2. Academic Validation
  3. DNA sequence-selective G-A cross-linking ADC payloads for use in solid tumour therapies

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

  • Commun Biol. 2022 Jul 29;5(1):741. doi: 10.1038/s42003-022-03633-0.
George Procopiou 1,  Paul J M Jackson 1,  Daniella di Mascio 2,  Jennifer L Auer 1,  Chris Pepper 3,  Khondaker Miraz Rahman 1 4,  Keith R Fox 2,  David E Thurston 5 6
Affiliations

Affiliations

  • 1 Femtogenix, Lawes Open Innovation Hub, Rothamsted Research, West Common, Harpenden, Hertfordshire, AL5 2JQ, UK.
  • 2 School of Biological Sciences, Life Sciences Building B85, University of Southampton, Southampton, Hampshire, SO17 1BJ, UK.
  • 3 Brighton and Sussex Medical School, University of Sussex, Brighton, BN1 9PX, UK.
  • 4 School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
  • 5 Femtogenix, Lawes Open Innovation Hub, Rothamsted Research, West Common, Harpenden, Hertfordshire, AL5 2JQ, UK. [email protected].
  • 6 School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK. [email protected].
PMID: 35906376 DOI: 10.1038/s42003-022-03633-0
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).

Figures