2. Academic Validation
  3. Synthesis and Evaluation of Camptothecin Antibody-Drug Conjugates

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

Affiliation

  • 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.

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