Bioconjug Chem. 2025 Nov 22. doi: 10.1021/acs.bioconjchem.5c00485. Online ahead of print.
ABSTRACT
DNA topoisomerase I (TOP1) inhibitor-based antibody-drug conjugates (ADCs) incorporating photosensitive camptothecin (CPT) analogs as payloads have emerged as a promising therapeutic strategy in oncology. However, their clinical potential is challenged by photoinduced instability during manufacturing, storage, and handling, which are typically conducted under ambient light conditions, using white light with wavelengths greater than 400 nm and minimal ultraviolet (UV) exposure. In this study, we systematically investigated, for the first time, the impact of ambient light exposure on TOP1 inhibitor-conjugated ADCs (TOP1-ADCs), and we revealed critical photodegradation mechanisms that compromise their physicochemical properties and therapeutic efficacy. Upon ambient light exposure, TOP1-ADCs underwent significant chemical, physical, and biofunctional changes, including visible color changes, aggregation, oxidation, drug loss, payload degradation, destabilization in CH2 domain, and reduced binding affinity to the neonatal Fc receptor (FcRn). Mechanistic studies revealed two distinct pathways driving this photodegradation: a reactive oxygen species (ROS) generation-mediated pathway and a direct payload self-photolysis-mediated pathway. In oxygen-rich environments, the ROS-generation-mediated pathway predominates, where the excited-state payload primarily transfers energy to molecule oxygen to induce ROS formation, leading to oxidation and subsequent aggregation and drug loss. Under oxygen-depleted conditions, direct payload photolysis becomes the primary degradation mechanism, resulting in payload degradation and more severe particular nonreducible aggregation formation. These findings highlighted the necessity of implementing stringent light-protective measures throughout the production, storage, and handling of TOP1-ADCs to preserve their stability, efficacy, and safety. The study provided critical insights into the photosensitivity of TOP1 inhibitor-based ADCs, offering a foundation for optimizing their development and clinical applications.
PMID:41273300 | DOI:10.1021/acs.bioconjchem.5c00485
