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

person Jeewon Lee Cellemedy, Seongnam, South Korea info_outline Jeewon Lee, Bo Ram Lee, Yong Hwan Seol, Hyun Ju Hwang

Authors person Jeewon Lee Cellemedy, Seongnam, South Korea info_outline Jeewon Lee, Bo Ram Lee, Yong Hwan Seol, Hyun Ju Hwang Organizations Cellemedy, Seongnam, South Korea, Korea University, Seoul, South Korea Abstract Disclosures Research Funding No funding sources reported 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 EC 50 , 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.