VXX-401, a novel anti-PCSK9 vaccine, reduces LDL-C in cynomolgus monkeys
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved..
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of LDL-C. LDL-C-lowering drugs, such as statins or monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9), are known to reduce the risk of cardiovascular diseases; however, statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a "high-risk" patient population or those who have failed other therapies. Based on the proven efficacy and safety profile of existing monoclonal antibodies, we have developed a peptide-based vaccine against PCSK9, VXX-401, as an alternative option to treat hypercholesterolemia and prevent ASCVD. VXX-401 is designed to trigger a safe humoral immune response against PCSK9, resulting in the production of endogenous antibodies and a subsequent 30-40% reduction in blood LDL-C. In this article, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C-lowering effects in nonhuman primates. In addition, antibodies induced by VXX-401 bind to human PCSK9 with high affinity and block the inhibitory effect of PCSK9 on LDL-C uptake in a hepatic cell model. A repeat-dose toxicity study conducted in nonhuman primates under good laboratory practices toxicity indicated a suitable safety and tolerability profile, with injection site reactions being the main findings. As a promising safe and effective LDL-C-lowering therapy, VXX-401 may represent a broadly accessible and convenient option to treat hypercholesterolemia and prevent ASCVD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:65 |
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| Enthalten in: |
Journal of lipid research - 65(2024), 2 vom: 10. Feb., Seite 100497 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Vroom, Madeline M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.02.2024 Date Revised 22.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jlr.2024.100497 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Vroom, Madeline M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a VXX-401, a novel anti-PCSK9 vaccine, reduces LDL-C in cynomolgus monkeys |
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| 500 | |a Date Completed 26.02.2024 | ||
| 500 | |a Date Revised 22.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of LDL-C. LDL-C-lowering drugs, such as statins or monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9), are known to reduce the risk of cardiovascular diseases; however, statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a "high-risk" patient population or those who have failed other therapies. Based on the proven efficacy and safety profile of existing monoclonal antibodies, we have developed a peptide-based vaccine against PCSK9, VXX-401, as an alternative option to treat hypercholesterolemia and prevent ASCVD. VXX-401 is designed to trigger a safe humoral immune response against PCSK9, resulting in the production of endogenous antibodies and a subsequent 30-40% reduction in blood LDL-C. In this article, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C-lowering effects in nonhuman primates. In addition, antibodies induced by VXX-401 bind to human PCSK9 with high affinity and block the inhibitory effect of PCSK9 on LDL-C uptake in a hepatic cell model. A repeat-dose toxicity study conducted in nonhuman primates under good laboratory practices toxicity indicated a suitable safety and tolerability profile, with injection site reactions being the main findings. As a promising safe and effective LDL-C-lowering therapy, VXX-401 may represent a broadly accessible and convenient option to treat hypercholesterolemia and prevent ASCVD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a PCSK9 inhibitor | |
| 650 | 4 | |a PCSK9 vaccine | |
| 650 | 4 | |a atherosclerosis | |
| 650 | 4 | |a atherosclerotic cardiovascular disease | |
| 650 | 4 | |a hypercholesterolemia | |
| 650 | 4 | |a hyperlipidemia | |
| 650 | 7 | |a PCSK9 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 650 | 7 | |a Proprotein Convertase 9 |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 650 | 7 | |a Hydroxymethylglutaryl-CoA Reductase Inhibitors |2 NLM | |
| 650 | 7 | |a Cholesterol, LDL |2 NLM | |
| 650 | 7 | |a Anticholesteremic Agents |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 700 | 1 | |a Lu, Hanxin |e verfasserin |4 aut | |
| 700 | 1 | |a Lewis, Maggie |e verfasserin |4 aut | |
| 700 | 1 | |a Thibodeaux, Brett A |e verfasserin |4 aut | |
| 700 | 1 | |a Brooks, Jeanne K |e verfasserin |4 aut | |
| 700 | 1 | |a Longo, Matthew S |e verfasserin |4 aut | |
| 700 | 1 | |a Ramos, Martina M |e verfasserin |4 aut | |
| 700 | 1 | |a Sahni, Jaya |e verfasserin |4 aut | |
| 700 | 1 | |a Wiggins, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Boyd, Justin D |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shixia |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Shuang |e verfasserin |4 aut | |
| 700 | 1 | |a Hellerstein, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Ryan, Valorie |e verfasserin |4 aut | |
| 700 | 1 | |a Powchik, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Dodart, Jean-Cosme |e verfasserin |4 aut | |
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