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Modulating Antibody-Drug Conjugate Payload Metabolism by Conjugation Site and Linker Modification.

Authors
  • Su, Dian1
  • Kozak, Katherine R1
  • Sadowsky, Jack1
  • Yu, Shang-Fan1
  • Fourie-O'Donohue, Aimee1
  • Nelson, Christopher1
  • Vandlen, Richard1
  • Ohri, Rachana1
  • Liu, Luna1
  • Ng, Carl1
  • He, Jintang1
  • Davis, Helen1
  • Lau, Jeff1
  • Del Rosario, Geoffrey1
  • Cosino, Ely1
  • Cruz-Chuh, Josefa Dela1
  • Ma, Yong1
  • Zhang, Donglu1
  • Darwish, Martine1
  • Cai, Wenwen2
  • And 7 more
  • 1 Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States. , (United States)
  • 2 Wuxi Biologics , 288 Fute Zhong Road , Waigaoqiao Free Trade Zone, Shanghai 200131 , China. , (China)
Type
Published Article
Journal
Bioconjugate Chemistry
Publisher
American Chemical Society
Publication Date
Apr 18, 2018
Volume
29
Issue
4
Pages
1155–1167
Identifiers
DOI: 10.1021/acs.bioconjchem.7b00785
PMID: 29481745
Source
Medline
Language
English
License
Unknown

Abstract

Previous investigations on antibody-drug conjugate (ADC) stability have focused on drug release by linker-deconjugation due to the relatively stable payloads such as maytansines. Recent development of ADCs has been focused on exploring technologies to produce homogeneous ADCs and new classes of payloads to expand the mechanisms of action of the delivered drugs. Certain new ADC payloads could undergo metabolism in circulation while attached to antibodies and thus affect ADC stability, pharmacokinetics, and efficacy and toxicity profiles. Herein, we investigate payload stability specifically and seek general guidelines to address payload metabolism and therefore increase the overall ADC stability. Investigation was performed on various payloads with different functionalities (e.g., PNU-159682 analog, tubulysin, cryptophycin, and taxoid) using different conjugation sites (HC-A118C, LC-K149C, and HC-A140C) on THIOMAB antibodies. We were able to reduce metabolism and inactivation of a broad range of payloads of THIOMAB antibody-drug conjugates by employing optimal conjugation sites (LC-K149C and HC-A140C). Additionally, further payload stability was achieved by optimizing the linkers. Coupling relatively stable sites with optimized linkers provided optimal stability and reduction of payloads metabolism in circulation in vivo.

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