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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
  • A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans

Definitions

• the present invention relates to a method of treatment and / or prevention of diseases associated with the presence of amyloid deposits, among which is Alzheimer's disease.
• AD Alzheimer's disease
• NFT neurofibrillar tangles
• amyloid deposits Intrauronale ⁇ neurofibrillar tangles are also present in other neurodegenerative diseases, but the presence of amyloid deposits both in intraneuronal spaces (neuritic plaques) and in the vicinity of the microvasculature (vascular plaques) seems to be characteristic of Alzheimer's disease.
• neuritic plaques appear to be the most frequent (Price, D.L., et al., Drug Development Research (1985) 5: 59-68).
• amyloid plaques The main component of these amyloid plaques is a 40-42 amino acid peptide called A ⁇ 4 amyloid peptide.
• the A ⁇ 4 amyloid peptide is a polypeptide originated by proteolysis from membrane glycoproteins called A ⁇ 4 amyloid peptide precursor proteins ( ⁇ APP). Being these proteins, precursors of the amyloid peptide, constituted by 695 to 770
• the 42 amino acid variant is the predominant form in the amyloid plaques located in brains of Alzheimer patients.
• EP526511 proposes the administration of homeopathic doses of A ⁇ to patients with pre-established AD. However, because the doses used hardly vary the levels of endogenous circulating A ⁇ in plasma, no therapeutic benefit is expected.
• Schenk et al. (Nature, 1999; 400: 173-177) describes the immunization with A ⁇ 42 of transgenic PDAPP mice, which overexpress human mutant APP, preventing the formation of amyloid plaques, neuritic dystrophy and astrogliosis.
• the present invention is directed to the treatment of Alzheimer's and other amyloid diseases by administration of a peptide, of the C-terminal part of A ⁇ , conjugated with a protein, which in a preferred embodiment of the present invention said protein is lapa hemocyanin ( KLH, Keyhole Limpet Hemocyanin in English).
• the present invention relates to a vaccine for the prevention and / or treatment of Alzheimer's disease and other related amyloid diseases.
• the invention provides a vaccine for the prevention and / or treatment of Alzheimer's disease and other related diseases, which overcomes the disadvantages associated with using endogenous peptides, proteins or immunogens.
• amyloid deposits examples include Islamic Hereditary Syndrome, multiple myeloma, spongiform encephalopathies, including Creutzfeldt-Jakob disease.
• the induction of an immune response can be active as when an immunogen is administered to induce antibodies that react with A ⁇ in a patient, or passive, such as when an antibody that reacts by itself with A ⁇ in a patient is administered.
• related amyloid diseases includes diseases associated with the accumulation of amyloid which may be restricted to one organ, localized amyloidosis, or diffused in several organs, systemic amyloidosis. Secondary amyloidosis can be associated with chronic infections (such as tuberculosis) or chronic inflammation (eg rheumatoid arthritis), Familial Mediterranean Fever (FMF) and other type of systemic amyloidosis found in patients on long-term hemodialysis treatment.
• chronic infections such as tuberculosis
• chronic inflammation eg rheumatoid arthritis
• Familial Mediterranean Fever Familial Mediterranean Fever
• Localized forms of amyloidosis include, but are not limited to, type II diabetes and any other disease related to it, neurodegenerative diseases with SCRAPIE, bovine spongiform encephalitis, Cretzf ldt-Jakob disease, Alzheimer's disease, cerebral amyloid angiopathy.
• passive immunization is used to refer to the administration of antibodies or fragments thereof to an individual with the intention of conferring immunity.
• the invention provides the use of either a peptide that acts as an immunogen or an antibody, in the preparation of a medicament for the prevention and / or treatment of a disease characterized by the accumulation of amyloid deposits.
• a peptide that acts as an immunogen or an antibody in the preparation of a medicament for the prevention and / or treatment of a disease characterized by the accumulation of amyloid deposits.
• These methods consist of the induction of an immune response against a peptide component of the amyloid deposits in the patient. Said induction can be active by administration of an immunogen or passive by administration of an antibody or an active fragment or derivative of an antibody.
• the disease is Alzheimer's disease.
• the medicine obtained can be used both in asymptomatic patients and in those who already show symptoms of the disease.
• compositions capable of eliciting an immune response directed against certain components of the amyloid plaques are effective for the treatment or prevention of diseases related to amyloid deposits.
• antibodies are obtained by immunization of mammals or birds, by using a peptide conjugated to a protein as an immunogen.
• the mammals used for their immunization can be ruminants, equidae, lagomorphs, carnivores, primates or any other animal that allows obtaining adequate amounts of serum to extract sufficient amount of antibody from it.
• the birds used for its immunization we can mention, not being considered in a limiting way, the galliformes, anseriformes and columbiformes, among others.
• a peptide conjugated to a protein that acts as an immunogen for the production of antibodies capable of specifically recognizing any of the predominant variants of the beta amyloid peptide A ⁇ 40 and A ⁇ 42 in the preparation of a medicament for the prevention and / or treatment of a disease characterized by the accumulation of amyloid deposits in the brain of a patient.
• the protein used for conjugation with the peptide is barnacle hemocyanin (KLH, Keyhole Limpet Hemocyanin in English).
• the peptide is selected from a group consisting of the peptide of SEQ ID NO 1, the peptide of SEQ ID NO 2, the peptide of SEQ ID NO 3, the peptide of SEQ ID NO 4, the peptides resulting from shortening by elimination of amino acid residues from the N-terminal and / or C-terminal ends of SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3 or SEQ ID NO 4 and the peptides resulting from lengthening by adding the appropriate amino acid residues to conjugate the protein to any of the peptides of SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3 or SEQ ID NO 4.
• the peptide is selected from the group consisting of the peptide of SEQ ID NO 1, the peptides with a sequence resulting from eliminating the N-terminal and / or C-terminal amino acid residues of SEQ ID NO 1 and the peptides resulting from adding to any of the preceding sequences, the amino acid residues necessary for protein conjugation.
• the peptide is selected from the group consisting of the peptide of SEQ ID NO 2, the peptides with a sequence resulting from eliminating the N-terminal and / or C-terminal amino acid residues of SEQ ID NO 2 and the peptides resulting from adding to any of the preceding sequences, the amino acid residues necessary for protein conjugation.
• the peptide is selected from the group consisting of the peptide of SEQ ID NO 3, the peptides with a sequence resulting from eliminating the N-terminal and / or C-terminal amino acid residues of SEQ ID NO 3 and the peptides resulting from adding to any of the preceding sequences, the amino acid residues necessary for protein conjugation.
• the peptide is selected from the group consisting of the peptide of SEQ ID NO 4, the peptides with a sequence resulting from eliminating the N-terminal and / or C-terminal amino acid residues of SEQ ID NO 4 and the peptides resulting from adding to any of the preceding sequences, the amino acid residues necessary for protein conjugation.
• an antibody or an active fragment or derivative of an antibody that specifically recognizes any of the predominant variants of the beta amyloid peptide, A ⁇ 40 and A ⁇ 42 in the preparation of a medicine for the prevention and / or treatment of a disease characterized by the accumulation of amyloid deposits in a patient's brain.
• the antibody or an active fragment or derivative of the antibody that specifically recognizes any of the predominant variants of the A ⁇ peptide is obtained from a peptide selected from a group consisting of SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3, SEQ ID NO 4, optionally shortened by elimination of the amino acid residues from the N-terminal and / or C-terminal ends, and optionally elongated by adding the appropriate amino acid residues to conjugate the protein.
• said antibody or active fragment or antibody derivative is obtained by immunization of mammals or birds with a peptide selected from the group consisting of the peptide of SEQ ID NO 1, the peptides with a sequence resulting from remove the N-terminal and / or C-terminal amino acid residues of SEQ ID NO 1 and the peptides resulting from adding to any of the preceding sequences, the amino acid residues necessary for protein conjugation.
• said antibody or fragment active or derived from the antibody is obtained by immunization of mammals or birds with a peptide selected from the group consisting of the peptide of SEQ ID NO 2, the peptides with a sequence resulting from elimination the N-terminal and / or C-terminal amino acid residues of SEQ ID NO 2 and the peptides resulting from adding to any of the preceding sequences, the amino acid residues necessary for protein conjugation.
• said antibody or fragment active or derived from the antibody is obtained by immunization of mammals or birds with a peptide selected from the group consisting of the peptide of SEQ ID NO 3, the peptides with a sequence resulting from elimination the N-terminal and / or C-terminal amino acid residues of SEQ ID NO 3 and the peptides resulting from adding to any of the preceding sequences, the amino acid residues necessary for protein conjugation.
• said antibody or fragment active or derived from the antibody is obtained by immunization of mammals or birds with a peptide selected from the group consisting of the peptide of SEQ ID NO 4, the peptides with a sequence resulting from elimination the N-terminal and / or C-terminal amino acid residues of SEQ ID NO 4 and the peptides resulting from adding to any of the preceding sequences, the amino acid residues necessary for protein conjugation.
• amino acids are abbreviated using the one-letter codes accepted in the field, in the form shown below:
• Trp tryptophan
• sequences described above in the present invention and identified as SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3 and SEQ ID NO 4 correspond to the following amino acid sequences:
• FIG. 1 Amyloid plaques in brains with Alzheimer's detected with the antibodies SAR-l, SAR-2, SAR-3 and SAR-4.
• Figure 2. Western blot in which the specificity of the antibodies is demonstrated.
• SAR-3 specifically detects the amyloid protein of 40 amino acids (A ⁇ 40), SAR-4 that of 42 amino acids (AE42) and SAR-1 the two isoforms, but having more affinity for the supposedly more neurotoxic A 42.
• a ⁇ 40 amyloid protein of 40 amino acids
• AE42 42 amino acids
• SAR-1 the two isoforms, but having more affinity for the supposedly more neurotoxic A 42.
• nanograms 10, 100, 200 or 500.
• the four polyclonal antibodies were generated by immunization of New Zealand White rabbits against the four KLH-coupled peptides that were used as immunogens.
• Each immunogen was injected into two rabbits, with five injections: the first intradermal injection of the peptide-KLH conjugate in PBS and emulsified in complete Freund's adjuvant and four more intramuscular, as a souvenir dose on days 14, 28, 49 and 80, of the same peptide-KLH conjugate in PBS but this time emulsified in incomplete Freund's adjuvant, control bleeding at 90 days being performed to detect the presence of antibodies.
• the serum was separated and prepurified by desalting and subsequently affinity antibodies were purified on a matrix composed of 1.5 ml of EMD-Epoxy activated material (Merck) to which 5mg of the corresponding peptide was added. .
• the purified fractions were stabilized in 0.1% BSA (Sigma) and stored at 4 ° C, with glycerol 20-50% being added as a cryoprotectant.
• the device used was a Miniprotean 3 from Bio-Rad.
• the center of the cuvette was filled with cathode buffer and the outside with anodic buffer, the composition of these buffers being the following:
• the transfer was performed for 2 hours at 200 mA. Stirring of the buffer with magnetic stirrer was maintained during the transfer.
• the antibodies and the milk powder were dissolved in PBS-T (PBS + 0.5% Tween 20), the washings also being performed with PBS-T. After the transfer, the membrane surface was blocked with 5% milk powder solution, for 1 hour with stirring and at room temperature (RT)
• the membrane was washed: 3 x 10 min. art It was subsequently incubated with secondary antibody: goat anti-rabbit conjugated to horseradish peroxidase (goat anti-rabbit-HRP) for 1 hour at RT (1: 10,000 in all cases).
• secondary antibody goat anti-rabbit conjugated to horseradish peroxidase (goat anti-rabbit-HRP) for 1 hour at RT (1: 10,000 in all cases).
• the membrane was incubated with the chemiluminescence kit solution. Using the Pharmacia ECL + Plus kit.
• the membrane was wrapped in cellophane paper and exposed to double emulsion film (Hyperfilm MP), for different times, between 30 sec. and 2 minutes
• Example 3 Immunohistochemistry with antibodies SAR-l, SAR-2, SAR-3 and SAR-4 in human brain tissue.
• tissue sections were fixed in paraffin following the following steps: a) fixation in 10% neutral formalin b) dehydration by successive passes in increasing concentrations of alcohol c) passes through xylol and paraffin, the latter in a 60-62 ° oven C d) realization of paraffin blocks, which are cut to 4 microns and mounted on slides
• Time was empirically controlled under stereomicroscope. To do this, a wash was first done in a 0.5 M Tris-HCl solution for 10 minutes with stirring, to continue incubation with a diaminobenzidine substrate (DAB) diluted in 0.05M Tris-HCl and to which 0.5 ⁇ l / ml of H202 at 4 ° C. Once the reaction was finished, three washes were carried out in PBS at 4 ° C for 5 minutes each and the dehydration was carried out in 70%, 90% and 100% ethanol for 2 minutes each, pass through 4-minute xylol and another 2-minute xylol pass, until they were mounted with Eukitt for observation under a microscope.
• DAB diaminobenzidine substrate
• SEQUENCE INFORMATION 4 SEQUENCE CHARACTERISTICS: LENGTH: 12 TYPE: amino acid MOLECULE TYPE: peptide SOURCE: Chemical Synthesis SEQUENCE DESCRIPTION: SEQ ID NO 4

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