Synthesis and Evaluation of Camptothecin Antibody-Drug Conjugates

  • ACS Med Chem Lett. 2019 Sep 6;10(10):1386-1392. doi: 10.1021/acsmedchemlett.9b00301.
Wei Li  1 ,  Karen H Veale  1 ,  Qifeng Qiu  1 ,  Kerstin W Sinkevicius  1 ,  Erin K Maloney  1 ,  Juliet A Costoplus  1 ,  Janet Lau  1 ,  Helen L Evans  1 ,  Yulius Setiady  1 ,  Olga Ab  1 ,  Stephen M Abbott  1 ,  Jenny Lee  1 ,  Somsinee Wisitpitthaya  1 ,  Anna Skaletskaya  1 ,  Lintao Wang  1 ,  Thomas A Keating  1 ,  Ravi V J Chari  1 ,  Wayne C Widdison  1
Affiliations
  • 1. ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
PMID: 31620223 DOI: 10.1021/acsmedchemlett.9b00301
Abstract

Antibody-drug conjugates (ADCs) that incorporate the exatecan derivative DXd in their payload are showing promising clinical results in solid tumor indications. The payload has an F-ring that also contains a second chiral center, both of which complicate its synthesis and derivatization. Here we report on new camptothecin-ADCs that do not have an F-ring in their payloads yet behave similarly to DXd-bearing conjugates in vitro and in vivo. This simplification allows easier derivatization of camptothecin A and B rings for structure-activity relationship studies and payload optimization. ADCs having different degrees of bystander killing and the ability to release hydroxyl or thiol-bearing metabolites following peptide linker cleavage were investigated.

Products