Discovery of novel antibody-drug conjugates bearing tissue protease specific linker with both anti-angiogenic and strong cytotoxic effects

• Published in: Bioorganic chemistry Vol. 137; p. 106575
• Main Authors: Li, Yanchen, Si, Ru, Wang, Jin, Hai, Ping, Zheng, Yongbiao, Zhang, Qingqing, Pan, Xiaoyan, Zhang, Jie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2023
• Subjects: Anti-angiogenesis; Anti-tumor selectivity; Antibody-drug conjugates; Bevacizumab Vedotin; Rapid drug release; Anti-angiogenesis; Rapid drug release; Bevacizumab Vedotin; Antibody-drug conjugates; Anti-tumor selectivity
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106575

Discovery of novel antibody-drug conjugates based on Bevacizumab and Vedotin. [Display omitted] •Bevaciuzmb Vedotin, a novel drug-antibody conjugate based on Bevacizumab, was prepared.•The combination of the histone B cleaved Linker MC-Val-PAB and the microtubulin inhibitor MMAE as the small molecule fraction of this ADC.•Bevaciuzmab Vedotin exhibited surprising anti-proliferative, pro-apoptotic and cell cycle blocking activities against various cancer cells, as well as migration inhibition of MCF-7 cells.•Bevaciuzmab Vedotin exhibited excellent in vitro anti-angiogenic activity and ability to block VEGF/VEGFR pathway. Bevacizumab is an FDA-approved class of monoclonal antibodies used to inhibit angiogenesis and promote normalization of blood vessels. It is usually combined with chemotherapeutic agents to treat a variety of solid tumors. However, the whole-body toxicities and toxicity associated with chemotherapy greatly limit the clinical use of this combination therapy. Antibody-drug conjugates (ADCs) couple monoclonal antibodies to cytotoxic molecules via a linker, utilizing the high specificity of monoclonal antibodies to tumor surface antigens to act as a “biological missile” to deliver chemotherapeutic drugs to the tumor site. Herein, we designed a bevacizumab-based ADC, Bevacizumab Vedotin, conjugating bevacizumab to the microtubulin inhibitor MMAE via a tissue protease-specific linker. Biological studies showed strong stability and good tumor cell targeting of our constructed ADCs; rapid drug release was achieved in the presence of exogenous histone protease B. In addition, Bevacizumab Vedotin exhibited good anti-proliferative, apoptosis-promoting and cell cycle-stalling effects on glioma (U87), hepatocellular carcinoma (HepG2), and breast cancer (MCF-7) cell lines. Further in vitro assays demonstrated the enhanced anti-migration activity against MCF-7, potent anti-angiogenic effects, and blockade of the VEGF/VEGFR pathway of Bevacizumab Vedotin.