Compositions and methods for reducing serum triglycerides
Inventors
Chackerian, Bryce • Remaley, Alan • Amar, Marcelo • Fowler, Alexandra
Assignees
UNM Rainforest Innovations • US Department of Health and Human Services
Publication Number
US-11633471-B2
Publication Date
2023-04-25
Expiration Date
2039-03-06
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Abstract
An immunogen generally includes a virus-like particle and an antigen linked to the virus-like particle. The antigen includes an antigenic portion of a polypeptide, wherein the polypeptide inhibits lipoprotein lipase (LPL) activity by binding to LPL. In some embodiments, the polypeptide is at least a portion of angiopoietin-like 3 (ANGPTL3). In other embodiments, the polypeptide is at least a portion of angiopoietin-like 4 (ANGPTL4). In other embodiments, the polypeptide at least a portion of angiopoietin-like 8 (ANGPTL8). In some embodiments, the virus-like particle is a Qbeta immunogenic carrier. In some of these embodiments, the antigen is linked to the virus-like particle through a Gly-Gly-Gly-Cys linker at the C-terminal of the antigen.
Core Innovation
The invention describes an immunogen comprising a virus-like particle linked to an antigenic portion of a polypeptide that inhibits lipoprotein lipase (LPL) activity by binding to LPL. In particular, the antigenic portion can be derived from angiopoietin-like proteins such as ANGPTL3, ANGPTL4, or ANGPTL8, with sequences having at least 80% similarity or identity to specific amino acid segments of these proteins. The virus-like particle can be a Qbeta immunogenic carrier, and the antigen can be linked via a Gly-Gly-Gly-Cys linker at the C-terminal of the antigen.
The problem addressed by the invention is the need to reduce elevated serum triglyceride levels, which are a risk factor for cardiovascular disease. Lipoprotein lipase metabolizes serum triglycerides, but its activity is inhibited by ANGPTL proteins. Existing therapies using monoclonal antibodies against ANGPTL3, ANGPTL4, or ANGPTL8 have been shown to lower triglycerides. The invention aims to provide a vaccine-based immunogen to evoke an immune response against ANGPTL proteins to reduce their LPL-inhibiting effects, thus lowering serum triglycerides.
The immunogen uses virus-like particles to enhance immunogenicity, enabling strong antibody responses even against self-antigens like ANGPTL proteins. Experiments with mice demonstrated that immunization with Qbeta virus-like particles conjugated to ANGPTL3 or ANGPTL4 peptides elicited high antibody titers and significantly reduced serum triglyceride levels after an olive oil challenge. The disclosed methods also encompass pharmaceutical compositions containing the immunogen, optionally with adjuvants, nucleic acids encoding the immunogen, expression vectors, and host cells for production.
Claims Coverage
The patent includes eight main inventive features based on 14 claims, covering the immunogen composition, its antigenic components, virus-like particle type, linking method, pharmaceutical composition, therapeutic methods, and nucleic acid and vector constructs.
Immunogen comprising virus-like particle linked to ANGPTL3 antigenic portion
An immunogen including a virus-like particle linked to an antigen comprising an antigenic portion of SEQ ID NO:1.
Antigen sequence similarity to ANGPTL3 residues
The antigen comprises an amino acid sequence with at least 80% sequence similarity to amino acids 32-47 or 32-57 of SEQ ID NO:1.
Use of Qbeta coat protein virus-like particles
The virus-like particle includes one or more Qbeta coat proteins.
Linker between antigen and VLP
The antigen is linked to the virus-like particle through a Gly-Gly-Gly-Cys (SEQ ID NO:6) linker at the C-terminal of the antigen.
Pharmaceutical composition including immunogen and carrier
A composition comprising the immunogen and a pharmaceutically-acceptable carrier, optionally with an adjuvant.
Method to reduce serum triglycerides by administering immunogen
A method administering a therapeutically effective amount of the immunogen to reduce serum triglycerides in a subject.
Combination therapy with immunogen and additional agents
The immunogen is administered with an adjuvant and/or additional therapeutic agents such as statins or fibric acid derivatives.
Nucleic acid, expression vector, and host cell encoding immunogen
Provision of nucleic acids encoding the immunogen, expression vectors containing such nucleic acids, and host cells comprising the expression vectors.
The claims collectively cover an immunogen composed of a virus-like particle linked to specific antigenic portions of ANGPTL3, pharmaceutical compositions containing this immunogen, therapeutic methods for reducing serum triglycerides using the immunogen, and genetic constructs and cells for producing the immunogen.
Stated Advantages
The immunogen elicits strong antibody responses against self-antigens that are normally poorly immunogenic by using virus-like particle display.
Vaccination with the immunogen reduces serum triglyceride levels in mice, demonstrating effective modulation of lipid metabolism.
Use of stable Qbeta virus-like particles as an immunogenic carrier enhances vaccine stability and immunogenicity.
The immunogen can be administered alone or in combination with adjuvants and other lipid-lowering therapeutic agents, offering versatile treatment options.
Documented Applications
Reducing serum triglycerides in subjects at risk or suffering from elevated triglyceride levels by administering the immunogen to induce an immune response against ANGPTL proteins.
Use of the immunogen in vaccine compositions for immunotherapy to lower triglyceride levels.
Co-administration of the immunogen with additional therapeutic agents such as statins or fibric acid derivatives for enhanced lipid management.
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