Open AccessAntitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C‐Lock linker
Author(s) -
Shi Baoying,
Wu Min,
Li Zhaohui,
Xie Zhangming,
Wei Xiaoyue,
Fan Jiansheng,
Xu Yingchun,
Ding Ding,
Akash Sajid Hamid,
Chen Shuqing,
Cao Sheldon
Publication year - 2019
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.2066
Subject(s) - in vivo , cytotoxic t cell , linker , antibody drug conjugate , cancer research , in vitro , payload (computing) , cytotoxicity , pharmacology , chemistry , conjugate , antibody , cancer cell , cancer , monoclonal antibody , medicine , biology , biochemistry , immunology , computer science , computer network , mathematical analysis , microbiology and biotechnology , mathematics , network packet , operating system
Antibody‐drug conjugates (ADCs) belong to a promising class of biopharmaceuticals in which target‐killing of tumor cells was achieved by marrying the potency of the cytotoxic payload with the tumor specificity of the antibody. Here we developed a novel ADC (ZV0508) that targets 5T4 oncofetal antigen, which is overexpressed in many carcinomas on both bulk tumor cells and cancer stem cells. A novel cytotoxic payload called Duostatin‐5 (Duo‐5) which was derived from monomethyl auristatin F (MMAF) was attached to a 5T4 targeting antibody (ZV05) by interchain cysteine cross‐linking conjugation via a disubstituted C‐Lock linker. We have investigated the antitumor efficacy of ZV0508 by in vitro and in vivo studies, and compared its antitumor activity with ZV05‐mcMMAF (ZV0501), in which MMAF was linked via a conventional noncleavable maleimidocaproyl linker. As results, ZV0508 exhibited ideal antiproliferative effects through blocking cell cycle and inducing cell apoptosis. The in vivo studies revealed that both ZV0501 and ZV0508 exhibited excellent antitumor activities even at a single dose. Although ZV0508 was inferior to ZV0501 in vitro, it elicited more durable antitumor responses than ZV0501 in vivo. The superior in vivo activity of ZV0508 may be due to the combined use of the disubstituted C‐Lock linker and the novel payload Duo‐5, resulting in a more stable and potent ADC. Taken together, these data suggest ZV0508 is a worthy candidate for the treatment of 5T4 positive cancers.