A bimolecular modification strategy for developing long-lasting bone anabolic aptamer

Abstract

The molecular weight of nucleic acid aptamers (20 kDa) is lower than the cut-off threshold of the renal filtration (30-50 kDa), resulting in a very short half-life, which dramatically limits their druggability. To address this, we utilized HC and DA, two newly designed coupling agents, for synergistic binding to human serum albumin (HSA). Both HC and DA are conjugated to a bone anabolic aptamer (Apc001) against sclerostin to form an Apc001OC conjugate with high binding affinity to HSA. Notably, HC and DA could synergistically facilitate prolonging the half-life of the conjugated Apc001 and promoting its bone anabolic potential. Using the designed blocking peptides, the mechanism studies indicate that the synergistic effect of HC-DA on pharmacokinetics and bone anabolic potential of the conjugated Apc001 is achieved via their synergistic binding to HSA. Moreover, biweekly Apc001OC at 50mg/kg shows comparable bone anabolic potential to the marketed sclerostin antibody given weekly at 25mg/kg. This proposed bimolecular modification strategy could help addressing druggability challenge for aptamers with a short half-life.