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

  • PLoS One. 2020 Sep 28;15(9):e0239813. doi: 10.1371/journal.pone.0239813.
Zu-Chian Chiang  1 ,  Yi-Kai Chiu  2 ,  Cheng-Chung Lee  1 ,  Nai-Shu Hsu  1 ,  Yueh-Liang Tsou  2 ,  Hong-Sen Chen  2 ,  Horng-Ru Hsu  2 ,  Tzung-Jie Yang  3 ,  An-Suei Yang  2 ,  Andrew H-J Wang  1
Affiliations
  • 1. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
  • 2. Genomics Research Center, Academia Sinica, Taipei, Taiwan.
  • 3. Drug Metabolism & Pharmacokinetics, Institute for Drug Evaluation Platform, Development Center for Biotechnology, Taipei, Taiwan.
PMID: 32986768 DOI: 10.1371/journal.pone.0239813
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 anti-HER2 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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