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Effect of anti-PCSK9 drugs on the association of PCSK9 to LDL

Anti-PCSK9 Drugs on PCSK9-LDL Association

Sara Matteucci
IRCCS MultiMedica, Milan, Italy
Valentina Pravatà
IRCCS MultiMedica, Milan, Italy
Francesco Maria Esposito
IRCCS MultiMedica, Milan, Italy
Angela Pirillo
Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy
Liliana Grigore
IRCCS MultiMedica, Milan, Italy
Alberico Luigi Catapano
IRCCS MultiMedica, Milan, Italy, and Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that is known to interact with the LDL receptor, thereby promoting its degradation and blunting the uptake of LDL from the circulation. In this context, anti-PCSK9 monoclonal antibodies (mAbs) and siRNAs have been approved for the treatment of hypercholesterolaemia. Previous studies have shown that a significant proportion of circulating PCSK9 is associated with LDL. The aim of our research is to investigate the effect of mAbs and siRNA on the association of PCSK9 protein with LDL. In this study, 10 statin-intolerant patients received treatment with anti-PCSK9 mAbs or siRNA, in addition to therapy with a low-dose statin and ezetimibe. Their plasma samples were analysed before and after 1, 3, and 6/9 months of treatment. The results showed that both the monoclonal antibodies and inclisiran reduced LDL-C levels by 50% to 60%. LDL-C levels decreased from 92±28 mg/dL to 44±26 mg/dL after siRNA treatment and reached 97±9, 27±10, 32±14, and 23±10 mg/dL after mAbs therapy. The circulating PCSK9 level decreased by 70% after the first siRNA injection, while it increased 10-fold after mAbs therapy. Regardless of treatment, the percentage of PCSK9 bound to LDL did not vary from baseline and remained constant during the treatment period. Whether this is of physiological relevance remains to be addressed.

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References

  1. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A 2003; 100:928-33. https://doi.org/10.1073/pnas.0335507100
  2. Norata GD, Tavori H, Pirillo A, et al. Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering. Cardiovasc Res 2016; 112:429-42. https://doi.org/10.1093/cvr/cvw194
  3. Gu HM, Adijiang A, Mah M, Zhang DW. Characterization of the role of EGF-A of low density lipoprotein receptor in PCSK9 binding. J Lipid Res 2013; 54:3345-57. https://doi.org/10.1194/jlr.M041129
  4. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017; 38:2459-72. https://doi.org/10.1093/eurheartj/ehx144
  5. Kosenko T, Golder M, Leblond G, et al. Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation. J Biol Chem 2013; 288:8279-88. https://doi.org/10.1074/jbc.M112.421370
  6. Packard CJ. Remnants, LDL, and the Quantification of Lipoprotein-Associated Risk in Atherosclerotic Cardiovascular Disease. Curr Atheroscler Rep 2022; 24:133-42. https://doi.org/10.1007/s11883-022-00994-z
  7. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013; 1:CD004816. https://doi.org/10.1002/14651858.CD004816.pub5
  8. Bao X, Liang Y, Chang H, et al. Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside. Signal Transduct Target Ther 2024; 9:13. https://doi.org/10.1038/s41392-023-01690-3
  9. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376:1713-22. https://doi.org/10.1056/NEJMoa1615664
  10. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379:2097-107. https://doi.org/10.1056/NEJMoa1801174
  11. Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020; 382:1507-19. https://doi.org/10.1056/NEJMoa1912387
  12. Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017; 376:41-51. https://doi.org/10.1056/NEJMoa1609243
  13. Seidah NG, Prat A, Pirillo A, et al. Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies. Cardiovasc Res 2019; 115:510-8. https://doi.org/10.1093/cvr/cvz003
  14. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41:111-88. https://doi.org/10.1093/eurheartj/ehz455
  15. Pirillo A, Tokgözoğlu L, Catapano AL. PCSK9 in extrahepatic tissues: What can we expect from its inhibition? European Atherosclerosis Journal 2023; 2:35-43. https://doi.org/10.56095/EAJ.V2I2.47
  16. Canclini L, Malvandi AM, Uboldi P, et al. The Association of Proprotein Convertase Subtilisin/Kexin Type 9 to Plasma Low-Density Lipoproteins: An Evaluation of Different Methods. Metabolites 2021; 11. https://doi.org/10.3390/metabo11120861
  17. Fan D, Yancey PG, Qiu S, et al. Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry 2008; 47:1631-9. https://doi.org/10.1021/bi7016359
  18. Tavori H, Fan D, Blakemore JL, et al. Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation. Circulation 2013; 127:2403-13. https://doi.org/10.1161/CIRCULATIONAHA.113.001592
  19. Fazio S, Minnier J, Shapiro MD, et al. Threshold Effects of Circulating Angiopoietin-Like 3 Levels on Plasma Lipoproteins. J Clin Endocrinol Metab 2017; 102:3340-8. https://doi.org/10.1210/jc.2016-4043
  20. Lagace TA. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr Opin Lipidol 2014; 25:387-93. https://doi.org/10.1097/MOL.0000000000000114
  21. Oleaga C, Hay J, Gurcan E, et al. Insights into the kinetics and dynamics of the furin-cleaved form of PCSK9. J Lipid Res 2021; 62:100003. https://doi.org/10.1194/jlr.RA120000964
  22. Tavori H, Giunzioni I, Linton MF, Fazio S. Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis. Circ Res 2013; 113:1290-5. https://doi.org/10.1161/CIRCRESAHA.113.302655
  23. Norata GD, Tibolla G, Catapano AL. Targeting PCSK9 for hypercholesterolemia. Annu Rev Pharmacol Toxicol 2014; 54:273-93. https://doi.org/10.1146/annurev-pharmtox-011613-140025

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