Procopiou et al GA Cross-Linking ADC Payloads Communications Biology (Nature) 2022.pdf (1.44 MB)
DNA sequence-selective G-A cross-linking ADC payloads for use in solid tumour therapies
journal contributionposted on 2023-06-10, 04:22 authored by George Procopiou, Paul J M Jackson, Daniella di Mascio, Jennifer L Auer, Christopher PepperChristopher Pepper, Khondaker Miraz Rahman, Keith R Fox, David E Thurston
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).
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