Proprotein convertase substilisin/kexin type 9 antagonism reduces low-density lipoprotein cholesterol in statin-treated hypercholesterolemic nonhuman primates.
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.
Rinat Laboratories, Pfizer Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA. hong.liang@pfizer.com
Hong
H
Liang
Javier
J
Chaparro-Riggers
Pavel
P
Strop
Tao
T
Geng
Janette E
JE
Sutton
Daniel
D
Tsai
Lanfang
L
Bai
Yasmina
Y
Abdiche
Jeanette
J
Dilley
Jessica
J
Yu
Si
S
Wu
S Michael
SM
Chin
Nicole A
NA
Lee
Andrea
A
Rossi
John C
JC
Lin
Arvind
A
Rajpal
Jaume
J
Pons
David L
DL
Shelton
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D020134:Catalytic Domain / Q000276:immunology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects*; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000379:methods; D000939:Epitopes / Q000276:immunology; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D011323:Primates; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011973:Receptors, LDL / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D012697:Serine Endopeptidases / Q000097:blood / Q000276:immunology / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
D061067:Antibodies, Monoclonal, Humanized; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004041:Dietary Fats; D000939:Epitopes; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011973:Receptors, LDL; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D019821:Simvastatin; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases