International Journal of Biological Sciences

Impact factor
3.873

ISSN 1449-2288

News feeds of IJBS published articles
My Manuscript
My Account

Journal of Biomedicinenew

Theranostics

International Journal of Medical Sciences

Journal of Cancer

Oncomedicine

Journal of Genomics

Journal of Bone and Joint Infection (JBJI)

Nanotheranostics

Journal of Genomics now in PubMed/PubMed Central. Submit manuscript...

PubMed Central Indexed in Journal Impact Factor

Int J Biol Sci 2012; 8(3):310-327. doi:10.7150/ijbs.3524

Research Paper

An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes

Liwen Zhang1✉, Timothy McCabe2, Jon H. Condra2, Yan G. Ni1, Laurence B. Peterson1, Weirong Wang3, Alison M. Strack1, Fubao Wang2, Shilpa Pandit1, Holly Hammond2, Dana Wood2, Dale Lewis1, Ray Rosa1, Vivienne Mendoza1, Anne Marie Cumiskey1, Douglas G. Johns1, Barbara C. Hansen10, Xun Shen1, Neil Geoghagen1, Kristian Jensen1, Lei Zhu5, Karol Wietecha5, Douglas Wisniewski4, Lingyi Huang, Jing Zhang Zhao, Robin Ernst, Richard Hampton, Peter Haytko, Frances Ansbro7, Shannon Chilewski7, Jayne Chin1, Lyndon J. Mitnaul1, Andrea Pellacani6, Carl P. Sparrow1, Zhiqiang An2,8, William Strohl2,9, Brian Hubbard1, Andrew S. Plump1, Daniel Blom1, Ayesha Sitlani1✉

1. Department of Atherosclerosis, Merck Research Laboratories, Rahway, NJ 07065;
2. Department of Biologics Research, Merck Research Laboratories, West Point, PA 19486;
3. Department of Preclinical DMPK, Merck Research Laboratories, West Point, PA 19486;
4. Department of In Vitro Sciences, Merck Research Laboratories, Rahway, NJ 07065;
5. Department of GEM Target Validation, Merck Research Laboratories, Rahway, NJ 07065;
6. Department of MBV and Early Biologics, Upper Gwynedd, PA 19454;
7. Department of Bioprocess and Bioanalytical, Merck Research Laboratories, West Point, PA 19486;
8. Present address: University of Texas Health Science Center, Houston, TX;
9. Present address: Centocor R&D, Inc., Radnor, PA 19087;
10. Departments of Internal Medicine and Pediatric, University of South Florida, Tampa, FL 33612.

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.

Keywords: PCSK9, low density lipoprotein cholesterol (LDL-C), hypercholesterolemia, LDL receptor, sterol regulatory element binding protein (SREBP), primary hepatocytes

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Zhang L, McCabe T, Condra JH, Ni YG, Peterson LB, Wang W, Strack AM, Wang F, Pandit S, Hammond H, Wood D, Lewis D, Rosa R, Mendoza V, Cumiskey AM, Johns DG, Hansen BC, Shen X, Geoghagen N, Jensen K, Zhu L, Wietecha K, Wisniewski D, Huang L, Zhao JZ, Ernst R, Hampton R, Haytko P, Ansbro F, Chilewski S, Chin J, Mitnaul LJ, Pellacani A, Sparrow CP, An Z, Strohl W, Hubbard B, Plump AS, Blom D, Sitlani A. An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes. Int J Biol Sci 2012; 8(3):310-327. doi:10.7150/ijbs.3524. Available from http://www.ijbs.com/v08p0310.htm