Int J Biol Sci 2012; 8(3):310-327. doi:10.7150/ijbs.3524
An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes
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.
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
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