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

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. Han

International journal of biological sciences, 01 January 2012, Vol.8(3), pp.310-327 [Peer Reviewed Journal]

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  • Title:
    An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes
  • Author: 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. Han
  • Description: 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...
  • Is Part Of: International journal of biological sciences, 01 January 2012, Vol.8(3), pp.310-327
  • Identifier: ISSN: 1449-2288 ; E-ISSN: 1449-2288
  • Subjects: Biology
  • Language: English
  • Source: Directory of Open Access Journals (DOAJ)

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