Method of treating alzheimer's disease

FIELD: medicine.

SUBSTANCE: invention is related medicine and concerns applications of antibodies specifically recognising any prevailing variants of beta-amyloid peptide, Aβ40 and Aβ42, in preparation of a drug applied for prevention and-or treatment of Alzheimer's disease.

EFFECT: invention provides prevention of progression or reduction of symptoms, and/or decrease in amyloid deposition in an individual when administering an immunostimulating dose of peptide or specific antibody.

7 cl, 3 ex, 2 dwg

 

The technical field to which the invention relates.

The present invention relates to a method of treatment and/or prevention of diseases associated with amyloid deposits, which include Alzheimer's disease.

The level of technology

Certain facts are known about the biochemical and metabolic phenomena associated with the presence of Alzheimer's disease (AD). Two structural and histopathological changes observed in the brain of cases of AD are neurofibrillary beams (NFT) and amyloid deposits. Vnutrineironalnah neurofibrillary beams are also present in other neurodegenerative diseases, but the presence of amyloid deposits in vnutrineironalnah space (naranya plaques)and in close proximity to the microvessels (vascular plaques), as it seems, is a characteristic feature of AD. Of them naranya plaques seem to be the most common (Price, D.L., and co-workers. Drug Development Research (1985) 5:59-68).

The main data component of amyloid plaques is a peptide of 40-42 amino acids, called amyloid peptide β4.

Amyloid peptide β4 is a polypeptide, which is formed as a result of proteolysis of membrane glycoproteins, denoted proteins-amyloid precursor peptide β4 (Papp). Data protein precursor amyloid peptide consists of from 695 to 770 amino acids, all of these are encoded in the same genome.

Identified two main options amyloid peptide β4, peptide β40 and β42 containing 40 and 42 amino acids, respectively, which have different tissue distribution both in physiological and in pathological conditions. Variant of 42 amino acids is the predominant form in amyloid plaques, localized in the brain of patients with AD.

Up to the present time offered a variety of possible solutions to ensure a possible vaccine against AD.

In the European patent EP 526511 proposed introduction of homeopathic doses β patients with pre-installed AD. However, because of the applied dose levels of circulating endogenous β in plasma vary considerably and, thus, the benefits of such therapy are expected.

Schenk et al. (Nature 1999; 400: 173-177) describe the immunization β42 PDAPP transgenic mice, which hyperexpression mutant RDAs person, preventing thereby the formation of amyloid plaques, the degeneration of neurites and astroglia.

In the application WO 9927944 (Schenk D.) described the treatment of AD by the introduction of patient β42.

Phase III clinical trials in 360 patients with a diagnosis of moderate and moderate AD in 4 European countries and in the United States, in which amyloid peptide β42 was used as antigen, was beautifully is placed after reports of encephalitis in some patients (Scrip Daily Online, 25 Feb 2002, S007455320, The Scientist 16[7]:22, April 1, 2002).

Among some of the possible problems that, when used as a vaccine endogenous protein (or a protein naturally present in the animal, which Vaccinium), as in the case of peptide β42 when the body responds by making antibodies against β42 and against smaller fractions, which may have also not yet known physiological functions, you can mention the problem of the possible development of autoimmune diseases caused by the production of antibodies against the endogenous protein, the difficulty in the development of the immune response due to the inability of the immune system to recognize endogenous antigens and the possible development of acute inflammatory response.

The present invention is the treatment of Alzheimer's disease and other amyloid diseases by administration of a peptide, C-terminal part β conjugated with protein, where in the preferred implementation of the present invention, this protein represents hemocyanin mollusk fissurella.

Disclosure of inventions

The present invention relates to a vaccine for the prevention and/or treatment of Alzheimer's disease and other related amyloid diseases.

In accordance with a preferred implementation of the present invention features a vaccine to prevent the/or treatment of Alzheimer's disease and other related diseases, which overcomes the drawbacks associated with peptides, proteins or endogenous immunogenum.

Examples of other diseases characterized by amyloid deposits are Icelandic inherited syndrome, multiple myeloma and spongiform encephalitis, including disease of Creutzfeldt-Jakob disease.

Induction of an immune response can be active, for example, when an immunogen is administered to the production of antibodies that interact with β the patient, or passive, for example, when injected antibody, which itself interacts with β the patient.

For the objectives of the present invention, the following terms are defined as follows.

The term “related amyloid disease” includes diseases associated with accumulation of amyloid, which can be limited to one authority, local amyloidosis, or distributed in several organs, systemic amyloidosis. Secondary amyloidosis may be associated with chronic infections (such as tuberculosis), familial Mediterranean fever (FMF) and other types of systemic amyloidosis found in patients with prolonged treatment with hemodialysis. Local forms of amyloidosis include, but are not limited to the above, type II diabetes and any other related to this disease, neurodegenerative disease spongiform encephalitis, to the conditions spongiform encephalitis, the disease of Creutzfeldt-Jakob disease, Alzheimer's disease, cerebral amyloid angiopathy.

The term “passive immunization” is used in relation to the introduction of antibodies or their fragments to the individual to create immunity in the individual.

In the first aspect of the invention includes the use of a peptide that acts or as an immunogen or as antibodies, in the preparation of medicines for the prevention and/or treatment of diseases characterized by accumulation of amyloid deposits. These methods consist in the induction of an immune response against a peptide component of an amyloid deposits in a patient. This induction can be active with the introduction of the immunogen or passive with the introduction of the antibody or active fragment or derivative of the antibody.

In a preferred implementation of the present invention the disease is a disease of Alzheimer's.

Received medication may be used in asymptomatic patients and in patients exhibiting symptoms of the disease.

In accordance with the present invention, compositions capable of inducing an immune response directed against specific components of amyloid plaques, is effective in the treatment or prevention of diseases associated with amyloid deposits. In particular, ACC is accordance with an aspect of the present invention, it is possible to prevent the progression or reduce the symptoms and/or reduce the deposition of amyloid in an individual when entering the patient immunostimulatory dose of peptide or antibody obtained against him.

In accordance with an aspect of the present invention, antibodies are produced by immunizing mammals or birds by using as immunogen peptide conjugated to a protein.

In accordance with a preferred implementation of the present invention, mammals, used for immunization may constitute ruminants, horses, lagomorphs, carnivores, primates, or any other animal, which you can get adequate amount of serum to separate her antibodies. Among birds, used for immunization, applicants may be noted, but not in terms of limitations, among other Galliformes, Anseriformes and Serves.

In accordance with a preferred implementation of the present invention proposed the use of a peptide conjugated to a protein, which acts as an immunogen for the production of antibodies that can specifically recognize any of the prevailing variants of beta-amyloid peptide β40 or β42 in preparation of medicines for the prevention and/or treatment of diseases characterized by the accumulation of AMI is odnyh deposits in the brain of the patient.

In accordance with the preferred implementation of the present invention, the protein used for conjugation with the peptide is a protein mollusk fissurella.

In accordance with the preferred implementation of the present invention, the peptide is selected from the group consisting of peptide SEQ ID No 1, peptide SEQ ID No 2, peptide SEQ ID No 3, peptide SEQ ID No 4, peptides resulting from shortening by removing amino acid residues from the N-end and/or the ends of the SEQ ID No 1, SEQ ID No 2, SEQ ID No 3 or SEQ ID No 4, and peptides obtained by lengthening by adding the residue to any of the peptides of SEQ ID No 1, SEQ ID No 2, SEQ ID No 3 or SEQ ID No 4.

In accordance with another preferred implementation, the peptide is selected from the group which includes the peptide SEQ ID No 1, a peptide with the sequence obtained by deletion of residues N-terminal and/or C-terminal amino acids of SEQ ID No 1, and the peptides obtained by adding to any of the preceding sequences of amino acid residues required for conjugation with protein.

In another preferred implementation of the present invention the peptide is selected from the group consisting of peptide SEQ ID No 2, peptides with the sequence obtained by deletion of residues N-terminal and/or C-terminal amino acids of SEQ ID No 2, and peptides produced from the s by adding to any of the preceding sequences amino acid residues, required for conjugation with protein.

In another preferred implementation of the present invention the peptide is selected from the group consisting of peptide SEQ ID No 3, peptides with the sequence obtained by deletion of residues N-terminal and/or C-terminal amino acids of SEQ ID No 3, and peptides obtained by adding to any of the preceding sequences of amino acid residues required for conjugation with protein.

In another preferred implementation of the present invention the peptide is selected from the group consisting of peptide SEQ ID No 4, peptides with the sequence obtained by deletion of residues N-terminal and/or C-terminal amino acids of SEQ ID No 4, and peptides obtained by adding to any of the preceding sequences of amino acid residues required for conjugation with protein.

In accordance with another implementation of the present invention, the application of the antibody or active fragment or derivative of the antibody, which specifically recognizes any of the prevailing variants of beta-amyloid peptide β40 or β42 in preparation of medicines for the prevention and/or treatment of diseases characterized by the accumulation of amyloid deposits in the brain of the patient.

In accordance with preferred the implementation of the present invention, the antibody or active fragment or derivative of the antibody, which specifically recognizes any of the prevailing variants of peptide β receive against a peptide selected from the group consisting of SEQ ID No 1, SEQ ID No 2, SEQ ID No 3, SEQ ID No 4, optional shortened by deleting amino acid residues from the N-end and/or With all, and need not be elongated by adding amino acid residues that are suitable for conjugation with protein.

In another preferred implementation, the specified antibody or active fragment or derivative of the antibody obtained by immunization of mammals or birds peptides selected from the group that includes the peptide SEQ ID No 1, a peptide with the sequence obtained by deleting N-terminal and C-terminal amino acid residues of SEQ ID No 1, and the peptides obtained by adding to any of the preceding sequences of amino acid residues required for conjugation with protein.

In another preferred implementation, the specified antibody or active fragment or derivative of the antibody obtained by immunization of mammals or birds peptides selected from the group that includes the peptide SEQ ID No 2, peptides with the sequence obtained by deleting N-terminal and C-terminal amino acid residues of SEQ ID No 2, the peptides, obtained by adding to any of the preceding sequences of amino acid residues required for conjugation with protein.

In another preferred implementation, the specified antibody or active fragment or derivative of the antibody obtained by immunization of mammals or birds peptides selected from the group that includes the peptide SEQ ID No 3, peptides with the sequence obtained by deleting N-terminal and C-terminal amino acid residues of SEQ ID No 3, and the peptides obtained by adding to any of the preceding sequences of amino acid residues required for conjugation with protein.

In another preferred implementation, the specified antibody or active fragment or derivative of the antibody obtained by immunization of mammals or birds peptides selected from the group that includes the peptide SEQ ID No 4, peptides with the sequence obtained by deleting N-terminal and C-terminal amino acid residues of SEQ ID No 4, and the peptides obtained by adding to any of the preceding sequences of amino acid residues required for conjugation with protein.

In this specification, amino acids reduce using single-letter codes used in this field, as follows:

A=Ala alanine

C=Cys = cysteine

D=Asp = aspartic acid

E=Glu = glutamic acid

F=Phe = phenylalanine

G=Gly = glycine

H=His = histidine

I=Ile = isoleucine

K=Lys = lysine

L=Leu = leucine

M=Met = methionine

N=Asn = asparagine

P=Pro = Proline

Q=Gin = glutamine

R=Arg = arginine

S=Ser = serine

T=Thr = threonine

V=Val = valine

W=Trp = tryptophan

Y=Tyr = tyrosine

The sequence described earlier in this invention and identified as SEQ ID No 1, SEQ ID No 2, SEQ ID No 3, SEQ ID No 4, correspond to the following amino acid sequences:

SEQ ID NO 1 LVFFAEDV

SEQ ID NO 2 GLMVGGVV

SEQ ID NO 3 GLMVGGVVIA

SEQ ID NO 4 RHDSGYEVHHQK

The antibodies raised against these peptides are given codes SAR-1, SAR-2, SAR-3 and e-4 in accordance with what is specified below:

SEQ ID NO 1 SAR-2

SEQ ID NO 2 SAR-3

SEQ ID NO 3 SAR-4

SEQ ID NO 4 SAR-l

Information related to the identification of peptide sequences described in the present invention, which is appended to this document in a format for computer reading, is a list of sequences that are present in this document.

EXAMPLES

The present invention is illustrated by the following examples.

Example 1. Obtaining polyclonal antibodies

By immunization of new Zealand white rabbits received four polyclonal antibodies against h for the four peptides conjugated to KLH, which were used as immunogen.

Each immunogen was injected with two rabbits, five injections each rabbit: the first intradermal injection of the conjugate peptide-KLH in SFR, emulsified in complete Freund's adjuvant, and four additional intramuscular injection as a maintenance dose at 14, 28, 49 and 80 days of the same conjugate the peptide-KLH in SFR, but this time emulsified in incomplete Freund's adjuvant, the selection of blood for 90 days to determine the presence of antibodies.

After collection, the blood was separated serum and produced a preliminary purification by desalting, and then the antibody was purified by affinity for the matrix, containing 1.5 ml of activated substances EMD-Epoxy (Merck), to which was added 5 mg of the corresponding peptide. Purified fractions were preserved in 0.1% BSA (Sigma) and kept at 4°C, and as a cryoprotectant you can add 20-50% glycerol.

Example 2. The Western blot turns to β

1. Electrophoresis

Used way Lemli described in Current Protocols in Molecular Biology, John Wiley and Sons, New York, 1998, modified to improve the separation of small peptides.

Used the device Miniprotean 3 from Bio-Rad.

Used 15% acrylamide gel, mixed with the following components:

The original solutions Separating gel (15%)Concentrating gel
40% acrylamide3, 75 ml500 ál
Tris 3 M, pH=8,453, 3 ml250 ál
Glycerin1, 05 ml-
Water1, 9 ml4,2 ál
DDS-Na 20%50 µl18,6 ál
APS 10%50 µl25 ál
TEMED10 ál5 ál

Used the original solutions of peptides β40 and 42 with a concentration of 1 mg/ml (dissolved in SFR). Selected the necessary amount of data solutions for each of the samples and brought up to 20 μl with SBLT (SBL + Tris base 2 M). The samples were then boiled for 5 minutes for denaturation of peptides and the possible removal of proteases.

The middle of the cell was filled with cathode buffer and the environment - anode buffer, and the composition of these buffers was as follows:

The anode buffer

24.2 g Tris base (final concentration 0.2 M)

Razbam the th to 1 l H 2About

To bring the pH to 8.9 concentrated model HC1

Store at 4°C for up to 1 month.

Cathode buffer

12,11 g Tris base (final concentration 0.1 M)

17,92 g Tricine (final concentration 0.1 M)

1 g DDS-Na (final concentration of 0.1%)

Dilute to 1 l H2O

Not to bring pH

Store at 4°C for up to 1 month.

Finally, the samples were introduced into the wells: 20 µl/well. Using Standard Polypeptide Kaleidoscope from Bio-Rad as a marker movement was started at low voltage (30 V) and then after about 1 hour of electrophoresis voltage was increased to 100 C.

2. Transfer to the membrane

Separated proteins in the gel were transferred to PVDF membrane using electroblotting. In the booklets for migration has posted the following.

Back - sponge - 3 sheets of Whatman paper (or filter paper - gel - membrane - 3 sheets of Whatman paper - sponge - side imprint.

After that, the cell was filled with buffer electroblotting:

Glycine 38 nm

Tris base 50 mm

Methanol 40%

The transfer was made within 2 hours at 200 mA. During the transfer buffer was stirred with a magnetic stirrer.

3. Incubation with antibodies

Antibodies and milk powder was dissolved in SFR-t (SFR+0.5% tween-20), leaching was also produced using SFR-T.

After transfer the membrane surface unit is listed a 5% solution of milk powder for 1 hour under stirring at room temperature (RT).

After that, the membrane was washed 2x5 minutes at RT.

Then it was incubated with the primary antibody (SAR-1, SAR-2, SAR-3 or e-4) for 1 hour at RT in a dilution of at least 1:500 in SFR-T.

The membrane was washed 3x10 min at RT. Then it was incubated with the secondary antibody: goat-HRP against rabbit for 1 hour at RT (1:10000 in all cases).

Again repeated wash the membrane 3×10 minutes at RT.

4. Color

After the last washing, the membrane was incubated with a solution chemoluminescence set using ECL kit+Plus from Pharmacia.

The membrane was wrapped in cellophane and exposed to film with a double emulsion (Hyperfilm MP from Amersham) for various periods of time from 30 seconds to 2 minutes.

Example 3. Immunohistochemistry with antibodies SAR-1, SAR-2, SAR-3 and SAR-4 tissue of the human brain

The tissue slices were fixed in paraffin according to the following stages:

a) fixation in neutral 10% formaldehyde;

b) dehydration through successive stages with increasing concentrations of alcohol;

c) wiring through xylene and paraffin, and the last stage is carried out in a furnace at 60-62°C;

d) obtaining paraffin blocks of sections 4 microns, which was mounted on the glass.

The slices were then deparaffinization wiring through the following solutions:

Xylene 100% 10 minutes

Xylene 100% 10 minutes

<> Ethanol 100% for 5 minutes

Ethanol 100% for 5 minutes

Ethanol 96% 5 minutes

Ethanol 90% in 5 minutes

Ethanol 70% 5 minutes

SFR 5 minutes ×3 times

Then they were processed as follows:

a) 96% formic acid for 3 minutes in a fume hood under stirring;

b) a quick water rinse;

c) washing SFR 2×5 minutes;

d) blocking of endogenous peroxidase for 15 minutes in a solution composed of 70 ml SFR, 30 ml of methanol and 1 ml of H2O g;

e) washing SFR 3×5 minutes;

f) washing SFR/T (0,5% Triton or tween-20 in SFR) 3×5 minutes;

(g) blocking of nonspecific binding with goat serum (normal goat serum)diluted 10:100 in SFR/T, within 2 hours;

h) incubation with the primary antibodies overnight at 4°C in a humid chamber:

Sar-1... a Dilution of 1:150 in SFR

Sar-2... a Dilution of 1:1500 in SFR

Sar-3... a Dilution of 1:1500 in SFR

Sar-4... a Dilution of 1:2000 in SFR;

i) washing SFR/T 3×5 minutes;

j) by incubation with secondary antibody (goat against rabbit)diluted 1:200 SFR, within 45 minutes;

(k) washing SFR 4×5 minutes;

l) incubation ABC (avidin-bioteknologi complex) Vector Labs in a dilution of 1:100 in SFR/T for 45 minutes in the dark when saving data conditions to completion of the development of painting;

m) washing SFR 3×5 minutes;

n) the expression in diaminobenzidine (DAB).

Time controlled the empirical the key under a stereoscopic microscope. For this, first of all, I made a wash in 0.5 M solution of Tris-HCl for 10 minutes under stirring, followed by incubation with diaminobenzidine substrate (DAB)dissolved in 0.05 M Tris-HCl, and which was added to 0.5 μl/ml of N2About2at 4°C. After the reaction was conducted three leaching in SFR at 4°C for 5 minutes each and then produced dehydration in ethanol at 70%, 90% and 100% for 2 minutes each time, the wiring through xylene for 4 minutes and then wiring through xylene for 2 minutes, after which the sections were mounted with Eukitt for examination under a microscope.

Sequence listing

Number of sequences: 4

Information about the sequence 1:

Sequence properties:

Length: 8

Type: amino acid

The molecule type: peptide

Source: Chemical synthesis

Description sequence:

SEQ ID NO 1

LeuValPhePheAlaGluAspVal
15is the

The sequence information 2:

Sequence properties:

Length: 8

Type: amino acid

The molecule type: peptide

Source: Chemical synthesis

Description sequence:

SEQ ID NO 2

GlyLeuMetValGlyGlyValVal
15

The sequence information 3:

Sequence properties:

Length: 10

Type: amino acid

The molecule type: peptide

Source: Chemical synthesis

Description sequence:

SEQ ID NO 3

GlyLeuMetValGlyGlyValValIle Ala
1510

The sequence information 4:

Sequence properties:

Length: 12

Type: amino acid

The molecule type: peptide

Source: Chemical synthesis

Description sequence:

SEQ ID NO 4

ArgHisAspSerGlyTyrGluValHisHisGinLys
1510

1. The use of a peptide conjugated to a protein, which deistvuet as an immunogen to generate antibodies, can specifically recognize any of the prevailing variants of beta-amyloid peptide β40 and β42 in preparation of medicines for the prevention and/or treatment of diseases characterized by the accumulation of amyloid deposits in the brain of a patient suffering from any of the diseases selected from Alzheimer's disease and cerebral amyloid angiopathy, characterized in that the peptide represents SEQ ID No 2.

2. The use according to claim 1, characterized in that the disease is a disease of Alzheimer's.

3. The use according to claim 1, characterized in that the disease is a cerebral amyloid angiopathy.

4. The use according to any one of the preceding paragraphs, characterized in that the protein is a protein mollusk fissurella (KLH).

5. The use of antibodies, or active fragment or derivative of the antibody, which specifically recognizes any of the prevailing variants of beta-amyloid peptide β40 and Aβ42 in preparation of medicines for the prevention and/or treatment of diseases characterized by the accumulation of amyloid deposits in the brain of a patient suffering from any of the diseases selected from Alzheimer's disease and cerebral amyloid angiopathy, and the antibody or its active fragment, or derivative of the antibody, which is passed specifically recognizes any of the prevailing variants of peptide β, obtained by immunization of mammals or birds peptide SEQ ID No 2.

6. The use according to claim 5, characterized in that the disease is a disease of Alzheimer's.

7. The use according to claim 5, characterized in that the disease is a cerebral amyloid angiopathy.



 

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12 cl

FIELD: veterinary science.

SUBSTANCE: invention relates to veterinary virology and biotechnology. The vaccine contains an active substance and a target additive. The vaccine active substance is represented by a mixture of avirulent refined antigen material from the VNIIZZh strain of cattle rednose virus, Herpesviridae family, Varicellavirus genus, collection of Federal State Institution "Russian National Research Institute for Control, Standardisation and Certification of Veterinary Preparations", "VNIIZZh-DEP", and of avirulent refined antigen material from the VNIIZZh strain of cattle coronavirus, Coronaviridae family, Coronavirus genus, collection of Federal State Institution "Russian National Research Institute for Control, Standardisation and Certification of Veterinary Preparations", "VNIIZZh-DEP", taken at a ratio of 1:1 and in quantities ensuring protective immune activity of each antigen in the animal organism after receipt of the target product injection. With the animals having been immunised the vaccine induces a high level of antigens against the pathogens of cattle rednose and coronoviral infection and is capable to protect varied age and sex group cattle livestock against the above diseases.

EFFECT: with the animals having been vaccinated immunity is generated within 10-15 days after the vaccine re-injection and sustains for at least 6 months.

12 cl, 6 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to agonists of neuropeptide-2 receptor with formula (I): Y-R1-R2-X-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-NH2(l), as well as their pharmaceutically acceptable salts, derivatives and fragments, in which substitutes assume values given in the description.

EFFECT: compounds and pharmaceutical compositions containing said compounds can be used to treat diseases which are modulated by neuropeptide-2 receptors, mainly obesity.

13 cl, 10 dwg, 1 tbl, 74 ex

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