A small biologic alternative to PCSK9 antibodies has been developed, which interferes with binding of PCSK9 to LDL receptor (LDLR) and thereby inhibits PCSK9-mediated degradation of LDLR. The molecule, DS-9001a, is comprised of an albumin binding domain fused to an artificial lipocalin mutein (ABD-fused Anticalin protein). Lipocalins are a family of proteins that contain a target binding loop region that can be mutated and selected to potently and specifically recognize and bind a target protein (Anticalin proteins). The Anticalin protein that potently inhibits binding of PCSK9 to LDLR tested in the current study is bound to albumin to extend the plasma elimination half-life.

This study investigated the pharmacokinetic and pharmacologic profiles of DS-9001a in rodents and cynomolgus monkeys, and evaluated combined effects of DS-9001a and atorvastatin to combination therapy of CETP inhibitor treatment with anacetrapib and atorvastatin, or both monotherapies.

In cynomolgus monkeys, a single administration of DS-9001a lowered LDL-c by about 62% for over 21 days. The duration of LDL-c suppression could be dose-dependently prolonged. Administration of a combination of atorvastatin and DS-9001a in human CETP/ApoB double transgenic mice resulted in reductions of non-HDL-c levels, to a greater extent than upon treatment with anacetrapib and atorvastatin. DS-9001a monotherapy lowered the levels of atherogenic oxidized LDL, as compared with vehicle treatment. Combination therapy of DS-9001a and atorvastatin further reduced ox-LDL levels.

DS-9001a can be produced in a microbial production system, considered suitable for mass production at low cost. It has a molecular weight of about 22kDa, which may yield a smaller administration volume than existing antibody therapy. ABD-fused Anticalin proteins could represent a promising new class of small biologic molecules.

Read more about this research online at J Pharmacol Exp Ther