Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Research Article

The Immunogenic Potential of PCSK9 Peptide Vaccine in Mice

Author(s): Sarina Ataei, Amir Abbas Momtazi-Borojeni, Shiva Ganjali, Maciej Banach and Amirhossein Sahebkar*

Volume 30, Issue 26, 2023

Published on: 08 December, 2022

Page: [3024 - 3031] Pages: 8

DOI: 10.2174/0929867329666220930114429

Price: $65

Abstract

Aim: To evaluate the immunogenic potential of the carrier-free peptide-based anti-PCSK9 (proprotein convertase subtilisin/kexin 9) vaccine in albino mice.

Methods: The immunogenic pcsk9 peptide and 0.4% alum adjuvant were mixed thoroughly at a 1:1 ratio and used as a vaccine formulation. To assess the humoral immune response, animals' blood was sampled two weeks after the last immunization. The ELISA method was employed to measure serum anti-PCSK9 antibody titers, PCSK9 concentrations, and PCSK9/LDLR interaction.

Results: ELISA analysis showed significant induction of IgG antibody titers by PCSK9 peptide vaccine in vaccinated mice sera compared to the control mice (in male and female mice were 12000±586 and 11566±642, respectively, p<0.001). Mechanistic analyses showed a significant reduction in serum PCSK9 concentrations by vaccine-induced antibodies in vaccine groups compared to the control groups (in male mice by 29±5 ng/mL (22.4%), p<0.001 and female mice by 26±5 ng / mL (21.0%), p<0.001). Serum concentrations of PCSK9 in control and vaccine groups were 131±8.6 ng / mL and 102±8.1 ng/ml in male mice and 124±6 ng/ml and 98±10 ng/ml in female mice, respectively. Moreover, vaccine-induced antibodies inhibited the PCSK9-LDLR interaction in male and female groups by 34% and 26%, respectively. No significant difference was detected between the male and female groups in all tests (p>0.05).

Conclusion: According to our results, the PCSK9 peptide vaccine provoked the humoral immune system in albino mice to produce functional antibodies that inhibit plasma PCSK9. These effects were seen in both genders without any significant difference.

Keywords: PCSK9, LDL-cholesterol, peptide vaccine

[1]
Mozaffarian, D.; Benjamin, E.J.; Go, A.S.; Arnett, D.K.; Blaha, M.J.; Cushman, M. Heart disease and stroke statistics-2015 update: A report from the American Heart Association. Circulation, 2015, 131(4), e29-e322.
[2]
Yusuf, S.; Hawken, S.; Ôunpuu, S.; Dans, T.; Avezum, A.; Lanas, F.; McQueen, M.; Budaj, A.; Pais, P.; Varigos, J.; Lisheng, L. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet, 2004, 364(9438), 937-952.
[http://dx.doi.org/10.1016/S0140-6736(04)17018-9] [PMID: 15364185]
[3]
Vallejo-Vaz, A.J.; De Marco, M.; Stevens, C.A.T.; Akram, A.; Freiberger, T.; Hovingh, G.K.; Kastelein, J.J.P.; Mata, P.; Raal, F.J.; Santos, R.D.; Soran, H.; Watts, G.F.; Abifadel, M.; Aguilar-Salinas, C.A.; Al-Khnifsawi, M.; AlKindi, F.A.; Alnouri, F.; Alonso, R.; Al-Rasadi, K.; Al-Sarraf, A.; Ashavaid, T.F.; Binder, C.J.; Bogsrud, M.P.; Bourbon, M.; Bruckert, E.; Chlebus, K.; Corral, P.; Descamps, O.; Durst, R.; Ezhov, M.; Fras, Z.; Genest, J.; Groselj, U.; Harada-Shiba, M.; Kayikcioglu, M.; Lalic, K.; Lam, C.S.P.; Latkovskis, G; Laufs, U.; Liberopoulos, E.; Lin, J.; Maher, V.; Majano, N.; Marais, A.D.; März, W.; Mirrakhimov, E.; Miserez, A.R.; Mitchenko, O.; Nawawi, H.M.; Nordestgaard, B.G.; Paragh, G.; Petrulioniene, Z.; Pojskic, B.; Postadzhiyan, A.; Reda, A.; Reiner, Ž.; Sadoh, W.E.; Sahebkar, A.; Shehab, A.; Shek, A.B.; Stoll, M.; Su, T.C.; Subramaniam, T.; Susekov, A.V.; Symeonides, P.; Tilney, M.; Tomlinson, B.; Truong, T.H.; Tselepis, A.D.; Tybjærg-Hansen, A.; Vázquez-Cárdenas, A.; Viigimaa, M.; Vohnout, B.; Widén, E.; Yamashita, S.; Banach, M.; Gaita, D.; Jiang, L.; Nilsson, L.; Santos, L.E.; Schunkert, H.; Tokgözoğlu, L.; Car, J.; Catapano, A.L; Ray, K.K EAS Familial Hypercholesterolaemia Studies Collaboration. EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC) Investigators. Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Atherosclerosis, 2018, 277, 234-255.
[http://dx.doi.org/10.1016/j.atherosclerosis.2018.08.051] [PMID: 30270054]
[4]
Brown, M.S.; Goldstein, J.L. A receptor-mediated pathway for cholesterol homeostasis. Science, 1986, 232(4746), 34-47.
[http://dx.doi.org/10.1126/science.3513311] [PMID: 3513311]
[5]
Malo, J.; Parajuli, A.; Walker, S.W. PCSK9: From molecular biology to clinical applications. Ann. Clin. Biochem., 2020, 57(1), 7-25.
[http://dx.doi.org/10.1177/0004563219864379] [PMID: 31257903]
[6]
Glerup, S.; Schulz, R.; Laufs, U.; Schlüter, K.D. Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease. Basic Res. Cardiol., 2017, 112(3), 32.
[http://dx.doi.org/10.1007/s00395-017-0619-0] [PMID: 28439730]
[7]
Seidah, N.G. The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer. J. Lipid Res., 2021, 62, 100130.
[http://dx.doi.org/10.1016/j.jlr.2021.100130] [PMID: 34606887]
[8]
Catapano, A.L.; Papadopoulos, N. The safety of therapeutic monoclonal antibodies: Implications for cardiovascular disease and targeting the PCSK9 pathway. Atherosclerosis, 2013, 228(1), 18-28.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.01.044] [PMID: 23466067]
[9]
Sahebkar, A.; Momtazi-Borojeni, A.A.; Banach, M. PCSK9 vaccine: So near, yet so far! Eur. Heart J., 2021, 42(39), 4007-4010.
[http://dx.doi.org/10.1093/eurheartj/ehab299] [PMID: 34151957]
[10]
Momtazi-Borojeni, A.A.; Pirro, M.; Xu, S.; Sahebkar, A. PCSK9 inhibition-based therapeutic approaches: An immunotherapy perspective. Curr. Med. Chem., 2022, 29(6), 980-999.
[http://dx.doi.org/10.2174/0929867328666211027125245] [PMID: 34711156]
[11]
Sahebkar, A.; Watts, G.F. New LDL-cholesterol lowering therapies: Pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin. Ther., 2013, 35(8), 1082-1098.
[http://dx.doi.org/10.1016/j.clinthera.2013.06.019] [PMID: 23932550]
[12]
Zambon, A.; Averna, M.; D’Erasmo, L.; Arca, M.; Catapano, A. New and emerging therapies for dyslipidemia. Endocrinol. Metab. Clin. North Am., 2022, 51(3), 635-653.
[http://dx.doi.org/10.1016/j.ecl.2022.02.004] [PMID: 35963633]
[13]
Do, R.Q.; Vogel, R.A.; Schwartz, G.G. PCSK9 inhibitors: Potential in cardiovascular therapeutics. Curr. Cardiol. Rep., 2013, 15(3), 345.
[http://dx.doi.org/10.1007/s11886-012-0345-z] [PMID: 23338726]
[14]
Sahebkar, A.; Watts, G.F. New therapies targeting apoB metabolism for high-risk patients with inherited dyslipidaemias: What can the clinician expect? Cardiovasc. Drugs Ther., 2013, 27(6), 559-567.
[http://dx.doi.org/10.1007/s10557-013-6479-4] [PMID: 23913122]
[15]
Galabova, G.; Brunner, S.; Winsauer, G.; Juno, C.; Wanko, B.; Mairhofer, A.; Lührs, P.; Schneeberger, A.; von Bonin, A.; Mattner, F.; Schmidt, W.; Staffler, G. Peptide-based anti-PCSK9 vaccines - an approach for long-term LDLc management. PLoS One, 2014, 9(12), e114469.
[http://dx.doi.org/10.1371/journal.pone.0114469] [PMID: 25474576]
[16]
Fattori, E.; Cappelletti, M.; Lo Surdo, P.; Calzetta, A.; Bendtsen, C.; Ni, Y.G.; Pandit, S.; Sitlani, A.; Mesiti, G.; Carfí, A.; Monaci, P. Immunization against proprotein convertase subtilisin-like/kexin type 9 lowers plasma LDL-cholesterol levels in mice. J. Lipid Res., 2012, 53(8), 1654-1661.
[http://dx.doi.org/10.1194/jlr.M028340] [PMID: 22611251]
[17]
Crossey, E.; Amar, M.J.A.; Sampson, M.; Peabody, J.; Schiller, J.T.; Chackerian, B.; Remaley, A.T. A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine, 2015, 33(43), 5747-5755.
[http://dx.doi.org/10.1016/j.vaccine.2015.09.044] [PMID: 26413878]
[18]
Chyu, K.Y.; Shah, P.K. In pursuit of an atherosclerosis vaccine: Chasing the Holy Grail. Circ. Res., 2018, 123(10), 1121-1123.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.313842] [PMID: 30359192]
[19]
Pulendran, B.; S Arunachalam, P.; O’Hagan, D.T. Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov., 2021, 20(6), 454-475.
[http://dx.doi.org/10.1038/s41573-021-00163-y] [PMID: 33824489]
[20]
Bachmann, M.F.; Dyer, M.R. Therapeutic vaccination for chronic diseases: A new class of drugs in sight. Nat. Rev. Drug Discov., 2004, 3(1), 81-88.
[http://dx.doi.org/10.1038/nrd1284] [PMID: 14666113]
[21]
Momtazi-Borojeni, A.A.; Jaafari, M.R.; Badiee, A.; Sahebkar, A. Long-term generation of antiPCSK9 antibody using a nanoliposome-based vaccine delivery system. Atherosclerosis, 2019, 283, 69-78.
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.02.001] [PMID: 30797988]
[22]
Momtazi-Borojeni, A.A.; Jaafari, M.R.; Badiee, A.; Banach, M.; Sahebkar, A. Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis. BMC Med., 2019, 17(1), 223.
[http://dx.doi.org/10.1186/s12916-019-1457-8] [PMID: 31818299]
[23]
Momtazi-Borojeni, A.A.; Jaafari, M.R.; Afshar, M.; Banach, M.; Sahebkar, A. PCSK9 immunization using nanoliposomes: Preventive efficacy against hypercholesterolemia and atherosclerosis. Arch. Med. Sci., 2021, 17(5), 1365-1377.
[http://dx.doi.org/10.5114/aoms/133885] [PMID: 34522266]
[24]
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. J. Nutr. Health Aging, 2009, 13(3), 264-267.
[http://dx.doi.org/10.1007/s12603-009-0070-5] [PMID: 19262965]
[25]
Landlinger, C.; Pouwer, M.G.; Juno, C.; van der Hoorn, J.W.A.; Pieterman, E.J.; Jukema, J.W.; Staffler, G.; Princen, H.M.G.; 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), 2499-2507.
[http://dx.doi.org/10.1093/eurheartj/ehx260] [PMID: 28637178]
[26]
Kawakami, R.; Nozato, Y.; Nakagami, H.; Ikeda, Y.; Shimamura, M.; Yoshida, S.; Sun, J.; Kawano, T.; Takami, Y.; Noma, T.; Rakugi, H.; Minamino, T.; Morishita, R. Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice. PLoS One, 2018, 13(2), e0191895.
[http://dx.doi.org/10.1371/journal.pone.0191895] [PMID: 29438441]
[27]
Momtazi-Borojeni, A.A.; Ebrahimi Nik, M.; Reza Jaafari, M.; Banach, M.; Sahebkar, A. Effects of immunisation against PCSK9 in mice bearing melanoma. Arch. Med. Sci., 2020, 16(1), 189-199.
[http://dx.doi.org/10.5114/aoms.2020.91291] [PMID: 32051723]
[28]
Momtazi-Borojeni, A.A.; Jaafari, M.R.; Abdollahi, E.; Banach, M.; Sahebkar, A. Impact of PCSK9 immunization on glycemic indices in diabetic rats. J. Diabetes Res., 2021, 2021
[http://dx.doi.org/10.1155/2021/4757170]
[29]
Pan, Y.; Zhou, Y.; Wu, H.; Chen, X.; Hu, X.; Zhang, H.; Zhou, Z.; Qiu, Z.; Liao, Y. A therapeutic peptide vaccine against PCSK9. Sci. Rep., 2017, 7(1), 12534.
[http://dx.doi.org/10.1038/s41598-017-13069-w] [PMID: 28970592]
[30]
Wu, D.; Pan, Y.; Yang, S.; Li, C.; Zhou, Y.; Wang, Y.; Chen, X.; Zhou, Z.; Liao, Y.; Qiu, Z. PCSK9Qβ-003 vaccine attenuates atherosclerosis in Apolipoprotein E-deficient mice. Cardiovasc. Drugs Ther., 2021, 35(1), 141-151.
[http://dx.doi.org/10.1007/s10557-020-07041-6] [PMID: 32725442]
[31]
You, S.; Guo, X.; Xue, X.; Li, Y.; Dong, H.; Ji, H.; Hong, T.; Wei, Y.; Shi, X.; He, B. PCSK9 hapten multicopy displayed onto carrier protein nanoparticle: An antiatherosclerosis vaccine. ACS Biomater. Sci. Eng., 2019, 5(9), 4263-4271.
[http://dx.doi.org/10.1021/acsbiomaterials.9b00434] [PMID: 33417782]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy