Cargando…

Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C‐Lock linker

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Shi, Baoying, Wu, Min, Li, Zhaohui, Xie, Zhangming, Wei, Xiaoyue, Fan, Jiansheng, Xu, Yingchun, Ding, Ding, Akash, Sajid Hamid, Chen, Shuqing, Cao, Sheldon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488119/
https://www.ncbi.nlm.nih.gov/pubmed/30843650
http://dx.doi.org/10.1002/cam4.2066
_version_ 1783414603627102208
author Shi, Baoying
Wu, Min
Li, Zhaohui
Xie, Zhangming
Wei, Xiaoyue
Fan, Jiansheng
Xu, Yingchun
Ding, Ding
Akash, Sajid Hamid
Chen, Shuqing
Cao, Sheldon
author_facet Shi, Baoying
Wu, Min
Li, Zhaohui
Xie, Zhangming
Wei, Xiaoyue
Fan, Jiansheng
Xu, Yingchun
Ding, Ding
Akash, Sajid Hamid
Chen, Shuqing
Cao, Sheldon
author_sort Shi, Baoying
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6488119
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-64881192019-05-23 Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C‐Lock linker Shi, Baoying Wu, Min Li, Zhaohui Xie, Zhangming Wei, Xiaoyue Fan, Jiansheng Xu, Yingchun Ding, Ding Akash, Sajid Hamid Chen, Shuqing Cao, Sheldon Cancer Med Cancer Biology 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. John Wiley and Sons Inc. 2019-03-07 /pmc/articles/PMC6488119/ /pubmed/30843650 http://dx.doi.org/10.1002/cam4.2066 Text en © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Cancer Biology
Shi, Baoying
Wu, Min
Li, Zhaohui
Xie, Zhangming
Wei, Xiaoyue
Fan, Jiansheng
Xu, Yingchun
Ding, Ding
Akash, Sajid Hamid
Chen, Shuqing
Cao, Sheldon
Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C‐Lock linker
title Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C‐Lock linker
title_full Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C‐Lock linker
title_fullStr Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C‐Lock linker
title_full_unstemmed Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C‐Lock linker
title_short Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C‐Lock linker
title_sort antitumor activity of a 5t4 targeting antibody drug conjugate with a novel payload derived from mmaf via c‐lock linker
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488119/
https://www.ncbi.nlm.nih.gov/pubmed/30843650
http://dx.doi.org/10.1002/cam4.2066
work_keys_str_mv AT shibaoying antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker
AT wumin antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker
AT lizhaohui antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker
AT xiezhangming antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker
AT weixiaoyue antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker
AT fanjiansheng antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker
AT xuyingchun antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker
AT dingding antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker
AT akashsajidhamid antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker
AT chenshuqing antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker
AT caosheldon antitumoractivityofa5t4targetingantibodydrugconjugatewithanovelpayloadderivedfrommmafviaclocklinker