JP2007300856A - Amyloid protein imitation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new antigen molecule for vaccine therapies for amyloid-related diseases, or a new antibody for indirect immunologic therapies for amyloid-related diseases. <P>SOLUTION: This amyloid protein imitation is a synthetic peptide which comprises a specific amino acid sequence or an amino acid sequence containing at least five amino acid residues at the amino terminal of the sequence and whose amino acid residue Xaa is one or more arbitrary amino acid residues, a derivative of the synthetic peptide, or their pharmacologically acceptable salt. An antibody for specifically recognizing the amyloid protein imitation. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a synthetic peptide that mimics a natural amyloid protein, a derivative thereof, or a pharmacologically acceptable salt thereof. More specifically, the present invention relates to amyloid protein mimics useful for vaccine therapy of amyloid-related diseases, polynucleotides encoding the same, and antibodies useful for indirect immunotherapy of amyloid-related diseases.

  In immunotherapy including vaccines, attacking target viruses, bacteria, and biopathogenic molecules using the functions of the bioimmune function leads to treatment. In many cases, it is known that the target etiological molecule is reduced or decreased to increase the effect, but side effects may occur at the same time. This is because a plurality of immune reactions occur in the antigen molecule, and reactions other than the expected immune action are considered to contribute to side effects.

  Intracranial nerve lesions in Alzheimer's disease occur before clinical abnormal symptoms such as disorientation, memory loss, memory loss, judgment loss, and behavioral abnormalities. Nerve lesions are amyloid protein deposition, neurofibrillary tangles, and cell loss degeneration. Among these, amyloid protein deposition is the initial pathological reaction.

  This amyloid protein consists of 42 amino acid sequences (positions 597-638 in SEQ ID NO: 3) by hydrolytic cleavage from the precursor amyloid precursor protein (APP; SEQ ID NO: 3). Aβ1-42, Aβ1-43 consisting of 43 amino acid sequences (positions 597-639 of SEQ ID NO: 3), Aβ1-40 consisting of 40 amino acid sequences (positions 597-636 of SEQ ID NO: 3) The Various variants of this amyloid protein are also known (for example, see Patent Document 1).

  It has been experimentally proven that amyloid protein has neurotoxicity (Non-Patent Documents 1 and 2), and is considered a key molecule for the onset of Alzheimer's disease. Amyloid protein deposits are not only Alzheimer's disease, but also tissue lesions that appear in Down's syndrome and normal aging brain tissue.

  Therefore, various treatment methods such as vaccine therapy targeting amyloid protein have been studied. For example, vaccine therapy using a synthetic peptide Aβ1-42 as an antigen (Non-patent Document 3) has been studied as a promising therapeutic method, but side effects that cause severe encephalitis have been pointed out (Non-patent Document 4). ). Indirect vaccine therapy or indirect immunotherapy using an anti-amyloid antibody (Non-Patent Document 5) is also attracting attention, but requires further investigation clinically.

The side effect of vaccine therapy is that the antigen site of the amyloid protein used as the antigen is on the amino-terminal side of Aβ4-10, the induced antibody is of the IgG2b type isotype, the intestinal immunization by oral administration, etc. Although the possibility of attenuation has been pointed out, it has not yet been determined as an improvement method. In addition, since the amino terminus of the peptide has high antigenicity and antibodies against this part are likely to be produced in many cases (Non-Patent Documents 6 and 7), there is a problem in producing highly specific antibodies or antibodies with limited antigenicity. It may become.
International Publication No. WO 2006/038729 A1 Pamphlet Yankner, BA et al., Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. (1989) Science. 245 (4916): 417-20. Yankner, BA, Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. (1990) Science. 1990 250 (4978): 279-82. Schenk, D., et al. Immunization with amyloid b-attenuates Alzheimer-disease-like pathology in the PDAPP mouse. (1999) Nature. 400, 173-6. Nicoll JAR, Wilkinson D, Holmes C, Steart P, Markham H & Weller RO. (2003) Nature Med. 9: 448-452. Neuropathology of human Alzheimer disease after immunization with amyloid- peptide: a case report. DeMattos et al. (2002) Science 295: 2264-7 .; Pfeifer, M. et al. Cerebral hemorrhage after passive anti-Aβ immunotherapy. (2002) Science 298: 1379-. Saido TC, Iwatsubo T., Mann DM, Shimada H., Ihara Y., Kawashima S. Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3 (pE), in senile plaques. (1995) Neuron 14 ( 2), 457-466. Arai, T., Akiyama H., Ikeda K., Kondo H., Mori H. Immunohistochemical localization of amyloid beta-protein with amino-terminal aspartate in the cerebral cortex of patients with Alzheimer's disease. (1999) Brain Res 823 (1 -2), 202-206.

  An object of the present invention is to provide a new antigen molecule for vaccine therapy for amyloid-related diseases or a new antibody for indirect immunotherapy for amyloid-related diseases.

The present invention provides the following as means for solving the above problems.
(1) A synthetic peptide consisting of the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence containing at least 5 amino acid residues at the amino terminus of SEQ ID NO: 1, wherein amino acid residue Xaa is one or more arbitrary amino acid residues, and derivatives thereof Or an amyloid protein mimetic that is a pharmacologically acceptable salt thereof.
(2) The amyloid protein mimic of the invention (1), wherein the amino acid residue Xaa in SEQ ID NO: 1 is Met.
(3) A synthetic peptide consisting of the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence containing at least 5 amino acid residues at the amino terminus of SEQ ID NO: 2, wherein amino acid residue Xaa is one or more arbitrary amino acid residues, and derivatives thereof Or an amyloid protein mimetic that is a pharmacologically acceptable salt thereof.
(4) The amyloid protein mimic of the invention (3), wherein the amino acid residue Xaa in SEQ ID NO: 2 is Met.
(5) A polynucleotide encoding the synthetic peptide according to any one of the inventions (1) to (4).
(6) An antibody that specifically recognizes the amyloid protein mimetic according to any one of the inventions (1) to (4).
(7) A therapeutic drug for amyloid-related diseases, comprising as an active ingredient the amyloid protein mimic according to any one of the inventions (1) to (4).
(8) A therapeutic agent for amyloid-related diseases, wherein the polynucleotide according to the invention (5) is in a state capable of being expressed in somatic cells.
(9) A therapeutic drug for amyloid-related diseases comprising the antibody according to the invention (6) as an active ingredient.

  In the present invention, “protein” and “peptide” mean a molecule composed of a plurality of amino acid residues linked to each other by peptide bonds.

  Furthermore, in the present invention, the term “amyloid-related disease” means, for example, Alzheimer's disease or Down's disease, a disease in which amyloid protein is known to be directly or indirectly involved in the pathogenesis, or its possibility is suspected, And refers to diseases in which amyloid protein is found in nerve lesions.

  Other terms and concepts in the present invention are defined in detail in the description of the embodiments and examples of the invention. The terms are basically based on the IUPAC-IUB Commission on Biochemical Nomenclature, or based on the meanings of terms commonly used in the field. Various techniques used for carrying out the invention can be easily and surely implemented by those skilled in the art based on known literatures and the like, except for the techniques that clearly indicate the source. For example, genetic engineering and molecular biology techniques are described in J. Sambrook, EF Fritsch & T. Maniatis, "Molecular Cloning: A Laboratory Manual (2nd edition)", Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (1989) DM Glover et al. Ed., "DNA Cloning", 2nd ed., Vol. 1 to 4, (The Practical Approach Series), IRL Press, Oxford University Press (1995); Ausubel, FM et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York, NY, 1995; edited by the Japanese Biochemical Society, “Sequel Biochemistry Experiment Course 1, Genetic Research Method II”, Tokyo Chemical Doujin (1986); Laboratory Lecture 2, Nucleic Acid III (Recombinant DNA Technology) ", Tokyo Chemical Doujin (1992); R. Wu ed.," Methods in Enzymology ", Vol. 68 (Recombinant DNA), Academic Press, New York (1980); R. Wu et al. Ed., "Methods in Enzymology", Vol. 100 (Recombinant DNA, Part B) & 101 (Recombinant DNA, Part C), Academic Press, New York (1983); R. Wu et al. ed., "Methods in Enzymology", Vol. 15 3 (Recombinant DNA, Part D), 154 (Recombinant DNA, Part E) & 155 (Recombinant DNA, Part F), Academic Press, New York (1987), etc. It can be carried out by substantially the same method or modification method. The pharmaceutical preparation of the present invention can be prepared by the method described in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990, etc., or the method described in the literature cited therein or substantially the same. In general, it can be carried out by the same method or modification method.

  In light of related research findings, the present inventor has confirmed that when amyloid protein is used as an antigen, antibodies that react with multiple epitopes (antigen recognition sites) are induced and produced in vivo. As a result of overlapping, it was found that the introduction of a non-natural antigen molecule that does not exist in vivo reduces the antibody activity induced by an epitope that causes a side effect, thereby completing the present invention.

  That is, the amyloid protein mimics of the inventions (1) to (4) are vaccine components (antigen molecules) that can reduce side effects for vaccine therapy against amyloid-related diseases.

  The polynucleotide of the invention (5) serves as an antigen-expressing molecule (DNA vaccine) for vaccine therapy against amyloid-related diseases.

  Furthermore, the antibody of the invention (6) is used as an antibody for indirect immunotherapy for amyloid-related diseases.

  One form in the amyloid protein mimic of the present invention is a synthetic peptide consisting of the amino acid sequence of SEQ ID NO: 1 (hereinafter sometimes referred to as “Aβ [-1-42]”), and another form is A synthetic peptide comprising the amino acid sequence of SEQ ID NO: 2 (hereinafter sometimes referred to as “Aβ [-1-40]”). The first position Xaa in SEQ ID NOs: 1 and 2 is an arbitrary amino acid residue of 1 or more (preferably 1 to 3). In particular, Met which is an amino acid residue immediately before amyloid protein in APP protein (SEQ ID NO: 3) is also preferable.

  Yet another embodiment of the present invention is a “single-chain peptide” comprising at least 5 amino acid sequences on the amino terminal side of SEQ ID NO: 1 or 2. That is, for an antibody having a short peptide as an antigen, for example, Biochem. J., 1990, Vol. 266, p. 497-504 (Ser-Glu-Asn-Tyr-Lys-Asp-Asn Anticytochromic P-450IA2 antibody), Biochem. J., 1992, Vol.288, p.195-205 (Lys-Lys-Asn-Gly-Arg-Ile-Leu-Thr-Leu-Pro-Arg) (Anti-insulin β-subunit monoclonal antibody prepared using -Ser-Asn-Pro-Ser as an antigen) and the like are known (In addition, Molecular and Cellular Biology, 1988, Vol.8, p.2159-2163, Cell, 1989, Vol.58, p.945-953). Therefore, even a single-chain peptide consisting of a continuous sequence in the above-mentioned range of SEQ ID NO: 1 or 2 can function as an antigen molecule for vaccine therapy, and can also function as an immunogen for producing antibodies for indirect immunotherapy. .

  The synthetic peptide of the present invention can be carried out, for example, according to the examples described later, and is a well-known method such as Boc (t-butyloxycarbonyl) reaction, DMSO oxidation, alkaline reaction, acidic reaction, epoxidation reaction. , Silica gel column chromatography, alkylation reaction, saponification reaction, heating reaction, decarboxylation reaction, condensation reaction, reverse phase high performance liquid chromatography and the like can be appropriately combined. In addition, for example, amino acid residues constituting the mutant amyloid protein are sequentially reacted, and the efficiency and purity of the reactants are appropriately tested. Furthermore, the synthesized peptide may be changed by normal temperature, high temperature, freeze-thaw treatment, etc. for various times. Specifically, for example, Merrifield, RBJ Solid phase peptide synthesis I. The synthesis of tetrapeptide. J. Amer. Chem. Soc. 85, 2149-2154, 1963; Fmoc Solid Phase Peptide Synthesis. A Practical Approach. Chan, WC and Can be performed according to White, PD, Oxford University Press, 2000.

  Yet another form of the synthetic peptide of the present invention is a “peptide derivative”. This derivative can be modified to promote synthesis and purification, to promote physical and chemical stabilization, stability and instability to metabolism in vivo, activation modification such as conditioning, and brain It may contain a control modification that increases and decreases the organ transportation efficiency including passage through the blood vessel barrier. As the regulatory modification herein, a sequence consisting of 11 amino acids of Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg (SEQ ID NO: 4) (Schwarze, SR, Ho, A Vocero-Akbani, A. & Dowdy, SF In vivo protein transduction: Delivery of a biologically active protein into the mouse Science 285: 1569-1572). By including this regulatory sequence linked to the N-terminal side by a peptide bond, the synthetic peptide is facilitated to cross the blood brain barrier and can reach the target site in the brain with better efficiency.

  Other modifications in peptide derivatives include acetylation, acylation, ADP-ribosylation, amidation, flavin covalent bond, heme moiety covalent bond, nucleotide or nucleotide derivative covalent bond, lipid or lipid derivative covalent bond, Phosphatidylinositol covalent bond, cross-linking, cyclization, disulfide bond, demethylation, cross-linking covalent bond formation, cystine formation, pyroglutamate formation, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodine , Methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, lipid binding, sulfation, selenoylation and the like. More specifically, the peptide derivative functions as a side chain of a residue or an N-terminal group or C-terminal group as long as the activity of the synthetic peptide is not destroyed and the composition containing the peptide is not toxic. It can be prepared as a sex group. For example, derivatives containing polyethylene glycol side chains that extend the survival of synthetic peptides in body fluids, or amides or acyls of carboxyl groups by reacting with aliphatic esters of carboxyl groups, ammonia, or primary or secondary amines N-acyl derivatives of free amino groups of amino acid residues formed with a moiety (eg alkanoyl or carbocyclic aroyl group) or free hydroxyl groups formed with acyl moieties (eg ceryl or threonyl residues) O-acyl derivatives of the hydroxyl group).

  Yet another form of the synthetic peptide of the present invention may be a pharmacologically acceptable “salt”. This salt means both a carboxyl group salt and an amino acid addition salt of a synthetic peptide. Salts of carboxyl groups can be formed by methods known in the art, such as inorganic salts such as sodium, calcium, ammonium, iron or zinc, and triethanolamine, arginine or lysine, piperidine, procaine, etc. Salts with organic bases such as formed with simple amines are included. Acid addition salts include, for example, salts with mineral acids such as hydrochloric acid or sulfuric acid and salts with organic acids such as acetic acid or oxalic acid. Of course, any such salt is premised on having substantially the same activity (antigenicity) as the synthetic peptide.

  The polynucleotide of the present invention is characterized by encoding the synthetic peptide. Such polynucleotides are based on the amino acid sequence of SEQ ID NO: 1 or 2, based on literature (eg, Carruthers (1982) Cold Spring Harbor Symp. Quant. Biol. 47: 411-418; Adams (1983) J. Am. Chem. Soc. 105: 661; Belousov (1997) Nucleic Acid Res. 25: 3440-3444; Frenkel (1995) Free Radic. Biol. Med. 19: 373-380; Blommers (1994) Biochemistry 33: 7886-7896; Narang ( 1979) Meth. Enzymol. 68:90; Brown (1979) Meth. Enzymol. 68: 109; Beaucage (1981) Tetra. Lett. 22: 1859; US Pat. No. 4,458,066). It can be synthesized in vitro by synthetic techniques.

  This polynucleotide is used not only as a material for genetically engineering the above synthetic peptide, but also for expressing the synthetic peptide in vivo and functioning as an antigen molecule for in vivo antibody production. it can. That is, it may be formulated for use in a DNA vaccine method (see, for example, US Pat. No. 5,580,859) in which a polynucleotide is introduced into the body as “naked DNA”, or in the form of a recombinant viral vector.

  The antibody of the present invention can be prepared using the above amyloid protein mimic as an antigen. That is, immunity induction of a humoral response and / or a cellular response to an antigen is carried out with the amyloid protein mimic of the present invention as an antigen alone or in the presence or absence of an adjuvant in the state of binding or coexisting with a carrier. Implemented by:

  More specifically, the antibody was prepared by immunizing a mouse with a Freund complete adjuvant suspension of the above amyloid protein mimic, and then immunizing a suspension that had been replaced with Freund incomplete adjuvant one month later. The same immunization operation can be repeated after 7 days. Alternatively, immunity can be induced by immunostimulating lymphocytes or their precursor cells under culture conditions. The carrier is not particularly limited as long as it does not adversely affect the host itself, for example, cellulose, physiological saline, buffered physiological saline, dextrose, water, glycerol, ethanol, polymerized amino acid, albumin and mixtures thereof. However, the present invention is not limited to this. As the animal to be immunized, a mouse, rat, rabbit, goat, horse, cow or the like is preferably used. The polyclonal antibody is obtained as a serum by a method known per se and by an antibody recovery method from the serum. A preferable means includes immunoaffinity chromatography.

  Monoclonal antibody production is performed by recovering a tissue (eg, spleen or lymph node) or cultured cells containing antibody activity from the immunized animal, and transferring it to a known permanent proliferative cell (eg, myeloma strain such as P3X63Ag8 strain). It is carried out by introducing the transformation means. For example, a hybridoma prepared from the antibody-producing cells and the permanently proliferating cells is cloned, a hybridoma producing an antibody that specifically recognizes the amyloid protein mimic according to the present invention is selected, and a culture solution of this hybridoma Recover antibody from. Examples include the hybridoma method (Kohler G. and Milstein C. (1975) Nature 256, 495-497), the trioma method (Kozbor et al. Immunology Today (1983) 4: 72), and the EBV method (Cole et al. There are various techniques as described in Monoclonal antibodies and cancer therapy, Alan R. Liss, Inc., (1985): 77-96).

  The antibody thus obtained is used as a drug component for indirect immunotherapy for amyloid-related diseases.

  The drug of the present invention is formulated by mixing the amyloid protein mimetic, polynucleotide, and antibody with the pharmacologically acceptable carrier according to the therapeutic purpose (vaccine therapy, indirect immunotherapy). can do. The carrier can be appropriately selected from a wide range depending on the administration form of the drug. For example, oral liquid preparations such as suspensions and syrups include sugars such as water, sucrose, sorbitol, and fructose, glycols such as polyethylene glycol, oils such as sesame oil and soybean oil, alkyl parahydroxybenzoates, and the like. And other flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets are excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropyl It can be formulated using a binder such as cellulose and gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin. Furthermore, an injection solution can be formulated using a carrier comprising a salt solution, a glucose solution, a mixture of salt water and a glucose solution, various buffers, or the like. Alternatively, it may be formulated in a powder state and mixed with the liquid carrier at the time of use to prepare an injection solution.

EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated further in detail and concretely, this invention is not limited to the following examples.
Example 1: Molecular form of amyloid protein mimetic peptide Amyloid proteins (Aβ [1-28], Aβ [1-40], Aβ [1-42], Aβ [25-35]) are commercially available products (American Peptide Company, Inc. CA, PEPTIDE INSTITUTE, Inc., Mihoh, Osaka), and the partial sequence of peptides Aβ [1-5] and Aβ [p3-8] (the amino terminus has a pyroglutamine structure with an amino group cyclized) Amyloid protein mimetic peptides Aβ [-1-40] and Aβ [-1-42] with methionine added to the amino terminus were prepared by the Amo peptide synthesizer using the Fmoc method and purified by reverse phase HPLC. used.

Amyloid protein mimetic peptide (Aβ [-1-40]) was dissolved in PBS and heated at 37 ° C. for 3 days. After adding a part of it to 200 mesh with a collodion membrane, negative staining was observed by uranium staining. Figure 1 shows the results. The fibrillar morphology formed from the amyloid protein mimetic peptide (Aβ [-1-40]) is the same as that of normal amyloid protein (Aβ [1-40] or Aβ [1-42]). Thus, it was confirmed that the morphological properties of the mimetic peptide were not different from the wild type amyloid protein.
Example 2: Characteristics of antibody and amino-terminal antibody reaction against amyloid protein mimetic peptide An antibody having an amyloid protein mimetic peptide (Aβ [-1-40]) as an antigen was prepared. For this purpose, mice were immunized with a suspension of synthetic peptide and Freund complete adjuvant dissolved in PBS. One month later, the suspension changed to Freund incomplete adjuvant was immunized, and the same immunization was repeated 7 days later. 100 microliters of blood was collected from the tail vein of the mouse, and its reactivity was confirmed. That is, prepare multiple PVDF membrane strips spotted with mimetic peptides (Aβ [-1-40]), block with PBS containing 20% bovine serum after drying, and then separate each membrane strip individually in a small reaction box The mouse serum (# 1 to # 8) diluted 150 times was allowed to react. The membrane strip was then confirmed by ECL color development using peroxidase-labeled anti-mouse IgG antibody as the secondary antibody.

  The membrane strip was dotted with 10 ng, 2 ng, 1 ng, 0.1 ng, PBS, bovine albumin (BSA) from the left on the PVDF membrane strip. As shown in FIG. 2, it was confirmed that the antiserum diluted 150 times required an antigen amount of at least 1 ng and was not detected with an antigen amount less than that. It does not react with PBS or bovine albumin (BSA).

  Next, it was confirmed that the prepared antibody recognizes the amino terminus. For this purpose, several synthetic peptides with different amino terminus were used. That is, a synthetic peptide (a: Aβ [1-5], b: Aβ [1-28], c: Aβ [1-40], d: Aβ whose amino terminus is the amino terminus of normal amyloid protein [1-42]), synthetic peptides without aspartic acid (e: Aβ [25-35], mimetic peptides (f: Aβ [-1-40], g: Aβ [-1-42]), and h: Dots each 5ng of BSA protein on the PVDF membrane (Fig. 3A), anti-peptide (Aβ [-1-40]) antibody (Fig. 3B) and anti-peptide (Aβ [1-5]) antibody ( The immunoreactivity was observed using FIG. 3C).

  Since anti-peptide (Aβ [1-5]) antibodies mainly recognize aspartic acid (Asp), which is the terminal amino acid of amyloid protein, all peptides (a, b, c, d) that start with this amino acid It does not recognize amyloid protein mimetic peptides (f, g).

  On the other hand, an antibody produced by using an amyloid protein mimetic peptide (Aβ [-1-40]) in which another amino acid is added to the amino terminus of amyloid protein as an antigen is a single-chain peptide (a, b, e) and Was not reacting. However, it also reacted with synthetic peptides (c: Aβ [1-40], d: Aβ [1-42]) corresponding to the full length of wild-type amyloid protein. This is because the anti-mimetic peptide (Aβ [-1-40]) antibody is a polyclonal antibody, and the amino acid sequence and structure of the amyloid protein other than its amino terminus, as well as the three-dimensional structure such as fibrous or oligomeric, are common. It shows that the epitope is an antigenic site other than the amino terminus.

  Based on the above results, an antibody that uses an unnatural amyloid protein mimetic peptide that does not exist in the body as an antigen reacts with an antigen molecule that contains an amino acid residue at the amino terminus. Since it does not exist, it can be seen that it does not react with in vivo molecules other than foreign antigens. That is, when the amino terminus is an epitope that causes side effects, the use of a mimetic peptide can significantly reduce the possibility of side effects.

It is a microscope image which shows the structure of an amyloid protein mimetic peptide (A (beta) [-1-40]). The lower right scale bar indicates 100 nm. It is the result of the dot test of the antibody produced by making the mimic peptide (Aβ [-1-40]) an antigen. It is the result of the dot test which tested the reactivity with respect to each synthetic peptide by an anti-peptide (A (beta) [-1-40]) antibody and an anti-peptide (A (beta) [1-5]) antibody.

Claims (9)

  A synthetic peptide consisting of the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence comprising at least 5 amino acid residues at the amino terminus of SEQ ID NO: 1, wherein amino acid residue Xaa is one or more arbitrary amino acid residues, or derivatives thereof An amyloid protein mimetic that is a pharmacologically acceptable salt of   The amyloid protein mimic of claim 1, wherein amino acid residue Xaa in SEQ ID NO: 1 is Met.   A synthetic peptide comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence containing at least 5 amino acid residues at the amino terminus of SEQ ID NO: 2, wherein amino acid residue Xaa is one or more arbitrary amino acid residues, or derivatives thereof An amyloid protein mimetic that is a pharmacologically acceptable salt of   4. The amyloid protein mimic of claim 3, wherein amino acid residue Xaa in SEQ ID NO: 2 is Met.   A polynucleotide encoding the synthetic peptide according to any one of claims 1 to 4.   An antibody that specifically recognizes the amyloid protein mimetic according to any one of claims 1 to 4.   An amyloid-related disease therapeutic agent comprising the amyloid protein mimic according to any one of claims 1 to 4 as an active ingredient.   A therapeutic agent for amyloid-related diseases, wherein the polynucleotide according to claim 5 is in a state capable of being expressed in somatic cells.   A therapeutic agent for amyloid-related diseases comprising the antibody according to claim 6 as an active ingredient.