Pyridinobenzodiazepines (PDDs) as Sequence-selective DNA Mono-alkylating Antibody–Drug Conjugate (ADC) Payloads

Abstract

Although five ADCs have been approved and over sixty others are in development, the majority contain payloads belonging to two classes: tubulin inhibitors and DNA-interactive agents. Challenges in the development of ADCs include managing off-target toxicity and hydrophobicity. Some DNA-interactive payload classes [e.g. pyrolobenzodiazepine (PBD] dimers) are notably hydrophobic, leading to problems such as aggregation during conjugation, and systemic toxicities of the resultant ADCs are also beginning to emerge in clinical settings. Thus, there is interest in developing novel payloads which retain the potency of DNA cross-linking agents but have lower hydrophobicity and a wider therapeutic window when part of an ADC. The pyridinobenzodiazepines (PDDs) are a new class of sequence-selective, DNA mono-alkylating ADC payload, which contain a polyheterocyclic chain with sufficient molecular span and DNA base-pair recognition properties to guide them to specific DNA sequences (e.g. transcription factor binding sites). The favourable hydrophobicity profile of the PDDs and ease of conjugation, along with their novel mechanism of action, significant in vitro cytotoxicity and in vivo tolerability and efficacy when in an ADC format, indicate that they represent a promising new class of ADC payloads.

A Novel Antibody-Drug Conjugate (ADC) Delivering a DNA Mono-Alkylating Payload to Chondroitin Sulfate Proteoglycan (CSPG4)-Expressing Melanoma

“…Currently, 29 ADCs have been developed based on a PBD dimer payload, 20 of which have entered clinical development, with nine in active clinical trials and 11 discontinued. PBD-based DNA cross-linking agents have been linked to concerns regarding on-and off-target toxicities due to non-specific uptake of the payloads into sensitive normal tissues, resulting in acute and delayed toxicity in both pre-clinical and clinical settings [44]. Toxicity issues led to the development of a similar class of payloads that still bind in the DNA minor groove but form mono-alkylated adducts instead which are less systemically toxic, potentially due to their ability to be more easily repaired by healthy cells.…”

“…Toxicity issues led to the development of a similar class of payloads that still bind in the DNA minor groove but form mono-alkylated adducts instead which are less systemically toxic, potentially due to their ability to be more easily repaired by healthy cells. Examples of mono-alkylating DNA-interactive payloads include the indolinobenzodiazepines (IGNs) and the PDDs [44]. Due to the mono-alkylating mechanism of action of the PDDs, there is evidence to suggest that they may enhance the therapeutic window of ADCs by reducing off-target cytotoxic effects.…”