PLoS ONE (Jan 2020)

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
https://doi.org/10.1371/journal.pone.0239813
Journal volume & issue
Vol. 15, no. 9
p. e0239813

Abstract

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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.