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
  • 1. BioScience Research Collaborative, Department of Chemistry, Rice University, Houston, TX 77005; [email protected] [email protected].
  • 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; [email protected] [email protected].
PMID: 34155147 DOI: 10.1073/pnas.2107042118
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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