An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising therapeutic target for treating coronary heart disease. We report a novel antibody 1B20 that binds to PCSK9 with sub-nanomolar affinity and antagonizes PCSK9 function in-vitro. In CETP/LDLR-hemi mice two successive doses of 1B20, administered 14 days apart at 3 or 10 mpk, induced dose dependent reductions in LDL-cholesterol (≥ 25% for 7-14 days) that correlated well with the extent of PCSK9 occupancy by the antibody. In addition, 1B20 induces increases in total plasma antibody-bound PCSK9 levels and decreases in liver mRNA levels of SREBP-regulated genes PCSK9 and LDLR, with a time course that parallels decreases in plasma LDL-cholesterol (LDL-C). Consistent with this observation in mice, in statin-responsive human primary hepatocytes, 1B20 lowers PCSK9 and LDLR mRNA levels and raises serum steady-state levels of antibody-bound PCSK9. In addition, mRNA levels of several SREBP regulated genes involved in cholesterol and fatty-acid synthesis including ACSS2, FDPS, IDI1, MVD, HMGCR, and CYP51A1 were decreased significantly with antibody treatment of primary human hepatocytes. In rhesus monkeys, subcutaneous (SC) dosing of 1B20 dose-dependently induces robust LDL-C lowering (maximal ~70%), which is correlated with increases in target engagement and total antibody-bound PCSK9 levels. Importantly, a combination of 1B20 and Simvastatin in dyslipidemic rhesus monkeys reduced LDL-C more than either agent alone, consistent with a mechanism of action that predicts additive effects of anti-PCSK9 agents with statins. Our results suggest that antibodies targeting PCSK9 could provide patients powerful LDL lowering efficacy on top of statins, and lower cardiovascular risk.

• Authors: Liwen Zhang, Timothy McCabe, Jon H Condra, Yan G Ni, Laurence B Peterson, Weirong Wang, Alison M Strack, Fubao Wang, Shilpa Pandit, Holly Hammond, Dana Wood, Dale Lewis, Ray Rosa, Vivienne Mendoza, Anne Marie Cumiskey, Douglas G Johns, Barbara C Hansen, Xun Shen, Neil Geoghagen, Kristian Jensen, Lei Zhu, Karol Wietecha, Douglas Wisniewski, Lingyi Huang, Jing Zhang Zhao, Robin Ernst, Richard Hampton, Peter Haytko, Frances Ansbro, Shannon Chilewski, Jayne Chin, Lyndon J Mitnaul, Andrea Pellacani, Carl P Sparrow, Zhiqiang An, William Strohl, Brian Hubbard, Andrew S Plump, Daniel Blom, Ayesha Sitlani
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 8 Issue 3 Pg. 310-27 ( 2012) ISSN: 1449-2288 [Electronic] Australia
• PMID: 22355267 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Anticholesteremic Agents
• CETP protein, human
• Cholesterol Ester Transfer Proteins
• Cholesterol, LDL
• RNA, Messenger
• Receptors, LDL
• Recombinant Proteins
• Sterol Regulatory Element Binding Proteins
• Simvastatin
• PCSK9 protein, human
• Pcsk9 protein, mouse
• Proprotein Convertase 9
• Proprotein Convertases
• Serine Endopeptidases

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Antibody Affinity
• Anticholesteremic Agents (administration & dosage, therapeutic use)
• Cells, Cultured (drug effects, metabolism)
• Cholesterol Ester Transfer Proteins (genetics, metabolism)
• Cholesterol, LDL (blood)
• Gene Expression Profiling
• Gene Expression Regulation (drug effects)
• Hep G2 Cells (drug effects, metabolism)
• Hepatocytes (drug effects, metabolism)
• Humans
• Immunization, Passive
• Lipid Metabolism (genetics)
• Liver (drug effects, metabolism)
• Macaca mulatta
• Metabolic Syndrome (drug therapy, genetics, therapy)
• Mice
• Mice, Transgenic
• Proprotein Convertase 9
• Proprotein Convertases (antagonists & inhibitors, biosynthesis, genetics, immunology)
• RNA, Messenger (metabolism)
• Receptors, LDL (biosynthesis, genetics)
• Recombinant Proteins (metabolism)
• Serine Endopeptidases (biosynthesis, genetics, immunology)
• Simvastatin (administration & dosage, therapeutic use)
• Sterol Regulatory Element Binding Proteins (physiology)