1. Academic Validation
  2. Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect

Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect

  • Proc Natl Acad Sci U S A. 2021 Jun 22;118(25):e2107042118. doi: 10.1073/pnas.2107042118.
K C Nicolaou 1 Stephan Rigol 2 Emmanuel N Pitsinos 2 3 Dipendu Das 2 Yong Lu 2 Subhrajit Rout 2 Alexander W Schammel 4 Dane Holte 4 Baiwei Lin 5 Christine Gu 5 Hetal Sarvaiya 5 Jose Trinidad 5 Nicole Barbour 5 Amanda M Valdiosera 5 Joseph Sandoval 6 Christina Lee 6 Monette Aujay 6 Hanan Fernando 7 Anukriti Dhar 7 Holger Karsunky 7 Nicole Taylor 8 Marybeth Pysz 8 Julia Gavrilyuk 9
Affiliations

Affiliations

  • 1 BioScience Research Collaborative, Department of Chemistry, Rice University, Houston, TX 77005; kcn@rice.edu julia.gavrilyuk@gmail.com.
  • 2 BioScience Research Collaborative, Department of Chemistry, Rice University, Houston, TX 77005.
  • 3 Laboratory of Natural Products Synthesis & Bioorganic Chemistry, Institute of Nanoscience and Nanotechnology, National Centre for Scientific Research "Demokritos", 153 10 Agia Paraskevi, Greece.
  • 4 Discovery Chemistry Department, AbbVie Inc., South San Francisco, CA 94080.
  • 5 Bioconjugation and Process Development Department, AbbVie Inc., South San Francisco, CA 94080.
  • 6 Assay Development Department, AbbVie Inc., South San Francisco, CA 94080.
  • 7 Cancer Biology Department, AbbVie Inc., South San Francisco, CA 94080.
  • 8 In Vivo Pharmacology Department, AbbVie Inc., South San Francisco, CA 94080.
  • 9 Discovery Chemistry Department, AbbVie Inc., South San Francisco, CA 94080; kcn@rice.edu julia.gavrilyuk@gmail.com.
Abstract

Antibody-drug conjugates (ADCs) have emerged as valuable targeted Anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, N-acetyl calicheamicin [Formula: see text], have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.

Keywords

antibody–drug conjugates; bystander killing effect; enediyne payloads.

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