DNA vaccine containing specific epitope of apolipoprotein (a)
Inventors
KYUTOKU, Mariko • Nakagami, Hironori • Koriyama, Hiroshi • NAKAGAMI, Futoshi • Morishita, Ryuichi
Assignees
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Publication Number
US-9913886-B2
Publication Date
2018-03-13
Expiration Date
Abstract
The present invention provides an agent for the treatment or prophylaxis of arteriosclerosis comprising an expression vector encoding a chimeric Hepatitis B virus core antigen polypeptide inserted with an amino acid sequence containing a specific epitope of apolipoprotein (a), wherein the amino acid sequence containing the specific epitope is inserted between the amino acid residues 80 and 81 of the hepatitis B virus core antigen polypeptide.
Core Innovation
The disclosed invention relates to a DNA vaccine or agent for treating arteriosclerosis or a disease caused by arteriosclerosis by administering an expression vector encoding a chimeric hepatitis B virus core antigen polypeptide. The antigen polypeptide comprises the amino acid sequence of SEQ ID NO: 1, inserted between amino acid residues 80 and 81 of the hepatitis B virus core antigen polypeptide. Expression of the engineered antigen polypeptide results in a decrease in lipoprotein(a) deposition and suppresses neointimal thickening.
A related aspect of the invention is a method of inducing a neutralizing antibody against lipoprotein(a) in a mammal. The method comprises administering an effective amount of an expression vector encoding the same chimeric hepatitis B virus core antigen polypeptide, and expression of the vector induces the neutralizing antibody against lipoprotein(a).
The document additionally frames the approach in terms of desired immunological outcomes, aiming to induce dominant humoral, neutralizing antibody responses against lipoprotein(a) while suppressing T-cell responses to avoid autoimmune or self-reactive T cell induction. It describes construct design consistent with hepatitis B virus core antigen self-assembly with surface epitope presentation, and the stated biological effects include reduced neointima and reduced vascular lipoprotein(a) deposition.
Claims Coverage
The document includes four independent claims. Across these independent claims, there are three main inventive aspects: administering an expression vector encoding a chimeric hepatitis B virus core antigen polypeptide with a SEQ ID NO: 1 insertion between residues 80 and 81, inducing a neutralizing antibody against lipoprotein(a), and decreasing lipoprotein(a) deposition and/or neointima formation for treating arteriosclerosis and arteriosclerosis-caused diseases.
Chimeric hepatitis B virus core antigen with SEQ ID NO: 1 inserted between residues 80 and 81
Administering to the mammal an effective amount of an expression vector encoding a chimeric hepatitis B virus core antigen polypeptide comprising the amino acid sequence of SEQ ID NO: 1, wherein the amino acid sequence of SEQ ID NO: 1 is inserted between amino acid residues 80 and 81 of the hepatitis B virus core antigen polypeptide.
Expression decreases lipoprotein(a) deposition and suppresses neointimal thickening
Expression of the expression vector results in a decrease in lipoprotein(a) deposition and suppresses neointimal thickening, thereby treating arteriosclerosis or a disease caused by arteriosclerosis selected from cerebral infarction, myocardial infarction, angina, sclerosis obliterans, vascular dementia, and vascular restenosis.
Inducing a neutralizing antibody against lipoprotein(a) by vector expression
Administering an effective amount of an expression vector encoding a chimeric hepatitis B virus core antigen polypeptide comprising an amino acid sequence encoded by SEQ ID NO: 1 inserted between amino acid residues 80 and 81 of the hepatitis B virus core antigen polypeptide, wherein expression of the vector induces a neutralizing antibody against lipoprotein(a) in the mammal.
Decreasing lipoprotein(a) deposition and/or neointima formation in a mammal with arteriosclerosis or an arteriosclerosis-caused disease
Administering an effective amount of an expression vector encoding a chimeric hepatitis B virus core antigen polypeptide comprising an amino acid sequence encoded by SEQ ID NO: 1 inserted between amino acid residues 80 and 81 of the hepatitis B virus core antigen polypeptide, wherein the mammal has arteriosclerosis or a disease caused by arteriosclerosis selected from cerebral infarction, myocardial infarction, angina, sclerosis obliterans, vascular dementia, and vascular restenosis, thereby decreasing lipoprotein(a) deposition and/or neointima formation in the mammal.
Across the independent claims, the methods rely on administering an expression vector encoding a chimeric hepatitis B virus core antigen polypeptide with a SEQ ID NO: 1 insertion between amino acid residues 80 and 81. Vector expression is linked to inducing a neutralizing antibody against lipoprotein(a) and to decreasing lipoprotein(a) deposition and suppressing neointimal thickening or decreasing neointima formation for treating arteriosclerosis and arteriosclerosis-caused diseases.
Stated Advantages
Decrease in lipoprotein(a) deposition.
Suppression of neointimal thickening.
Decreasing lipoprotein(a) deposition and/or neointima formation.
Induction of a neutralizing antibody against lipoprotein(a).
Treatment of arteriosclerosis and diseases caused by arteriosclerosis, selected from cerebral infarction, myocardial infarction, angina, sclerosis obliterans, vascular dementia, and vascular restenosis.
Suppression of T-cell responses to avoid autoimmune or self-reactive T cell induction.
Reduction of inflammatory cytokine expression (IL-1β, TNF-α, MCP-1).
Documented Applications
Treating arteriosclerosis in a mammal.
Treating a disease caused by arteriosclerosis in a mammal, selected from cerebral infarction, myocardial infarction, angina, sclerosis obliterans, vascular dementia, and vascular restenosis.
Inducing a neutralizing antibody against lipoprotein(a) in a mammal.
Decreasing lipoprotein(a) deposition and/or neointima formation in a mammal with arteriosclerosis or a disease caused by arteriosclerosis.
Use in an Lp(a) transgenic carotid ligation model, with reduced neointima and reduced vascular lipoprotein(a) deposition.
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