Compositions comprising a 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-11696941-B2
Publication Date
2023-07-11
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, particularly a virus-like particle (VLP) of an RNA-bacteriophage, such as Qbeta. The vaccine construct induces an immune response effective to lower blood cholesterol levels and treat or prevent dyslipidemias and PCSK9-related disorders in mammals with reduced frequency of administration compared to passive immunity strategies.
PCSK9 is a protein that mediates LDL receptor degradation, increasing circulating LDL cholesterol. Current therapies using anti-PCSK9 antibodies require frequent administration and are expensive. Thus, there is a need for a vaccine that safely induces antibodies antagonizing PCSK9 activity to reduce plasma LDL cholesterol.
The vaccine construct comprises antigenic PCSK9 peptides, such as SEQ ID NO:3 (NVPEEDGTRFHRQASKC) or SEQ ID NO:4 (CKSAQRHFRTGDEEPVN), linked to Qbeta VLPs. Peptides may be in L- or D-isomeric forms and linked typically through a bifunctional cross-linker like SMPH. The vaccine elicits an anti-PCSK9 immune response lowering LDL cholesterol by at least 2%, 5%, 10%, 20%, 30%, or 50%. Methods include immunization and combination with other agents like statins.
Claims Coverage
The claims include four main inventive features covering compositions and therapeutic methods involving PCSK9 peptides linked to Qbeta VLP carriers with specific peptide sequences and methods of treating dyslipidemia and cardiovascular conditions.
Composition comprising two antigenic PCSK9 peptides linked to Qbeta VLP carriers
The composition comprises a first antigenic PCSK9 peptide with sequence NVPEEDGTRFHRQASKC (SEQ ID NO:3) linked to a Qbeta bacteriophage VLP and a second antigenic PCSK9 peptide comprising SIPWNLERIIP (mouse, amino acids 150-160 of SEQ ID NO:1) or SIPWNLERITP (human, amino acids 153-163 of SEQ ID NO:2) also linked to a Qbeta VLP; the composition may lack statins or have statins at ineffective doses.
Incorporation of D-isomeric amino acids in antigenic peptides
At least one amino acid in the antigenic PCSK9 peptide(s) is in the D-isomeric form, expanding immunogenic and stability properties.
Linkage of antigenic peptides to Qbeta VLP via a SMPH cross-linker
The peptides are linked to the immunogenic carrier through a succinimidyl-6[β-maleimidopropionamido]hexanoate (SMPH) hetero-bifunctional cross-linker molecule enabling oriented conjugation.
Methods of treating dyslipidemia and cardiovascular conditions with vaccine constructs
Methods comprise administering therapeutically effective amounts of the vaccine composition to individuals to prevent, alleviate or treat dyslipidemia (various hyperlipidemias, xanthomatosis, lecithin:cholesterol acetyltransferase deficiency) or atherosclerosis, coronary artery disease, cardiovascular disease, acute coronary syndrome, including combinations with other lipid-modifying treatments (statins, bile acid sequestrants, niacin, fibric acid derivatives).
The claimed invention covers compositions comprising two specific PCSK9 antigenic peptides linked to Qbeta VLP immunogenic carriers, optionally containing D-amino acids and coupled via SMPH cross-linkers, and methods of treating lipid disorders and cardiovascular diseases by administering these vaccine compositions, with or without co-therapy with other lipid-lowering agents.
Stated Advantages
The vaccine effectively lowers blood cholesterol levels in mammals, notably reducing LDL-cholesterol by up to approximately 50%.
It reduces the frequency of administration compared to passive immunotherapies such as monoclonal antibody treatments against PCSK9.
The use of virus-like particles (Qbeta VLPs) as immunogenic carriers allows for high antigen density and robust, stable vaccine constructs.
The vaccine constructs elicit durable and high titer anti-PCSK9 antibodies that cross-react with PCSK9 protein, potentially producing sustained therapeutic effects.
Combination with statins results in synergistic therapeutic benefits beyond statin monotherapy.
Documented Applications
Vaccination for prevention, treatment, or alleviation of PCSK9-related disorders including lipid disorders such as hyperlipidemia (types I-V), secondary hypertriglyceridemia and hypercholesterolemia, familial hypercholesterolemia, familial combined hyperlipidemia, xanthomatosis, and lecithin:cholesterol acetyltransferase deficiency.
Treatment of arteriosclerotic conditions including atherosclerosis, coronary artery disease, cardiovascular disease, and acute coronary syndrome.
Use in treating Alzheimer's disease.
Combination therapy with cholesterol-reducing agents such as statins, bile acid sequestrants, niacin, fibric acid derivatives, and long chain alpha omega dicarboxylic acids.
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