A novel DNA sequence-selective, guanine mono-alkylating ADC payload suitable for solid tumour treatment

Abstract

Pyridinobenzodiazepines (PDDs) are a new class of DNA mono-alkylating antibody–drug conjugate (ADC) payloads that can be linked through their C9 position to a sequence recognition component, guiding them to specific DNA sequences. Compound 18 is a PDD monomer with a unique sequence-selectivity profile and high cytotoxicity in vitro (e.g., IC₅₀ = 0.30 nM in SW60; 1.6 nM in LIM1215 and 0.142 nM in SW48 cell line, after 96 hours incubation). To evaluate its potential as an ADC payload, an amine functionality was introduced into the terminal phenyl ring, and the modified compound was conjugated to trastuzumab (drug–antibody ratio [DAR] = 1.6). The resulting ADC exhibits significant in vivo efficacy in a pancreatic cancer xenograft model using BALB-c mice transplanted with the CAPAN-1 cell line. Complete tumour regression is observed out to 60 days after a single dose of 2 mg kg⁻¹ comparing favourably to a 10 mg kg⁻¹ dose of trastuzumab deruxtecan (Enhertu®). The novel ADC has a good tolerability profile, with a maximum tolerated dose (MTD) above 15 mg kg⁻¹. The tolerability and efficacy profile of compound 18 in an ADC format suggests that PDDs represent a potentially valuable new class of payloads for the treatment of solid tumours.