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

Research output: Contribution to journalArticlepeer-review

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

Original languageEnglish
Article number741
Pages (from-to)741
Number of pages1
JournalCommunications Biology
Issue number1
Published29 Jul 2022

Bibliographical note

Funding Information: All authors except C.P. are either paid employees/consultants (G.P., P.J.M.J., D.E.T.) or recipients of grants funded by Femtogenix Ltd (D.d.M, K.R.F.). G.P., P.J.M.J., K.M.R and D.E.T. hold shares and/or share options in the company. C.P declares no competing interests. Publisher Copyright: © 2022, The Author(s).

King's Authors


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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