A new modality of anti-cancer drug: Ferritin-drug conjugates.

Abstract

e14590 Background: Success criteria of ADCs is the target overexpression in tumor, i.e. in general ~ 14-fold in tumor vs. normal cells, which is the reason why it is hardly possible to develop clinically potent ADCs against several cancers with low target expression, which remains a major challenge yet, although fam-trastuzumab deruxtecan-nxki (Enhertu; AZN) and sacituzumab govitecan-hziy (Trodelvy; Gilead) recently exhibit an exceptionally enhanced efficacy for TNBC. Methods: Payloads were conjugated to a human apoferritin-derived, cancer-targeting scaffold (a self-assembled 24-mer protein with a diameter of ~ 12 nm, showing a high avidity for cancer cells) via a particular payload-releasing linker based on thiol-maleimide/imidazole-metal ion/EDC-NHS chemistry. Results: A new modality of anti-cancer drug - ferritin-drug conjugates (FDCs) - was developed, demonstrating a notably enhanced performance in cancer treatment as compared to current, clinically available anti-cancer drugs such as fam-trastuzumab deruxtecan-nxki, which is due to the important advantages such as far lowered EC50, high cancer-targeting efficiency, excellent structural stability (even in DMSO (up to 30%)), high loading capacity (high drug to ferritin ratio (DFR > 20)) and consistent homogeneity in drug conjugation, no immune side effects, reduced drug resistance, and/or reduced off-target toxicity. Conclusions: FDCs are believed to open up a novel, attractive clinical route for both potent and safe therapy of a broad range of cancers.