Abstract 1750: Design and development of a novel highly sequence-selective guanine mono-alkylating DNA-interactive ADC payload suitable for solid tumor treatments
Authors: Andriollo Paolo , Procopiou George , di Mascio Daniella M. , Jackson Paul J. , Rahman Khondaker M. , Fox Keith R. , Thurston David E. 
Published: June 2022

Antibody-Drug Conjugates (ADCs) are a fast-growing class of targeted cancer therapeutic agents with over ten approved and greater than 100 in various stages of clinical development.

The pyridinobenzodiazepines (PDDs) are a new class of DNA-interactive sequence-selective Guanine mono-alkylating ADC payloads which contain a sequence recognition component with sufficient span to guide them to specific DNA sequences (e.g., transcription factor binding sites).

A high potency PDD, FGX15-147, has been developed that contains a bi-aryl moiety capable of forming an intramolecular ‘sigma-hole’ interaction with DNA bases, thus providing the molecule with a unique sequence-selectivity profile when compared to other DNA-interactive agents. DNA footprinting data will be presented indicating that the molecule, which spans 8-9 DNA base pairs in the minor groove, has an increased sequence selectivity compared with related analogues, preferring DNA regions containing two guanines 2-4 base pairs apart. FGX15-147 is highly cytotoxic in vitro (e.g., IC50 = 0.30 nM in SW60; 1.6 nM in LIM1215 and 0.142 nM in SW48, after 96 hours incubation), and is thought to exert its activity through a combination of DNA alkylation and inhibiting the binding of important oncogenic transcription factors such as Hypoxia Inducible Factor (HIF) to DNA (demonstrated through an in vitro Transcription Factor Array assay). HIF is known to be involved in the development of a large number of solid malignancies, including pancreatic cancer.

To explore the utility of FGX15-147 as an ADC payload, it was conjugated to trastuzumab in a stochastic manner (DAR 1.6) using a Maleimide-Valine-Alanine linker construct. The resulting ADC exhibited significant in vivo efficacy in a low copy number HER2+ pancreatic cancer Human Tumor Xenograft model using BALB-c mice transplanted with the CAPAN-1 cell line. Complete tumor regression was observed out to 60 days after a single dose of 2 mg/kg comparing favorably to a 10 mg/kg dose of trastuzumab deruxtecan (Enhertu®) in the same study in which substantial tumor regrowth had occurred by 57 days. In a standard mouse model, the FGX15-147-based ADC had a good tolerability profile with a Maximum Tolerated Dose (MTD) of at least 16 mg/kg.

Overall, the favorable tolerability and efficacy profile of FGX15-147 in an ADC format suggests that it represents a potentially valuable approach for the treatment of solid tumors.

Citation Format: Paolo Andriollo, George Procopiou, Daniella M. di Mascio, Paul J. Jackson, Khondaker M. Rahman, Keith R. Fox, David E. Thurston. Design and development of a novel highly sequence-selective guanine mono-alkylating DNA-interactive ADC payload suitable for solid tumor treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1750.