A novel therapeutic vaccine targeting the soluble TNFα receptor II to limit the progression of cardiovascular disease: AtheroVax™
The burden of atherosclerotic cardiovascular disease contributes to a large proportion of morbidity and mortality, globally. Vaccination against atherosclerosis has been proposed for over 20 years targeting different mediators of atherothrombosis; however, these have not been adequately evaluated in...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Cardiovascular Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1206541/full |
| _version_ | 1797777689954746368 |
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| author | Patrick L. Iversen Nicholas Kipshidze Nodar Kipshidze George Dangas Eduardo Ramacciotti Zurab Kakabadze Jawed Fareed |
| author_facet | Patrick L. Iversen Nicholas Kipshidze Nodar Kipshidze George Dangas Eduardo Ramacciotti Zurab Kakabadze Jawed Fareed |
| author_sort | Patrick L. Iversen |
| collection | DOAJ |
| description | The burden of atherosclerotic cardiovascular disease contributes to a large proportion of morbidity and mortality, globally. Vaccination against atherosclerosis has been proposed for over 20 years targeting different mediators of atherothrombosis; however, these have not been adequately evaluated in human clinical trials to assess safety and efficacy. Inflammation is a driver of atherosclerosis, but inflammatory mediators are essential components of the immune response. Only pathogenic forms of sTNFR2 are acted upon while preserving the membrane-bound (wild-type) TNFR2 contributions to a non-pathogenic immune response. We hypothesize that the inhibition of sTNRF2 will be more specific and offer long-term treatment options. Here we describe pre-clinical findings of an sTNFR2-targeting peptide vaccine (AtheroVax™) in a mouse model. The multiple pathways to synthesis of the soluble TNFRII receptor (sTNFRII) were identified as sTNFRII(PC), sTNFRII(Δ7), and sTNFRII(Δ7,9). The sTNFRII(Δ7) peptide, NH2-DFALPVEKPLCLQR-COOH is specific to sTNFR2 based on an mRNA splice-variant in which exon 6 is joined to exon 8. The role of sTNFRII(Δ7) as a mediator of prolonged TNFα activity by preventing degradation and clearance was investigated. Inflammation is a critical driver of onset, progression and expansion of atherosclerosis. The TNFα ligand represents a driver of inflammation that is mediated by a splice variant of TNFR2, referred to as sTNFRII(Δ7). The multiple forms of TNFRII, both membrane bound and soluble, are associated with distinctly different phenotypes. sTNFRII(PC) and sTNFRII(Δ7) are not equivalent to etanercept because they lack a clearance mechanism. The unique peptide associated with sTNFRII(Δ7) contains a linear B-cell epitope with amino acids from both exon 6 and exon 8 supporting the vaccine design. Animal studies to evaluate the vaccine are ongoing, and results will be forthcoming. We describe a peptide vaccine targeting sTNFR2 in limiting the progression of atherosclerosis. A therapeutic vaccine limiting the progression of atherosclerosis will greatly contribute to the reduction in morbidity and mortality from cardiovascular disease. It is likely the vaccine will be used in combination with the current standards of care and lifestyle modifications. |
| first_indexed | 2024-03-12T23:08:25Z |
| format | Article |
| id | doaj.art-35eb871ae7bc4b8baeffedcd9978a4ff |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-03-12T23:08:25Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-35eb871ae7bc4b8baeffedcd9978a4ff2023-07-18T10:08:27ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-07-011010.3389/fcvm.2023.12065411206541A novel therapeutic vaccine targeting the soluble TNFα receptor II to limit the progression of cardiovascular disease: AtheroVax™Patrick L. Iversen0Nicholas Kipshidze1Nodar Kipshidze2George Dangas3Eduardo Ramacciotti4Zurab Kakabadze5Jawed Fareed6Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United StatesNew York Cardiovascular Research, New York, NY, United StatesMailman School of Public Health, Columbia University, New York, NY, United StatesDepartment of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, United StatesScience Valley Research Institute, Sao Paulo, BrazilHead Department of Clinical Anatomy, Tbilisi State Medical University, Tbilisi, GeorgiaDepartment of Molecular Pharmacology and Neuroscience, Loyola University Medical Center, Maywood, IL, United StatesThe burden of atherosclerotic cardiovascular disease contributes to a large proportion of morbidity and mortality, globally. Vaccination against atherosclerosis has been proposed for over 20 years targeting different mediators of atherothrombosis; however, these have not been adequately evaluated in human clinical trials to assess safety and efficacy. Inflammation is a driver of atherosclerosis, but inflammatory mediators are essential components of the immune response. Only pathogenic forms of sTNFR2 are acted upon while preserving the membrane-bound (wild-type) TNFR2 contributions to a non-pathogenic immune response. We hypothesize that the inhibition of sTNRF2 will be more specific and offer long-term treatment options. Here we describe pre-clinical findings of an sTNFR2-targeting peptide vaccine (AtheroVax™) in a mouse model. The multiple pathways to synthesis of the soluble TNFRII receptor (sTNFRII) were identified as sTNFRII(PC), sTNFRII(Δ7), and sTNFRII(Δ7,9). The sTNFRII(Δ7) peptide, NH2-DFALPVEKPLCLQR-COOH is specific to sTNFR2 based on an mRNA splice-variant in which exon 6 is joined to exon 8. The role of sTNFRII(Δ7) as a mediator of prolonged TNFα activity by preventing degradation and clearance was investigated. Inflammation is a critical driver of onset, progression and expansion of atherosclerosis. The TNFα ligand represents a driver of inflammation that is mediated by a splice variant of TNFR2, referred to as sTNFRII(Δ7). The multiple forms of TNFRII, both membrane bound and soluble, are associated with distinctly different phenotypes. sTNFRII(PC) and sTNFRII(Δ7) are not equivalent to etanercept because they lack a clearance mechanism. The unique peptide associated with sTNFRII(Δ7) contains a linear B-cell epitope with amino acids from both exon 6 and exon 8 supporting the vaccine design. Animal studies to evaluate the vaccine are ongoing, and results will be forthcoming. We describe a peptide vaccine targeting sTNFR2 in limiting the progression of atherosclerosis. A therapeutic vaccine limiting the progression of atherosclerosis will greatly contribute to the reduction in morbidity and mortality from cardiovascular disease. It is likely the vaccine will be used in combination with the current standards of care and lifestyle modifications.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1206541/fullatherosclerotic cardiovascular diseasetumor necrosis factor alphaTNFRIIsoluble TNFRIItherapeutic vaccinepeptide vaccine |
| spellingShingle | Patrick L. Iversen Nicholas Kipshidze Nodar Kipshidze George Dangas Eduardo Ramacciotti Zurab Kakabadze Jawed Fareed A novel therapeutic vaccine targeting the soluble TNFα receptor II to limit the progression of cardiovascular disease: AtheroVax™ Frontiers in Cardiovascular Medicine atherosclerotic cardiovascular disease tumor necrosis factor alpha TNFRII soluble TNFRII therapeutic vaccine peptide vaccine |
| title | A novel therapeutic vaccine targeting the soluble TNFα receptor II to limit the progression of cardiovascular disease: AtheroVax™ |
| title_full | A novel therapeutic vaccine targeting the soluble TNFα receptor II to limit the progression of cardiovascular disease: AtheroVax™ |
| title_fullStr | A novel therapeutic vaccine targeting the soluble TNFα receptor II to limit the progression of cardiovascular disease: AtheroVax™ |
| title_full_unstemmed | A novel therapeutic vaccine targeting the soluble TNFα receptor II to limit the progression of cardiovascular disease: AtheroVax™ |
| title_short | A novel therapeutic vaccine targeting the soluble TNFα receptor II to limit the progression of cardiovascular disease: AtheroVax™ |
| title_sort | novel therapeutic vaccine targeting the soluble tnfα receptor ii to limit the progression of cardiovascular disease atherovax™ |
| topic | atherosclerotic cardiovascular disease tumor necrosis factor alpha TNFRII soluble TNFRII therapeutic vaccine peptide vaccine |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1206541/full |
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