DNA sequence-selective G-A cross-linking ADC payloads for use in solid tumour therapies.
George ProcopiouPaul J M JacksonDaniella di MascioJennifer L AuerChris PepperKhondaker Miraz RahmanKeith R FoxDavid E ThurstonPublished in: Communications biology (2022)
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).
Keyphrases
- circulating tumor
- endothelial cells
- cell free
- weight loss
- mouse model
- single molecule
- induced pluripotent stem cells
- pluripotent stem cells
- bariatric surgery
- photodynamic therapy
- diffusion weighted imaging
- squamous cell carcinoma
- randomized controlled trial
- magnetic resonance imaging
- clinical trial
- body mass index
- radiation therapy
- roux en y gastric bypass
- drug delivery
- adipose tissue
- placebo controlled
- adverse drug
- contrast enhanced
- obese patients