DNA sequence-selective G-A cross-linking ADC payloads for use in solid tumour therapies

George Procopiou, Paul J.M. Jackson, Daniella di Mascio, Jennifer L. Auer, Chris Pepper, Khondaker Miraz Rahman, Keith R. Fox, David E. Thurston

Research output: Contribution to journalArticlepeer-review

Abstract

Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and haematological malignancies. There is a demand for new payloads with novel mechanisms of action that may offer enhanced therapeutic efficacy, especially in patients who develop resistance. We report here a class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads that simultaneously alkylate guanine (G) and adenine (A) bases in the DNA minor groove with a defined sequence selectivity. The lead payload, FGX8-46 (6), produces sequence-selective G-A cross-links and affords cytotoxicity in the low picomolar region across a panel of 11 human tumour cell lines. When conjugated to the antibody cetuximab at an average Drug-Antibody Ratio (DAR) of 2, an ADC is produced with significant antitumour activity at 1 mg/kg in a target-relevant human tumour xenograft mouse model with an unexpectedly high tolerability (i.e., no weight loss observed at doses as high as 45 mg/kg i.v., single dose).

Original languageEnglish
Article number741
Pages (from-to)741
Number of pages1
JournalCommunications Biology
Volume5
Issue number1
DOIs
Publication statusPublished - 29 Jul 2022

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