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

• Published in: Bioconjugate chemistry Vol. 30; no. 1; pp. 200 - 209
• Main Authors: Ratnayake, Anokha S, Chang, Li-ping, Tumey, L. Nathan, Loganzo, Frank, Chemler, Joseph A, Wagenaar, Melissa, Musto, Sylvia, Li, Fengping, Janso, Jeffrey E, Ballard, T. Eric, Rago, Brian, Steele, Greg L, Ding, WeiDong, Feng, Xidong, Hosselet, Christine, Buklan, Vlad, Lucas, Judy, Koehn, Frank E, O’Donnell, Christopher J, Graziani, Edmund I
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16.01.2019
• Subjects: Alcohols; Animals; Antineoplastic Agents, Immunological - chemistry; Biological Products - chemistry; Cell Line, Tumor; Citrulline; Conjugates; Damage assessment; Deoxyribonucleic acid; Depsipeptides - blood; Depsipeptides - chemistry; Depsipeptides - pharmacokinetics; DNA; DNA - chemistry; DNA damage; Echinomycin - chemistry; ErbB-2 protein; Genes, erbB-2; Half-Life; Heterografts; Humans; Immunoconjugates - chemistry; Immunoglobulins; Intercalating Agents - chemistry; Lysine; Mice; Monoclonal antibodies; Natural products; Organic chemistry; Payloads; Peptides; Trastuzumab; Trastuzumab - chemistry; Valine
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.8b00843

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.