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preliminary communication

Reduction of LDL cholesterol by a monoclonal antibody to PCSK9 in rodents and nonhuman primates

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Pages 737-743 | Published online: 18 Jan 2017

  • Zhang DW, Lagace TA, Garuti R et al. Binding of proprotein convertase subtilisin/ kexin type 9 to epidermal growth factor‑like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol Chem. 282(25), 18602–18612 (2007).
  • Abifadel M, Varret M, Rabes JP et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34(2), 154–156 (2003). ▪▪ PCSK9 was identified as the third locus associated with autosomal dominant hypercholesterolemia, a risk factor for coronary heart disease.
  • Timms KM, Wagner S, Samuels ME et al. A mutation in PCSK9 causing autosomaldominant hypercholesterolemia in a Utah pedigree. Hum. Genet. 114(4), 349–353 (2004).
  • Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37(2), 161–165 (2005). ▪▪ Authors identified loss-of-function PCSK9 mutations in subjects with low plasma cholesterol levels. The reported mutations were common in African–Americans (combined frequency 2%) and were associated with a 40% reduction in plasma levels of LDL cholesterol.
  • Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354(12), 1264–1272 (2006). ▪▪ Demonstrates that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of nonlipid-related cardiovascular risk factors.
  • Zhao Z, Tuakli‑Wosornu Y, Lagace TA et al. Molecular characterization of loss‑of‑function mutations in PCSK9 and identification of a compound heterozygote. Am. J. Hum. Genet. 79(3), 514–523 (2006).
  • Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a southern African population. Atherosclerosis 193(2), 445–448 (2007).
  • Valenzuela DM, Murphy AJ, Frendewey D et al. High‑throughput engineering of the mouse genome coupled with high‑resolution expression analysis. Nat. Biotechnol. 21(6), 652–659 (2003).
  • Poueymirou WT, Auerbach W, Frendewey D et al. F0 generation mice fully derived from gene‑targeted embryonic stem cells allowing immediate phenotypic analyses. Nat. Biotechnol. 25(1), 91–99 (2007).
  • Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol‑fed mice. J. Lipid Res. 44(11), 2109–2119 (2003).
  • Rashid S, Curtis DE, Garuti R et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Natl Acad. Sci. USA 102(15), 5374–5379 (2005).
  • Chan JC, Piper DE, Cao Q et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc. Natl Acad. Sci. USA 106(24), 9820–9825 (2009).
  • Ni YG, Di Marco S, Condra JH et al. A PCSK9‑binding antibody that structurally mimics the EGF(A) domain of LDL‑receptor reduces LDL cholesterol in vivo. J. Lipid Res. 52(1), 78–86 (2011).
  • Liang H, Chaparro‑Riggers J, Strop P et al. Proprotein convertase substilisin/kexin type 9 antagonism reduces low‑density lipoprotein cholesterol in statin‑treated hypercholesterolemic nonhuman primates. J. Pharmacol. Exp. Ther. 340(2), 228–236 (2012).
  • Stein EA, Mellis S, Yancopoulos GD et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366(12), 1108–1118 (2012).
  • McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J. Am. Coll. Cardiol. 59(25), 2344–2353 (2012).
  • Stein EA, Gipe D, Bergeron J et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce lowdensity lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a Phase 2 randomised controlled trial. Lancet 380(9836), 29–36 (2012).
  • Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta‑analysis of data from 170,000 participants in 26 randomised trials. Lancet 376(9753), 1670–1681 (2010).
  • Emberson JR, Kearney PM, Blackwell L et al. Lack of effect of lowering LDL cholesterol on cancer: meta‑analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS ONE 7(1), e29849 (2012).
  • Kitkungvan D, Lynn Fillipon NM, Dani SS, Downey BC. Low‑density lipoprotein cholesterol target achievement in patients at high risk for coronary heart disease. J. Clin. Lipidol. 4(4), 293–297 (2010).
  • Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low‑density lipoprotein cholesterol <50 mg/ dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J. Am. Coll. Cardiol. 57(16), 1666–1675 (2011).
  • Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E. Can low‑density lipoprotein be too low? The safety and efficacy of achieving very low low‑density lipoprotein with intensive statin therapy: a PROVE IT‑TIMI 22 substudy. J. Am. Coll. Cardiol. 46(8), 1411–1416 (2005).
  • LaRosa JC, Grundy SM, Kastelein JJ, Kostis JB, Greten H. Safety and efficacy of atorvastatin‑induced very low‑density lipoprotein cholesterol levels in patients with coronary heart disease (a post-hoc analysis of the treating to new targets [TNT] study). Am. J. Cardiol. 100(5), 747–752 (2007).
  • Tremblay AJ, Lamarche B, Lemelin V et al. Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men. J. Lipid Res. 52(3), 558–565 (2011).
  • Costet P, Hoffmann MM, Cariou B, Guyomarc’h Delasalle B, Konrad T, Winkler K. Plasma PCSK9 is increased by fenofibrate and atorvastatin in a nonadditive fashion in diabetic patients. Atherosclerosis 212(1), 246–251 (2010).
  • Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N. Engl. J. Med. 367(20), 1891–1900 (2012).

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