Intracellular macromolecular targets of ADC cytotoxic payload

Intracellular macromolecular targets of ADC cytotoxic payloads refer to the specific biological structures within a cell that are disrupted by the potent 'warhead' component of an antibody-drug conjugate. Upon binding to a cell-surface antigen and subsequent internalization via endocytosis, the ADC releases its payload, which typically migrates to either the cytoskeleton or the genome (Tsuchikama & An, 2018). The most common targets are tubulin, where payloads like auristatins and maytansinoids inhibit mitosis by disrupting microtubule dynamics, and DNA, where agents like calicheamicins or pyrrolobenzodiazepines cause irreversible alkylation or double-strand breaks (Beck et al., 2017). More recently, Topoisomerase I has emerged as a key target for camptothecin-derived payloads such as DXd and SN-38, which inhibit DNA replication and transcription (Goldenberg & Sharkey, 2020). By interfering with these essential cellular processes, the payloads trigger programmed cell death (apoptosis), effectively killing the malignant cell while minimizing systemic exposure to the toxin.

Other names

Antibody-drug conjugate payload targetsADC warhead targetsCytotoxic payload targetsIntracellular ADC targets

Inhibition of microtubule polymerization or depolymerization, induction of DNA double-strand breaks, DNA alkylation, or inhibition of Topoisomerase I, leading to cell cycle arrest and apoptosis (Tsuchikama & An, 2018; Beck et al., 2017).