Vaccines Targeting PSCK9 for the Treatment of Hyperlipidemia

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.

Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5:230–42.

Catapano AL, Graham I, Backer De, Cooney G, et al. ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016;2016(253):281–344.

Mendis S, Chestnov O. The global burden of cardiovascular diseases: a challenge to improve. Curr Cardiol Rep. 2014;16:486.

Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R, Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81. https://doi.org/10.1016/s0140-6736(10)61350-5.

Pittman DG, Chen W, Bowlin SJ, Foody JM. Adherence to statins, subsequent healthcare costs, and cardiovascular hospitalisations. Am J Cardiol. 2011;107(11):1662–6.

Zhang L, Song K, Zhu M, Shi J, Zhang H, Xu L, Chen Y. Proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism, atherosclerosis and ischemic stroke. Int J Neurosci. 2016;126(6):675–80. https://doi.org/10.3109/00207454.2015.1057636.

Weinreich M, Frishman WH. Antihyperlipidemic therapies targeting PCSK9. Cardiol Rev. 2014;22(3):140–6.

Davis CG, Goldstein JL, Südhof TC, et al. Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region. Nature. 1986;326:760–5.

Rudenko G, Henry L, Henderson K, et al. Structure of the LDL receptor extracellular domain at endosomal pH. Science. 2002;298:2353–8.

Chernogubova E, Strawbridge R, Mahdessian H, Mälarstig A, Krapivner S, Gigante B, Hellénius ML, de Faire U, Franco-Cereceda A, Syvänen AC, Troutt JS. Common and low-frequency genetic variants in the PCSK9 locus influence circulating PCSK9 levels. Arterioscleros Thromb Vasc Biol. 2012;32(6):1526–34.

Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, Kim JB, Scott R, Wasserman SM, Bays H, MENDEL-2 Investigators. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomised, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2531–40.

Lyall D, Ward J, Banach M, Smith GD, Gill J, Pell J, Holmes M, Sattar N (2018) PCSK9 genetic variants, life-long lowering of LDL-cholesterol and cognition: a large-scale Mendelian randomisation study. bioRxiv. 2018;335877. https://www.biorxiv.org/content/10.1101/335877v1. Accessed 12 Mar 2020.

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. 2006;354:1264–72.

Rosenson RS, Hegele RA, Koenig W. Cholesterol-lowering agents: PCSK9 inhibitors today and tomorrow. Circ Res. 2019;124(3):364–85.

Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–22. https://doi.org/10.1056/nejmoa1615664.

Schwartz GG, Bessac L, Berdan LG, et al. effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular out- comes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J. 2014;168:682–9. https://doi.org/10.1016/j.ahj.2014.07.028.

Schwartz GG, Steg PG, Szarek M, ODYSSEY OUTCOMES Committees and Investigators, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–107. https://doi.org/10.1056/nejmoa1801174.

García RC, Cid CM, Ruiz AS, López AM, Cano EP, López YJ, Rojas JJ. 4CPS-020 use, efficacy and adherence to treatment with PCKS9 inhibitors in real clinical practice. Eur J Hosp Pharm. 2020;27:A56.

Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PL, Kastelein JJ. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382:1507–19.

Lambracht-Washington D, Rosenberg RN. Advances in the development of vaccines for Alzheimer’s disease. Discov Med. 2013;15:319–26.

Melero I, Gaudernack G, Gerritsen W, Huber C, Parmiani G, Scholl S, Thatcher N, et al. Therapeutic vaccines for cancer: and overview of clinical trials. Nat Rev Clin Oncol. 2014;11:509–24.

Ambuhl PM, Tissot AC, Fulurja A, Maurer P, Nussberger J, Sabat R, Nief V, et al. A vaccine for hypertension based on virus like particles: preclinical efficacy and phase I safety and immunogenicity. J Hypertens. 2007;25:63–72.

Wherrett DK, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, et al. Antigen-based therapy with glutaminic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet. 2011;378:319–27.

Kao DJ, Hodges RS. Advantages of a synthetic peptide immunogen over a protein immunogen in the development of an anti-pilus vaccine for Pseudomonas aeruginosa. Chem Biol Drug Des. 2009;74:33–42. https://doi.org/10.1111/j.1747-0285.2009.00825.x.

Goldsby R, Kindt TJ, Osborne BA, Kuby J. Chapter 2: Cells and Organs of the Immune System. In: Immunology, 5th ed. New York: W.H. Freeman and Company; 2003. pp 24–56.

Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373–84.

Margolick JB, Markham RB, Scott AL. Infectious disease epidemiology: theory and practice. Chapter 10. In: Nelson KE, Masters CF, editors. The immune system and host defense against infections. Boston: Jones and Bartlett; 2006. p. 317–43.

Schijns VE (2001) Activation and programming of adaptive immune responses by vaccine adjuvants. [Last cited on 2010 Jan 7]. http://www.vetscite.org/publish/articles/000027/index.html. Accessed 12 Mar 2020.

McKee AS, Marrack P. Old and new adjuvants. Curr Opin Immunol. 2017;47:44–51.

Kobiyama K, Saigusa R, Ley K. Vaccination against atherosclerosis. Curr Opin Immunol. 2019;59:15–24.

Chackerian B, Durfee MR, Schiller JT. Virus-like display of a neo-self-antigen reverses B cell anergy in a B cell receptor transgenic mouse model. J Immunol. 2008;180:5816–25.

Chackerian B, Durfee MR, Schiller JT. Virus-like display of a neo-self-antigen reverses B cell anergy in a B cell receptor transgenic mouse model. J Immunol. 2008;180:5816–25.

Fattori E, Cappelletti M, Lo Surdo P, Calzetta A, Bendtsen C, Ni YG, Pandit S, Sitlani A, Mesiti G, Carfi A, Monaci P. Immunization against proprotein convertase subtilisin-like/kexin type 9 lowers plasma LDL-cholesterol levels in mice. J Lipid Res. 2012;53:1654–61.

Jurtz V, Paul S, Andreatta M, Marcatili P, Peters B, Nielsen M. NetMHCpan-4.0: improved peptide-MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data. J Immunol. 2017;199:3360–8. https://doi.org/10.4049/jimmunol.1700893.

Schneeberger A, Mandler M, Otava O, Zauner W, Mattner F, Schmidt W. Development of AFFITOPE vaccines for Alzheimer’s disease (AD)—from concept to clinical testing. JNHA. 2009;13(3):264–7.

Galabova G, Brunner S, Winsauer G, et al. Peptide-based anti-PCSK9 vaccines—an approach for long-term LDLc management. PLoS ONE. 2014;9:e114469.

Harris JR, Markl J. Keyhole limpet hemocyanin (KLH): a biomedical review. Micron. 1999;30(6):597–623.

Landlinger C, Pouwer MG, Juno C, van der Hoorn JW, Pieterman EJ, Jukema JW, Staffler G, Princen HM, Galabova G. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE* 3Leiden, CETP mice. Eur Heart J. 2017;38(32):2499–507.

Westerterp M, van der Hoogt CC, de Haan W, Offerman EH, Dallinga-Thie GM, Jukema JW, Havekes LM, Rensen PC. Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE* 3-Leiden mice. Arterioscler Thromb Vasc Biol. 2006;26(11):2552–9.

Kuhnast S, van der Hoorn JW, Pieterman EJ, van den Hoek AM, Sasiela WJ, Gusarova V, Peyman A, Schafer HL, Schwahn U, Jukema JW, Princen HM. Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J Lipid Res. 2014;55:2103–12.

Chackerian B, Remaley A. Vaccine strategies for lowering LDL by immunisation against proprotein convertase subtilisin/kexin type 9. Curr Opin Lipidol. 2016;27:345–50.

Crossey E, Amar MJ, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT. A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine. 2015;33:5747–55.

Bachmann MF, Whitehead P. Active immuno therapy for chronic diseases. Vaccine. 2013;31:1777–84.

Tissot AC, Maurer P, Nussberger J, Sabat R, Pfister T, Ignatenko S, et al. Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study. Lancet. 2008;371:821–7.

Chackerian B, Rangel M, Hunter Z, Peabody DS. Virus and virus-like particle-based immunogens for Alzheimer’s disease induce antibody responses against amyloid-β without concomitant T cell responses. Vaccine. 2006;24(37–39):6321–31.

Kawakami R, Nozato Y, Nakagami H, Ikeda Y, Shimamura M, Yoshida S, Sun J, Kawano T, Takami Y, Noma T, Rakugi H. Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice. PLoS ONE. 2018;13(2):e0191895.

Momtazi-Borojeni AA, Jaafari MR, Badiee A, Sahebkar A. Long-term generation of antiPCSK9 antibody using a nanoliposome-based vaccine delivery system. Atherosclerosis. 2019;1(283):69–78.

https://clinicaltrials.gov/ct2/show/NCT02508896. Accessed 12 Mar 2020.