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Synthesis and Evaluation of Camptothecin Antibody-Drug Conjugates.

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.

SUBMITTER: Li W

PROVIDER: S-EPMC6792168 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Synthesis and Evaluation of Camptothecin Antibody-Drug Conjugates.

Li Wei W Veale Karen H KH Qiu Qifeng Q Sinkevicius Kerstin W KW Maloney Erin K EK Costoplus Juliet A JA Lau Janet J Evans Helen L HL Setiady Yulius Y Ab Olga O Abbott Stephen M SM Lee Jenny J Wisitpitthaya Somsinee S Skaletskaya Anna A Wang Lintao L Keating Thomas A TA Chari Ravi V J RVJ Widdison Wayne C WC

ACS medicinal chemistry letters 20190906 10

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 <i>in vitro</i> and <i>in vivo</i>. This simplification allows easier derivatiz ...[more]

PMID: 31620223

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