Composition comprising PCSK9 peptide conjugated to a Qbeta carrier and methods of using the same
Inventors
Remaley, Alan • Schiller, John T. • Amar, Marcelo • Chackerian, Bryce
Assignees
UNM Rainforest Innovations • US Department of Health and Human Services
Publication Number
US-10925938-B2
Publication Date
2021-02-23
Expiration Date
2035-02-11
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Abstract
A vaccine construct comprising an antigenic PCSK9 peptide and an immunogenic carrier, and methods of using the same that are effective to lower blood cholesterol levels in a mammal and treat dyslipidemias and related disease states in a mammal without the frequency of administration required by passive immunity strategies.
Core Innovation
The invention provides a vaccine construct comprising an antigenic PCSK9 peptide linked to an immunogenic carrier, specifically a virus-like particle (VLP) of an RNA-bacteriophage such as Qbeta. The vaccine construct and its associated methods effectively lower blood cholesterol levels in a mammal and treat dyslipidemias and related disease states, utilizing immunization to induce antibodies against PCSK9, thereby reducing the need for frequent administration required by passive immunity strategies.
The problem addressed is that current treatments to reduce LDL cholesterol by administration of anti-PCSK9 monoclonal antibodies are expensive and require frequent administration to produce therapeutic effects. There is a need for a vaccine that can safely induce antibodies antagonizing the activity of PCSK9 to treat various therapeutic conditions associated with PCSK9, such as increased plasma LDL cholesterol levels, in a manner that reduces the burden of frequent dosing.
The vaccine constructs comprise antigenic PCSK9 peptides, including specific sequences such as NVPEEDGTRFHRQASKC (SEQ ID NO:3) and its reverse CKSAQRHFRTGDEEPVN (SEQ ID NO:4), linked to an immunogenic carrier like Qbeta bacteriophage VLPs, often using a hetero-bifunctional cross-linker such as SMPH. These compositions induce high-titer anti-PCSK9 antibodies that cross-react with native PCSK9 protein, leading to lowered LDL-cholesterol levels, and are effective in treating patients with elevated LDL-cholesterol and related cardiovascular conditions. The vaccine constructs may be administered alone or combined with other agents, such as statins, providing a durable immune response with potential for long-lasting protection.
Claims Coverage
The claims include one composition claim and multiple method claims, focusing on vaccine constructs comprising specific PCSK9 peptides linked to Qbeta VLPs and their therapeutic uses for dyslipidemias and cardiovascular diseases. There are multiple inventive features concerning composition components, linkage chemistry, and treatment methods.
Composition comprising PCSK9 peptides linked to Qbeta VLP immunogenic carrier
A composition comprising a first antigenic PCSK9 peptide having the amino acid sequence NVPEEDGTRFHRQASKC (SEQ ID NO:3) linked to a bacteriophage Qbeta virus-like particle (VLP) carrier and a second antigenic PCSK9 peptide comprising amino acid sequences SIPWNLERIIP (aa 150-160 of SEQ ID NO:1) or SIPWNLERITP (aa 153-163 of SEQ ID NO:2) also linked to a Qbeta VLP carrier.
Use of D-isomeric amino acids in PCSK9 peptides
The composition wherein at least one amino acid in the PCSK9 peptide(s) is in the D-isomeric form, allowing for stable and effective antigen presentation.
Chemical linking of PCSK9 peptides via SMPH cross-linker
Linkage of at least one immunogenic carrier to a PCSK9 peptide through a succinimidyl-6-[β-maleimidopropionamido]hexanoate (SMPH) hetero-bifunctional cross-linker molecule, enabling oriented and efficient conjugation.
Same or different VLP carriers presenting multiple PCSK9 peptides
Both PCSK9 antigenic peptides can be linked to the same Qbeta VLP or separately linked to distinct Qbeta VLPs, providing flexibility in vaccine construct design.
Inclusion of adjuvants in composition
The composition may further include at least one adjuvant to enhance immune response.
Methods for preventing or treating dyslipidemia by administration of the composition
Methods of administering a therapeutically effective amount of the claimed composition to individuals to prevent, alleviate, or treat various forms of dyslipidemia including hyperlipidemias, familial hypercholesterolemia, and related disorders.
Combination therapy with cholesterol-lowering agents
Administration of the composition in combination with additional therapeutic agents such as statins, bile acid sequestrants, niacin, fibric acid derivatives, or long chain alpha, omega-dicarboxylic acids for enhanced therapeutic effect.
Methods for treating cardiovascular and related diseases
Methods for preventing, alleviating, or treating conditions such as atherosclerosis, coronary artery disease, cardiovascular disease, and acute coronary syndrome using the composition.
The claims cover compositions comprising specific PCSK9 peptides conjugated to Qbeta VLPs via SMPH cross-linkers, optionally containing D-amino acids and adjuvants, and methods of use for preventing and treating dyslipidemias and cardiovascular diseases, including in combination with other cholesterol-lowering therapies.
Stated Advantages
The vaccine construct induces high-titer, durable anti-PCSK9 antibodies that cross-react with native PCSK9 protein.
Vaccination leads to significant reduction in LDL-cholesterol and other lipid parameters, providing effective treatment of dyslipidemias.
The approach reduces the frequency of administration compared to passive immunity strategies like monoclonal antibody therapy.
The use of stable Qbeta VLPs allows for robust antigen display and high antigen density, improving immunogenicity.
Combining the vaccine with statin therapy can produce synergistic cholesterol-lowering effects.
Documented Applications
Treatment and prevention of dyslipidemias including hyperlipidemia types I-V, secondary hypertriglyceridemia, hypercholesterolemia, familial hypercholesterolemia, familial combined hyperlipidemia, xanthomatosis, and lecithin:cholesterol acetyltransferase deficiency.
Treatment and prevention of arteriosclerotic conditions such as atherosclerosis, coronary artery disease, and cardiovascular disease.
Treatment and prevention of Alzheimer's disease.
Use in combination with other cholesterol-lowering agents such as statins, bile acid sequestrants, niacin, fibric acid derivatives, and long chain alpha, omega-dicarboxylic acids.
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