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Proprotein convertase substilisin/kexin type 9 antagonism reduces low-density lipoprotein cholesterol in statin-treated hypercholesterolemic nonhuman primates.

Liang H, Chaparro-Riggers J, Strop P, Geng T, Sutton JE, Tsai D, Bai L, Abdiche Y, Dilley J, Yu J, Wu S, Chin SM, Lee NA, Rossi A, Lin JC, Rajpal A, Pons J, Shelton DL
J Pharmacol Exp Ther 340 228-36 (2012)
Cited: 68 times
EuropePMC logo PMID: 22019884

Abstract

Proprotein convertase substilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein (LDL) receptor (LDLR) and thereby increases serum LDL-cholesterol (LDL-C). We have developed a humanized monoclonal antibody that recognizes the LDLR binding domain of PCSK9. This antibody, J16, and its precursor mouse antibody, J10, potently inhibit PCSK9 binding to the LDLR extracellular domain and PCSK9-mediated down-regulation of LDLR in vitro. In vivo, J10 effectively reduces serum cholesterol in C57BL/6 mice fed normal chow. J16 reduces LDL-C in healthy and diet-induced hypercholesterolemic cynomologous monkeys, but does not significantly affect high-density lipoprotein-cholesterol. Furthermore, J16 greatly lowered LDL-C in hypercholesterolemic monkeys treated with the HMG-CoA reductase inhibitor simvastatin. Our data demonstrate that anti-PCSK9 antibody is a promising LDL-C-lowering agent that is both efficacious and potentially additive to current therapies.

Articles - 3sqo mentioned but not cited (7)

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Reviews citing this publication (23)

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Articles citing this publication (38)

  1. Increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCSK9. Chaparro-Riggers J, Liang H, DeVay RM, Bai L, Sutton JE, Chen W, Geng T, Lindquist K, Casas MG, Boustany LM, Brown CL, Chabot J, Gomes B, Garzone P, Rossi A, Strop P, Shelton D, Pons J, Rajpal A. J. Biol. Chem. 287 11090-11097 (2012)
  2. Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. Mitchell T, Chao G, Sitkoff D, Lo F, Monshizadegan H, Meyers D, Low S, Russo K, DiBella R, Denhez F, Gao M, Myers J, Duke G, Witmer M, Miao B, Ho SP, Khan J, Parker RA. J Pharmacol Exp Ther 350 412-424 (2014)
  3. PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Kysenius K, Muggalla P, Mätlik K, Arumäe U, Huttunen HJ. Cell. Mol. Life Sci. 69 1903-1916 (2012)
  4. Synthetic farnesoid X receptor agonists induce high-density lipoprotein-mediated transhepatic cholesterol efflux in mice and monkeys and prevent atherosclerosis in cholesteryl ester transfer protein transgenic low-density lipoprotein receptor (-/-) mice. Hambruch E, Miyazaki-Anzai S, Hahn U, Matysik S, Boettcher A, Perović-Ottstadt S, Schlüter T, Kinzel O, Krol HD, Deuschle U, Burnet M, Levi M, Schmitz G, Miyazaki M, Kremoser C. J Pharmacol Exp Ther 343 556-567 (2012)
  5. A method for integrative structure determination of protein-protein complexes. Schneidman-Duhovny D, Rossi A, Avila-Sakar A, Kim SJ, Velázquez-Muriel J, Strop P, Liang H, Krukenberg KA, Liao M, Kim HM, Sobhanifar S, Dötsch V, Rajpal A, Pons J, Agard DA, Cheng Y, Sali A. Bioinformatics 28 3282-3289 (2012)
  6. Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. Zhang Y, Eigenbrot C, Zhou L, Shia S, Li W, Quan C, Tom J, Moran P, Di Lello P, Skelton NJ, Kong-Beltran M, Peterson A, Kirchhofer D. J. Biol. Chem. 289 942-955 (2014)
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  9. Characterization of proprotein convertase subtilisin/kexin type 9 (PCSK9) trafficking reveals a novel lysosomal targeting mechanism via amyloid precursor-like protein 2 (APLP2). DeVay RM, Shelton DL, Liang H. J. Biol. Chem. 288 10805-10818 (2013)
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  19. Determining the binding affinity of therapeutic monoclonal antibodies towards their native unpurified antigens in human serum. Bee C, Abdiche YN, Pons J, Rajpal A. PLoS ONE 8 e80501 (2013)
  20. Generation and Characterization of a Novel Small Biologic Alternative to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Antibodies, DS-9001a, Albumin Binding Domain-Fused Anticalin Protein. Masuda Y, Yamaguchi S, Suzuki C, Aburatani T, Nagano Y, Miyauchi R, Suzuki E, Yamamura N, Nagatomo K, Ishihara H, Okuno K, Nara F, Matschiner G, Hashimoto R, Takahashi T, Nishizawa T. J Pharmacol Exp Ther 365 368-378 (2018)
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  22. An In Vitro Cynomolgus Vascular Surrogate System for Preclinical Drug Assessment and Human Translation. Cole BK, Simmers MB, Feaver R, Qualls CW, Collado MS, Berzin E, Figler RA, Pryor AW, Lawson M, Mackey A, Manka D, Wamhoff BR, Turk JR, Blackman BR. Arterioscler. Thromb. Vasc. Biol. 35 2185-2195 (2015)
  23. Application of a catenary PBPK model to predict the disposition of "catch and release" anti-PCSK9 antibodies. Glassman PM, Balthasar JP. Int J Pharm 505 69-78 (2016)
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  25. Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics. Khoshnejad M, Patel A, Wojtak K, Kudchodkar SB, Humeau L, Lyssenko NN, Rader DJ, Muthumani K, Weiner DB. Mol. Ther. 27 188-199 (2019)
  26. Pharmacokinetics and pharmacodynamics of bococizumab, a monoclonal antibody to PCSK9, after single subcutaneous injection at three sites [NCT 02043301]. Wang EQ, Plotka A, Salageanu J, Sattler C, Yunis C. Cardiovasc Ther 35 (2017)
  27. The discovery of PCSK9 inhibitors: A tale of creativity and multifaceted translational research. Elguindy A, Yacoub MH. Glob Cardiol Sci Pract 2013 343-347 (2013)
  28. A Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for Bococizumab, a Humanized Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, and Its Application in Early Clinical Development. Udata C, Garzone PD, Gumbiner B, Joh T, Liang H, Liao KH, Williams JH, Meng X. J Clin Pharmacol 57 855-864 (2017)
  29. Letter Antihyperlipidemic therapies targeting PCSK9: Novel therapeutic agents for lowering low-density lipoprotein cholesterol. Liu MH. Int. J. Cardiol. 195 212-214 (2015)
  30. Comparative Pharmacokinetics and Pharmacodynamics of Bococizumab Following a Single Subcutaneous Injection Using Drug Substance Manufactured at Two Sites or Administration via Two Different Devices. Wang EQ, Plotka A, Salageanu J, Baltrukonis D, Mridha K, Frederich R, Sullivan BE. Clin Pharmacol Drug Dev 8 40-48 (2019)
  31. Population PK/PD modeling of low-density lipoprotein cholesterol response in hypercholesterolemic participants following administration of bococizumab, a potent anti-PCSK9 monoclonal antibody. Wang EQ, Kaila N, Plowchalk D, Gibiansky L, Yunis C, Sweeney K. CPT Pharmacometrics Syst Pharmacol 12 2013-2026 (2023)
  32. Reduction of therapeutic antibody self-association using yeast-display selections and machine learning. Makowski EK, Chen H, Lambert M, Bennett EM, Eschmann NS, Zhang Y, Zupancic JM, Desai AA, Smith MD, Lou W, Fernando A, Tully T, Gallo CJ, Lin L, Tessier PM. MAbs 14 2146629 (2022)
  33. Assessing the Potential Risk of Cross-Reactivity Between Anti-Bococizumab Antibodies and Other Anti-PCSK9 Monoclonal Antibodies. Wang EQ, Bukowski JF, Yunis C, Shear CL, Ridker PM, Schwartz PF, Baltrukonis D. BioDrugs 33 571-579 (2019)
  34. Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment. Chodorge M, Celeste AJ, Grimsby J, Konkar A, Davidsson P, Fairman D, Jenkinson L, Naylor J, White N, Seaman JC, Dickson K, Kemp B, Spooner J, Rossy E, Hornigold DC, Trevaskis JL, Bond NJ, London TB, Buchanan A, Vaughan T, Rondinone CM, Osbourn JK. Sci Rep 8 17545 (2018)
  35. Pharmacokinetics and exploratory efficacy biomarkers of bococizumab, an anti-PCSK9 monoclonal antibody, in hypercholesterolemic Japanese subjects
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  36. Pharmacokinetics, pharmacodynamics, and safety of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, in healthy subjects when administered in co-mixture with recombinant human hyaluronidase: A phase 1 randomized trial. Bass A, Plotka A, Mridha K, Sattler C, Kim AM, Plowchalk DR. Health Sci Rep 1 e61 (2018)
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