2. Academic Validation
  3. Stabilizing a Tubulysin Antibody-Drug Conjugate To Enable Activity Against Multidrug-Resistant Tumors

Stabilizing a Tubulysin Antibody-Drug Conjugate To Enable Activity Against Multidrug-Resistant Tumors

  • ACS Med Chem Lett. 2017 Sep 5;8(10):1037-1041. doi: 10.1021/acsmedchemlett.7b00243.
Leanna R Staben 1,  Shang-Fan Yu 1,  Jinhua Chen 2,  Gang Yan 2,  Zijin Xu 2,  Geoffrey Del Rosario 1,  Jeffrey T Lau 1,  Luna Liu 1,  Jun Guo 1,  Bing Zheng 1,  Josefa Dela Cruz-Chuh 1,  Byoung-Chul Lee 1,  Rachana Ohri 1,  Wenwen Cai 3,  Hongxiang Zhou 3,  Katherine R Kozak 1,  Keyang Xu 1,  Gail D Lewis Phillips 1,  Jiawei Lu 3,  John Wai 2,  Andrew G Polson 1,  Thomas H Pillow 1
Affiliations

Affiliations

  • 1 Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Wuxi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 3 Wuxi Biologics, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
PMID: 29057047 DOI: 10.1021/acsmedchemlett.7b00243
Abstract

The tubulysins are promising Anticancer cytotoxic agents due to the clinical validation of their mechanism of action (microtubule inhibition) and their particular activity against multidrug-resistant tumor cells. Yet their high potency and subsequent systemic toxicity make them prime candidates for targeted therapy, particularly in the form of antibody-drug conjugates (ADCs). Here we report a strategy to prepare stable and bioreversible conjugates of tubulysins to Antibodies without loss of activity. A peptide trigger along with a quaternary ammonium salt linker connection to the tertiary amine of tubulysin provided ADCs that were potent in vitro. However, we observed metabolism of a critical acetate ester of the drug in vivo, resulting in diminished conjugate activity. We were able to circumvent this metabolic liability with the judicious choice of a propyl ether replacement. This modified tubulysin ADC was stable and effective against multidrug-resistant lymphoma cell lines and tumors.

Keywords

Antibody−drug conjugate (ADC); Pgp; linker; multidrug-resistance; tubulysin.

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