2. Academic Validation
  3. Natural Product Bis-Intercalator Depsipeptides as a New Class of Payloads for Antibody-Drug Conjugates

Natural Product Bis-Intercalator Depsipeptides as a New Class of Payloads for Antibody-Drug Conjugates

  • Bioconjug Chem. 2019 Jan 16;30(1):200-209. doi: 10.1021/acs.bioconjchem.8b00843.
Anokha S Ratnayake 1,  Li-Ping Chang 1,  L Nathan Tumey 1,  Frank Loganzo 2,  Joseph A Chemler 1,  Melissa Wagenaar 1,  Sylvia Musto 2,  Fengping Li 1,  Jeffrey E Janso 1,  T Eric Ballard 1,  Brian Rago 1,  Greg L Steele 1,  WeiDong Ding 1,  Xidong Feng 1,  Christine Hosselet 2,  Vlad Buklan 2,  Judy Lucas 2,  Frank E Koehn 1,  Christopher J O'Donnell 1,  Edmund I Graziani 1
Affiliations

Affiliations

  • 1 Medicine Design , Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States.
  • 2 Oncology Research , Pfizer Worldwide Research and Development , 401 North Middletown Road , Pearl River , New York 10965 , United States.
PMID: 30543418 DOI: 10.1021/acs.bioconjchem.8b00843
Abstract

A potent class of DNA-damaging agents, natural product bis-intercalator depsipeptides (NPBIDs), was evaluated as ultrapotent payloads for use in antibody-drug conjugates (ADCs). Detailed investigation of potency (both in cells and via biophysical characterization of DNA binding), chemical tractability, and in vitro and in vivo stability of the compounds in this class eliminated a number of potential candidates, greatly reducing the complexity and resources required for conjugate preparation and evaluation. This effort yielded a potent, stable, and efficacious ADC, PF-06888667, consisting of the bis-intercalator, SW-163D, conjugated via an N-acetyl-lysine-valine-citrulline- p-aminobenzyl alcohol- N, N-dimethylethylenediamine (AcLysValCit-PABC-DMAE) linker to an engineered variant of the anti-Her2 mAb, trastuzumab, catalyzed by transglutaminase.

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