Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 15 to 23 amino acid residues in defined sequence
Reexamination Certificate
2003-03-04
2004-11-30
Wax, Robert A. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
15 to 23 amino acid residues in defined sequence
C530S300000, C530S350000, C435S069100
Reexamination Certificate
active
06825318
ABSTRACT:
BACKGROUND OF THE INVENTION
Blood serum lipids include cholesterol, triglycerides (TG), free fatty acid, phospholipid and the like, and exist in blood stream in the form of lipoproteins which are complexes of lipid and apolipoprotein.
Of these lipoproteins, low density lipoprotein (LDL) is the major carrier for TG and cholesterol. The number of patients suffering from arteriosclerosis, coronary artery disease, or cardiac infarction caused by elevated LDL-cholesterol level in blood has increased considerably due to changes in diet or other factors.
Research has focused on elucidating the etiology of the above-identified diseases and discovering methods for lowering the level of LDL-cholesterol in patients suffering from these diseases.
LDL-cholesterol, a major etiological factor for adult disease related to lipid metabolism, may be converted to high density lipoprotein (HDL) by macrophages. In addition, LDL-cholesterol may be converted to another material or be converted to bile acid in the liver (Brown, M. S. and Goldstein, J. L., 1983, Annu. Rev. Biochem., 52: 223-261).
Apolipoprotein B-100 is a major protein part of LDL and exists also in very low density lipoprotein (VLDL) and chylomicron. LDL-cholesterol in blood may be removed through phagocytosis by macrophages where an antibody in the blood stream is induced by recognizing the apolipoprotein B-100, since apolipoprotein B-100 leads LDL particles to bind to LDL-receptors exposed on the cell surface (Dalum I., et al., 1997, Mol. Immunol., 34 (16-17): 1113-20).
Where a macromolecule, such as an antibody, is bound to apolipoprotein B-100, which exists on the surface of LDL, lipases, such as lipoprotein lipase, cannot hydrolize TG and the like due to steric hindrance caused by the macromolecule bound to apolipoprotein B-100. Consequently, the formation of free fatty acid, a major factor for obesity, can be inhibited by means of the antibody which can bind to apolipoprotein B-100.
Recently, vaccine-based methods for lowering LDL-cholesterol and for inhibiting the outbreak of arteriosclerosis have been tried in various animal models such as mouse and rabbit. For example, C. R. Alving reported that cholesterol may be modified by metabolites or its oxidation and that the modified cholesterol can be a strong antigenic determinants in some cases (Alving, C. R., et al., 1989, Biochem. Soc. Trans., 17 (4): 637-9; Alving, C. R., et al., 1996, J. Lab. Clin. Med., 127: 40-49; Alving, C. R., et al., 1996, Curr. Top. Microbiol. Immunol., 210: 181-6).
Furthermore, it has been reported that an endogenous antibody for cholesterol exists in blood serum (Wu, J. T., L. L., 1997, Clin. Lab. Med., 17 (3): 595-604, Review). It has also been reported that hypercholesterolemia and arteriosclerosis are remarkably reduced in rabbits injected with cholesterol-containing liposomes followed by maintenance on cholesterol-containing meal relative to control rabbits that were maintained on the same diet, but did not receive the liposomes.
The antibody induced by cholesterol vaccination is immunoglobin M (IgM), which binds to VLDL, intermediate density lipoprotein (IDL) and LDL. Based on the above, it is believed that a vaccine for treatment or prevention of hyperlipoidemia or arteriosclerosis caused by high level of cholesterol, will be possible (Bailey, J. M., 1994, Science, 264: 1067-1068; Palinski, W. et al., 1995, Proc. Natl. Acad. Sci. USA., 92 (3): 821-5; Wu, R. et al, 1999, Hypertension, 33 (1): 53-9).
The present inventors have found that obesity can be effectively prevented by mimetic peptide epitopes of apolipoprotein B-100, and based on the above, have developed a vaccine composition for treatment of obesity.
SUMMARY OF THE INVENTION
Therefore, some embodiments of the present invention provide a mimetic peptide for the epitope of apolipoprotein B-100, concatemers of the peptide, and modified peptides.
Additionally, some embodiments of the present invention provide a process for preparing the above mimetic peptide for the epitope of apolipoprotein B-100, concatemers of the peptide, and modified peptides.
Some embodiments of the present invention provide a vaccine composition for treatment or prevention of obesity, which comprises the above mimetic peptide for the epitope of apolipoprotein B100, concatemers of the peptide, and modified peptides.
Mimetic peptides for the epitope of apolipoprotein B-100 of the present invention may be selected from peptides of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 or the mixtures thereof.
The invention further provides a method for preparing mimetic peptide, concatemers of the peptide, and modified peptides, which comprises: i) a step for inserting DNAs which encodes the above mimetic peptide, concatemer of the peptide or modified peptide into a vector, ii) a step for transforming the above vector into host cells, and then incubating them, and iii) a step for isolating the above mimetic peptide, concatemer or modified peptide from the above host cells.
REFERENCES:
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Ahn, Sang Hoon, Naturally Occuring Mutations Near Precore Translational Initiation Site Reduce Hepatitis B E Antigen Production. Heptology, (Oct., 2002) vol. 36, No. 4 Part 2, pp. 370A.*
Alving CR et al., 1999, “Naturally occurring antibodies to cholesterol: a new theory of LDL cholesterol metabolism”Immunol Today20(8):362-366.
Ruihua W et al., 1999, “Autoantibodies to O×LDL are decreased in individuals with borderline hypertension”Hypertension, 33:53-59.
Stadler BM et al., 1999,“Mimotope and anti-idiotypic vaccines to induce an anti-IgE response”Int Arch Allergy Immunol118(2-4):119-121.
Dalum I et al., 1997, “Induction of cross-reactive antibodies against a self protein by immunization with a modified self protein containing a foreign T helper epitope”Molecular Immunology, 34(16-17):1113-1120.
Wu JT et al., 1997, “Autoantibodies against oxidized LDL: A potential marker for atherosclerosis”Clinics In Laboratory Medicine, 17(3):595-604.
Alving CR et al., 1996, “Antibodies to cholesterol: Biological implications of antibodies to lipids”Curr Top Mocrobid Immunol, 210:181-186.
Alving CR et al., 1996, “Immunization with cholesterol-rich liposomes induces anti-cholesterol antibodies and reduces diet-induced hypercholesterolemia and plaque formation”J Lab Clin Med, 127(1):40-49.
Soued M et al., 1996, “Chylomicron remnant uptake by enterocytes is receptor dependent”Am J Physiol270(1 Pt 1):G203-G212.
Palinski W et al., 1995, “Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis”Proc. Natl. Acad. Sci USA, 92:821-825.
Steward MW et al., 1995, “A mimotope from a solid-phase peptide library induces a measles virus-neutralizing and protective antibody response”J Virol69(12):7668-7673.
Bailey JM et al., 1994, “Cholesterol vaccines”Science, 264:1064-1068.
Young SG, 1990, “Recent progress in understanding apolipoprotein B”Circulation82(5):1574-1594.
Alving CR et al., 1989, “Naturally occurring autoantibodies to cholesterol in humans”Biochemical Society Transactions, 17:637-639.
Knott TJ et al., 1986, “Complete protein sequence and identification of structural domains of human apolipoprotein B”Nature323(6090):734-738.
Brown MS et al., 1983, “Lipoprotein metabolism in the macrophage: Implications for cholesterol deposition in Atherosclerosis”Ann. Review Biochem, 52:223-261.
Joung Hae-Jung
Kim Hyo-Joon
Baker & Botts LLP
Kim Hyo-Joon
Mondesi Robert B.
Wax Robert A.
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