Fc Multisite Conjugation and Prolonged Delivery of the Folate-Targeted Drug Conjugate EC140

Small molecule-drug conjugate (SMDC) is a targeted drug delivery technology that develops in parallel with the antibody-drug conjugate. However, the clinical translation of SMDC faces challenges due to its limited circulating half-life in vivo. The drawback in pharmacokinetics is that it restricts the exposure time of SMDC to tumor tissues and ultimately reduces the therapeutic efficacy. In this study, we chemically conjugated a folate-targeted SMDC EC140 to the long-circulating Fc protein at multiple sites, yielding a stable and high-DAR Fc-SMDC conjugate (Fc-EC140). Fc-EC140 can bear approximately 4 molecules of EC140 per Fc protein (drug-antibody ratio = 4.1) and display enhanced potency in folate receptor (FR)-positive tumor cells compared to the SMDC comparator. In addition, Fc-EC140 retains the FcRn-mediated recycling function and displays an extended half-life of 28 h in the mice. In vivo, antitumor experiments demonstrate that intravenous administration of Fc-EC140 (Q7D × 3 at a dose of 15 mg/kg) nearly cures the KB tumors, which is far more effective than the comparator EC140 administrated at equivalent doses. This study presents a new strategy for the targeted delivery of SMDC.