragment drug conjugate, anti-VEGFR2 F(ab′)2-SS31, comprising the anti-VEGFR2 F(ab′)2 fragment linked to the mitochondria-targeted antioxidant peptide SS31. We find that introduction of SS31 potentiates the efficacy of anti-VEGFR2 F(ab′)2. These findings provide proof of concept for the premise that antibody fragment drug conjugate improves renal distribution and merits drug validation in renal disease therapy.

Date: 2023
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DOI: 10.1038/s41467-023-43847-2

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