Cytotoxic Payloads for Antibody – Drug Conjugates 2019
DOI: 10.1039/9781788012898-00349
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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… Show more

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Cited by 2 publications
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“…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.…”
Section: Discussionmentioning
confidence: 99%
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“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Discussionmentioning
confidence: 99%