Proprotein convertase subtilisin kexin-9 (PCSK9) is an important pharmacological target for decreasing low density lipoprotein (LDL); however, it is seemingly inaccessible to small molecule approaches. Compared with therapeutic IgG antibodies, targeting circulating PCSK9 with smaller molecular scaffolds could offer different profiles and reduced dose burdens. This inspired genesis of PCSK9-binding Adnectins, a protein family derived from human fibronectin-10th-type III–domain and engineered for high-affinity target binding. BMS-962476, an ∼11-kDa polypeptide conjugated to polyethylene glycol to enhance pharmacokinetics, binds with subnanomolar affinity to human. Treatment of cynomolgus monkeys with BMS-962476 rapidly suppressed free PCSK9 >99% and LDL-cholesterol ∼55% with subsequent 6-fold increase in total PCSK9, suggesting reduced clearance of circulating complex. Liver sterol response genes were consequently downregulated, following which LDL and total PCSK9 returned to baseline.
See article at J Pharmacol Exp Ther 2014, 350:412–424.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics