Peptide‐Drug Conjugates: A New Hope for Cancer
Amy Armstrong, Fleur Coburn, Yanyamba Nsereko, Othman Al Musaimi
Abstract
Peptide-drug conjugates (PDCs) are advancing as targeted cancer therapies, leveraging lessons from antibody-drug conjugates (ADCs) to improve tumour specificity. These molecules combine a homing peptide with a cytotoxic payload via a linker, enabling precise drug delivery while sparing healthy tissue. Despite their potential, PDCs face challenges including metabolic instability, premature payload release and rapid clearance, limiting clinical success. Only Lutathera remains FDA-approved after Pepaxto's withdrawal, though Pepaxto retains EMA and MHRA approval-highlighting regulatory and technical complexities. Most PDCs target overexpressed receptors (e.g., somatostatin and GnRH), though novel designs like CBX-12 employ alternative strategies. Currently, six PDCs are in Phase III trials, with ~96 in development, signalling growing interest. This review explores how ADC research has guided PDC optimisation, particularly in linker chemistry and payload selection. We analyse key structural features governing PDC efficacy, including peptide-receptor binding and intracellular trafficking. Innovations in stable linkers and tumour-selective activation mechanisms are critical to overcoming pharmacokinetic hurdles. Promising candidates in late-stage trials are highlighted, emphasising their potential to address unmet needs in oncology. By refining targeting precision and payload delivery, next-generation PDCs may expand treatment options for resistant cancers, bridging the gap between biologics and small-molecule therapies.