Proprotein convertase substilisin/kexin type 9 antagonism reduces low-density lipoprotein cholesterol in statin-treated hypercholesterolemic nonhuman primates
Journal
Journal of Pharmacology and Experimental Therapeutics
Journal Volume
340
Journal Issue
2
Pages
228
Date Issued
2012-02
Author(s)
Liang, Hong
Chaparro-Riggers, Javier
Strop, Pavel
Geng, Tao
Sutton, Janette E
Bai, Lanfang
Abdiche, Yasmina
Dilley, Jeanette
Yu, Jessica
Wu, Si
Chin, S Michael
Lee, Nicole A
Rossi, Andrea
Lin, John C
Rajpal, Arvind
Pons, Jaume
Shelton, David L
Abstract
Proprotein convertase substilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein (LDL) receptor (LDLR) and thereby increases serum LDL-cholesterol (LDL-C). We have developed a humanized monoclonal antibody that recognizes the LDLR binding domain of PCSK9. This antibody, J16, and its precursor mouse antibody, J10, potently inhibit PCSK9 binding to the LDLR extracellular domain and PCSK9-mediated down-regulation of LDLR in vitro. In vivo, J10 effectively reduces serum cholesterol in C57BL/6 mice fed normal chow. J16 reduces LDL-C in healthy and diet-induced hypercholesterolemic cynomologous monkeys, but does not significantly affect high-density lipoprotein-cholesterol. Furthermore, J16 greatly lowered LDL-C in hypercholesterolemic monkeys treated with the HMG-CoA reductase inhibitor simvastatin. Our data demonstrate that anti-PCSK9 antibody is a promising LDL-C-lowering agent that is both efficacious and potentially additive to current therapies.
Subjects
SECRETED PCSK9; FAMILIAL HYPERCHOLESTEROLEMIA; LDL CHOLESTEROL; SUBTILISIN/KEXIN TYPE-9; PLASMA-CHOLESTEROL; IN-VIVO; RECEPTOR; MICE; GENE; DEGRADATION
SDGs
Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
Type
journal article