title: 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.affiliation: Department of Atherosclerosis, Merck Research Laboratories, Rahway, NJ 07065, USA. liwen@optonline.net
authors.forename: Liwen
authors.initials: L
authors.lastname: Zhang
authors.forename: Timothy
authors.initials: T
authors.lastname: McCabe
authors.forename: Jon H
authors.initials: JH
authors.lastname: Condra
authors.forename: Yan G
authors.initials: YG
authors.lastname: Ni
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Peterson
authors.forename: Weirong
authors.initials: W
authors.lastname: Wang
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
authors.forename: Fubao
authors.initials: F
authors.lastname: Wang
authors.forename: Shilpa
authors.initials: S
authors.lastname: Pandit
authors.forename: Holly
authors.initials: H
authors.lastname: Hammond
authors.forename: Dana
authors.initials: D
authors.lastname: Wood
authors.forename: Dale
authors.initials: D
authors.lastname: Lewis
authors.forename: Ray
authors.initials: R
authors.lastname: Rosa
authors.forename: Vivienne
authors.initials: V
authors.lastname: Mendoza
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Cumiskey
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Johns
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Hansen
authors.forename: Xun
authors.initials: X
authors.lastname: Shen
authors.forename: Neil
authors.initials: N
authors.lastname: Geoghagen
authors.forename: Kristian
authors.initials: K
authors.lastname: Jensen
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Karol
authors.initials: K
authors.lastname: Wietecha
authors.forename: Douglas
authors.initials: D
authors.lastname: Wisniewski
authors.forename: Lingyi
authors.initials: L
authors.lastname: Huang
authors.forename: Jing Zhang
authors.initials: JZ
authors.lastname: Zhao
authors.forename: Robin
authors.initials: R
authors.lastname: Ernst
authors.forename: Richard
authors.initials: R
authors.lastname: Hampton
authors.forename: Peter
authors.initials: P
authors.lastname: Haytko
authors.forename: Frances
authors.initials: F
authors.lastname: Ansbro
authors.forename: Shannon
authors.initials: S
authors.lastname: Chilewski
authors.forename: Jayne
authors.initials: J
authors.lastname: Chin
authors.forename: Lyndon J
authors.initials: LJ
authors.lastname: Mitnaul
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellacani
authors.forename: Carl P
authors.initials: CP
authors.lastname: Sparrow
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
authors.forename: William
authors.initials: W
authors.lastname: Strohl
authors.forename: Brian
authors.initials: B
authors.lastname: Hubbard
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Plump
authors.forename: Daniel
authors.initials: D
authors.lastname: Blom
authors.forename: Ayesha
authors.initials: A
authors.lastname: Sitlani
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000915:Antibody Affinity; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007116:Immunization, Passive; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008253:Macaca mulatta; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D051779:Sterol Regulatory Element Binding Proteins / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D000924:Anticholesteremic Agents; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D011994:Recombinant Proteins; D051779:Sterol Regulatory Element Binding Proteins; D019821:Simvastatin; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases