Preparation and characterization of antibody-drug conjugates acting on HER2-positive cancer cells

Zu Chian Chiang; Yi Kai Chiu; Cheng Chung Lee; Nai Shu Hsu; Yueh Liang Tsou; Hong Sen Chen; Horng Ru Hsu; Tzung Jie Yang; An Suei Yang; Andrew H.J. Wang

doi:10.1371/journal.pone.0239813

Preparation and characterization of antibody-drug conjugates acting on HER2-positive cancer cells

Zu Chian Chiang
, Yi Kai Chiu
, Cheng Chung Lee
, Nai Shu Hsu
, Yueh Liang Tsou
, Hong Sen Chen
, Horng Ru Hsu
, Tzung Jie Yang
, An Suei Yang
, Andrew H.J. Wang

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

Two systems of antibody-drug conjugates (ADCs), noncleavable H32-DM1 and cleavable H32-VCMMAE, were developed by using different linkers and drugs attached to the antiHER2 antibody H32, which is capable of cell internalization. Activated functional groups, including an N-hydroxysuccinimidyl (NHS) ester and a maleimide, were utilized to make the ADCs. Mass spectrometry, hydrophobic interaction chromatography, polyacrylamide gel electrophoresis, and in vitro cell assays were performed to analyze and optimize the ADCs. Several H32-VCMMAE ADCs were established with higher DARs and greater synthetic yields without compromising potency. The anticancer efficacy of H32-DM1 was 2- to 8-fold greater than that of Kadcyla^®. The efficacy of H32-VCMMAE was in turn better than that of H32-DM1. The anticancer efficacy of these ADCs against N87, SK-BR-3 and BT474 cells was in the following order: H32-VCMMAE series > H32-DM1 series > Kadcyla^®. The optimal DAR for H32-VCMMAE was found to be 6.6, with desirable attributes including good cell penetration, a releasable payload in cancer cells, and high potency. Our results demonstrated the potential of H32-VCMMAE as a good ADC candidate.

Original language	English
Article number	e0239813
Journal	PLoS ONE
Volume	15
Issue number	9 September
DOIs	https://doi.org/10.1371/journal.pone.0239813
Publication status	Published - Sept 2020
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General

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10.1371/journal.pone.0239813

Cite this

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title = "Preparation and characterization of antibody-drug conjugates acting on HER2-positive cancer cells",

abstract = "Two systems of antibody-drug conjugates (ADCs), noncleavable H32-DM1 and cleavable H32-VCMMAE, were developed by using different linkers and drugs attached to the antiHER2 antibody H32, which is capable of cell internalization. Activated functional groups, including an N-hydroxysuccinimidyl (NHS) ester and a maleimide, were utilized to make the ADCs. Mass spectrometry, hydrophobic interaction chromatography, polyacrylamide gel electrophoresis, and in vitro cell assays were performed to analyze and optimize the ADCs. Several H32-VCMMAE ADCs were established with higher DARs and greater synthetic yields without compromising potency. The anticancer efficacy of H32-DM1 was 2- to 8-fold greater than that of Kadcyla{\textregistered}. The efficacy of H32-VCMMAE was in turn better than that of H32-DM1. The anticancer efficacy of these ADCs against N87, SK-BR-3 and BT474 cells was in the following order: H32-VCMMAE series > H32-DM1 series > Kadcyla{\textregistered}. The optimal DAR for H32-VCMMAE was found to be 6.6, with desirable attributes including good cell penetration, a releasable payload in cancer cells, and high potency. Our results demonstrated the potential of H32-VCMMAE as a good ADC candidate.",

author = "Chiang, \{Zu Chian\} and Chiu, \{Yi Kai\} and Lee, \{Cheng Chung\} and Hsu, \{Nai Shu\} and Tsou, \{Yueh Liang\} and Chen, \{Hong Sen\} and Hsu, \{Horng Ru\} and Yang, \{Tzung Jie\} and Yang, \{An Suei\} and Wang, \{Andrew H.J.\}",

note = "Publisher Copyright: Copyright: {\textcopyright} 2020 Chiang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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AU - Chiang, Zu Chian

AU - Chiu, Yi Kai

AU - Lee, Cheng Chung

AU - Hsu, Nai Shu

AU - Tsou, Yueh Liang

AU - Chen, Hong Sen

AU - Hsu, Horng Ru

AU - Yang, Tzung Jie

AU - Yang, An Suei

AU - Wang, Andrew H.J.

N1 - Publisher Copyright: Copyright: © 2020 Chiang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2020/9

Y1 - 2020/9

N2 - Two systems of antibody-drug conjugates (ADCs), noncleavable H32-DM1 and cleavable H32-VCMMAE, were developed by using different linkers and drugs attached to the antiHER2 antibody H32, which is capable of cell internalization. Activated functional groups, including an N-hydroxysuccinimidyl (NHS) ester and a maleimide, were utilized to make the ADCs. Mass spectrometry, hydrophobic interaction chromatography, polyacrylamide gel electrophoresis, and in vitro cell assays were performed to analyze and optimize the ADCs. Several H32-VCMMAE ADCs were established with higher DARs and greater synthetic yields without compromising potency. The anticancer efficacy of H32-DM1 was 2- to 8-fold greater than that of Kadcyla®. The efficacy of H32-VCMMAE was in turn better than that of H32-DM1. The anticancer efficacy of these ADCs against N87, SK-BR-3 and BT474 cells was in the following order: H32-VCMMAE series > H32-DM1 series > Kadcyla®. The optimal DAR for H32-VCMMAE was found to be 6.6, with desirable attributes including good cell penetration, a releasable payload in cancer cells, and high potency. Our results demonstrated the potential of H32-VCMMAE as a good ADC candidate.

AB - Two systems of antibody-drug conjugates (ADCs), noncleavable H32-DM1 and cleavable H32-VCMMAE, were developed by using different linkers and drugs attached to the antiHER2 antibody H32, which is capable of cell internalization. Activated functional groups, including an N-hydroxysuccinimidyl (NHS) ester and a maleimide, were utilized to make the ADCs. Mass spectrometry, hydrophobic interaction chromatography, polyacrylamide gel electrophoresis, and in vitro cell assays were performed to analyze and optimize the ADCs. Several H32-VCMMAE ADCs were established with higher DARs and greater synthetic yields without compromising potency. The anticancer efficacy of H32-DM1 was 2- to 8-fold greater than that of Kadcyla®. The efficacy of H32-VCMMAE was in turn better than that of H32-DM1. The anticancer efficacy of these ADCs against N87, SK-BR-3 and BT474 cells was in the following order: H32-VCMMAE series > H32-DM1 series > Kadcyla®. The optimal DAR for H32-VCMMAE was found to be 6.6, with desirable attributes including good cell penetration, a releasable payload in cancer cells, and high potency. Our results demonstrated the potential of H32-VCMMAE as a good ADC candidate.

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Preparation and characterization of antibody-drug conjugates acting on HER2-positive cancer cells

Abstract

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