Cytotoxic payload intracellular targets

Cytotoxic payload intracellular targets encompass the essential cellular machinery targeted by the effector molecules of antibody-drug conjugates (ADCs) and other ligand-directed toxins. These targets are primarily categorized into those affecting structural proteins, such as microtubules, and those affecting genetic integrity, including DNA and Topoisomerase I (Beck et al., 2017; Chau et al., 2019). For instance, auristatins and maytansinoids target tubulin to disrupt mitotic spindle formation, while camptothecin analogs like SN-38 and DXd inhibit Topoisomerase I to cause lethal DNA strand breaks (Nakada et al., 2019; Syrigos et al., 2022). The therapeutic efficacy of drugs hitting these targets relies on the successful delivery and release of the payload within the target cell, often mediated by lysosomal degradation of the carrier (Bross et al., 2001). However, the high potency of these payloads against ubiquitous intracellular targets poses significant safety challenges, including off-target toxicities like neutropenia and neuropathy, which are often driven by the systemic release of the payload or "bystander" effects on neighboring healthy cells.

Other names

Intracellular ADC targetsCytotoxic drug targetsPayload-binding sitesEffector targets

Inhibition of microtubule assembly or disassembly, induction of DNA double-strand breaks, DNA alkylation, and inhibition of Topoisomerase I leading to DNA damage and apoptosis (Beck et al., 2017; Nakada et al., 2019).