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

نویسندگان

  • 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
چکیده

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.

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عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2012