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ACS Med Chem Lett. 2017 Sep 5;8(10):1037-1041. doi: 10.1021/acsmedchemlett.7b00243. eCollection 2017.

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

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  • 1Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2Wuxi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 3Wuxi Biologics, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.


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.


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

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