WO2001039796A2 - Vaccin destine a la prevention et au traitement de la maladie d'alzheimer et d'autres maladies associees aux substances amyloides - Google Patents

Vaccin destine a la prevention et au traitement de la maladie d'alzheimer et d'autres maladies associees aux substances amyloides Download PDF

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Publication number
WO2001039796A2
WO2001039796A2 PCT/CA2000/001413 CA0001413W WO0139796A2 WO 2001039796 A2 WO2001039796 A2 WO 2001039796A2 CA 0001413 W CA0001413 W CA 0001413W WO 0139796 A2 WO0139796 A2 WO 0139796A2
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group
compound
immunogenic
vaccine
groups
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PCT/CA2000/001413
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English (en)
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WO2001039796A3 (fr
Inventor
Robert Chalifour
Lise HÉBERT
Xianqi Kong
Francine Gervais
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Neurochem Inc.
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Priority to MXPA02005576A priority Critical patent/MXPA02005576A/es
Priority to EP00981111A priority patent/EP1235587A2/fr
Priority to KR1020027006845A priority patent/KR20020073341A/ko
Priority to BR0016022-9A priority patent/BR0016022A/pt
Priority to JP2001541528A priority patent/JP2004500354A/ja
Priority to AU18473/01A priority patent/AU784312B2/en
Application filed by Neurochem Inc. filed Critical Neurochem Inc.
Priority to IL14992400A priority patent/IL149924A0/xx
Priority to CA002388559A priority patent/CA2388559A1/fr
Publication of WO2001039796A2 publication Critical patent/WO2001039796A2/fr
Publication of WO2001039796A3 publication Critical patent/WO2001039796A3/fr
Priority to NO20022531A priority patent/NO20022531L/no
Priority to HK03100407.4A priority patent/HK1049279A1/zh

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0007—Nervous system antigens; Prions
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to a new stereochemically based "non-self" antigen vaccine for the prevention and/or treatment of Alzheimer's and other amyloid related diseases.
  • Amyloidosis refers to a pathological condition characterized by the presence of amyloid fibers.
  • Amyloid is a generic term referring to a group of diverse but specific protein deposits (intracellular and/or extracellular) which are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural features and common x-ray diffraction and infrared spectra. Amyloid-related diseases can either be restricted to one organ or spread to several organs. The first instance is referred to as “localized amyloidosis" while the second is referred to as "systemic amyloidosis”.
  • amyloidotic diseases can be idiopathic, but most of these diseases appear as a complication of a previously existing disorder.
  • primary amyloidosis can appear without any other pathology or can follow plasma cell dyscrasia or multiple myeloma.
  • Secondary amyloidosis is usually seen associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis).
  • a familial form of secondary amyloidosis is also seen in Familial Mediterranean Fever (FMF). This familial type of amyloidosis, as one of the other types of familial amyloidosis, is genetically inherited and is found in specific population groups.
  • FMF Familial Mediterranean Fever
  • amyloidosis deposits are found in several organs and are thus considered systemic amyloid diseases. Another type of systemic amyloidosis is found in long-term hemodialysis patients. In each of these cases, a different amyloidogenic protein is involved in amyloid deposition. "Localized amyloidoses" are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit.
  • neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt- Jakob disease and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system.
  • AScr protease-resistant form of a prion protein
  • ADcr another neurodegenerative disorder
  • the plaque and blood vessel amyloid is formed by the deposition of fibrillar A ⁇ amyloid protein.
  • Other diseases such as adult-onset diabetes (Type II diabetes) are characterized by the localized accumulation of amyloid in the pancreas.
  • amyloidotic fibrils once deposited, can become toxic to the surrounding cells.
  • the A ⁇ fibrils organized as senile plaques have been shown to be associated with dead neuronal cells and microgliosis in patients with Alzheimer's disease.
  • a ⁇ peptide was shown to be capable of triggering an activation process of microglia (brain macrophages), which would explain the presence of microgliosis and brain inflammation found in the brain of patients with Alzheimer's disease.
  • amyloidogenic protein IAPP has been shown to induce ⁇ -islet cell toxicity in vitro.
  • appearance of IAPP fibrils in the pancreas of Type II diabetic patients could contribute to the loss of the ⁇ islet cells (Langerhans) and organ dysfunction.
  • Alzheimer's disease develop a progressive dementia in adulthood, accompanied by three main structural changes in the brain: diffuse loss of neurons in multiple parts of the brain; accumulation of intracellular protein deposits termed neurofibrillary tangles; and accumulation of extracellular protein deposits termed amyloid or senile plaques, surrounded by misshapen nerve terminals (dystrophic neurites).
  • a main constituent of these amyloid plaques is the amyloid- ⁇ peptide (A ⁇ ), a 40-42 amino-acid protein that is produced through cleavage of the ⁇ -amyloid precursor protein (APP).
  • the present invention relates to a stereochemically based "non-self" antigen vaccine for the prevention and/or treatment of Alzheimer's and other amyloid related diseases.
  • One aim of the present invention is to provide a vaccine for the prevention and treatment of Alzheimer's and other amyloid related diseases, which overcomes the drawbacks associated with using naturally occurring peptides, proteins or immunogens.
  • a vaccine is provided which is produced using a "non-self" peptide or protein synthesized from the unnatural D-configuration amino acids, to avoid the drawbacks of using "self” proteins.
  • the peptides need not be aggregated to be operative or immunogenic as opposed to the prior art vaccines.
  • a method for preventing and/or treating an amyloid-related disease in a subject which features administering to the subject an antigenic amount of an all-D peptide which elicits production of antibodies against the all-D peptide, and elicit an immune response by the subject, therefore preventing fibrillogenesis and associated cellular toxicity, wherein the antibodies interact with at least one region of an amyloid protein, e.g., ⁇ sheet region and GAG-binding site region, immunogenic fragments thereof, protein conjugates thereof, immunogenic derivative peptides thereof, immunogenic peptides thereof, and immunogenic peptidomimetics thereof.
  • These vaccines may be used in the prevention and/or treatment of amyloid related diseases, and in the manufacture of medicaments for preventing and/or treating amyloid-related diseases.
  • a vaccine for preventing and/or treating an amyloid-related disease in a subject comprises an antibody which interacts with amyloid proteins to prevent fibrillogenesis, wherein the antibodies are raised against an antigenic amount of an all-D peptide interacting with at least one region of an amyloid protein, e.g., ⁇ sheet region and GAG-binding site region, A ⁇ (1-42, all-D), immunogenic fragments thereof, protein conjugates thereof, immunogenic derivative peptides thereof, immunogenic peptides thereof, and immunogenic peptidomimetics thereof.
  • These vaccines may be used in the prevention and/or treatment of amyloid related diseases, and in the manufacture of medicaments for preventing and/or treating amyloid-related diseases.
  • the compound is a compound of Formula I:
  • P is an all-D peptide interacting with at least one region of an amyloid protein, e.g., ⁇ sheet region and GAG-binding site region, A ⁇ (1-42, all-D), immunogenic fragments thereof, immunogenic derivatives thereof, protein conjugates thereof, immunogenic peptides thereof, and immunogenic peptidomimetics thereof;
  • R' is an N-terminal substituent, e.g.:
  • ⁇ lower alkyl groups e.g., acyclic or cyclic having 1 to 8 carbon atoms, without or with functional groups, e.g., carboxylate, sulfonate and phosphonate; ⁇ aromatic groups;
  • acyl groups e.g., alkylcarbonyl, arylcarbonyl, sulfonyl and phosphonyl groups; and R" is a C-terminal substituent, e.g., hydroxy, alkoxy, aryloxy, unsubstituted or substituted amino groups.
  • R' and R" are identical or different, wherein alkyl or aryl group of R' and R" are further substituted with functionalities such as halide (e.g., F, Cl, Br, and I), hydroxyl, alkoxyl, aryloxyl, hydroxycarbonyl, alkoxylcarbonyl, aryloxycarbonyl, carbamyl, unsubstituted or substituted amino, sulfo or alkyloxysulfonyl, phosphono or alkoxyphosphonyl groups.
  • halide e.g., F, Cl, Br, and I
  • the amyloid related disease may be Alzheimer's disease.
  • a method for preventing and/or treating of an amyloid related disease in a subject comprising administering to the subject an antigenic amount of a compound of Formula I:
  • P is an all-D peptide interacting with at least one region of an amyloid protein, e.g., ⁇ sheet region and GAG-binding site region, A ⁇ (1-42, all-D), immunogenic fragments thereof, immunogenic derivatives thereof, protein conjugates thereof, immunogenic peptides thereof, and immunogenic peptidomimetics thereof;
  • R' is an N-terminal substituent selected from the group consisting of:
  • acyl groups e.g., alkylcarbonyl, arylcarbonyl, sulfonyl and phosphonyl groups
  • the compound elicits an immune response by the subject, preventing fibrillogenesis.
  • a vaccine for preventing and/or treating an amyloid-related disease in a subject comprising an antigenic amount of an all-D peptide which interacts with at least one region of an amyloid protein, e.g., ⁇ sheet region and GAG-binding site region, A ⁇ (1-42, all-D) peptide, immunogenic fragments thereof, protein conjugates thereof, immunogenic derivative peptides thereof, immunogenic peptides thereof, and immunogenic peptidomimetics thereof, wherein the compound elicits an immune response by the subject and prevents fibrillogenesis.
  • an amyloid protein e.g., ⁇ sheet region and GAG-binding site region
  • a ⁇ (1-42, all-D) peptide immunogenic fragments thereof, protein conjugates thereof, immunogenic derivative peptides thereof, immunogenic peptides thereof, and immunogenic peptidomimetics thereof, wherein the compound elicits an immune response by the subject and prevents fibrillogenesis.
  • FIG. 1 illustrates the targeted sites for the antigenic fragments
  • FIGs. 4A to 4C illustrate electron micrographs showing the effect of anti-D KLVFFA peptide antibodies (FIG. 4B) and anti-L KLVFFA peptide antibodies(FIG. 4C) with respect to a control (FIG. 4A) on fibrillogenesis;
  • FIGs. 5A to 5D illustrate the immunohistochemistry of anti-D KLVFFA on aggregated A ⁇ peptide in brain sections of retrosplenial cortex (FIG. 5A) and parietal cortex (FIG. 5C) and the histochemistry (Thioflavin S assay) of anti-D KLVFFA on aggregated A ⁇ peptide in the same brain sections of retrospinal cortex (FIG. 5B) and parietal cortex (FIG. 5D);
  • FIGs. 6A to 6D illustrate the immunohistochemistry of anti-L KLVFFA antibodies on aggregated A ⁇ peptide in brain sections of parietal cortex (FIG. 6A) and entorhinal cortex
  • FIG. 6C and the histochemistry (Thioflavin S assay) of anti-L KLVFFA antibodies on aggregated A ⁇ peptide in the same brain sections of parietal cortex (FIG. 6B) and entorhinal cortex (FIG. 6D); and FIG 7 illustrates the response of rabbits to KLH-conjugated all-L and all-D KLVFFA
  • peptidomimetic includes non-peptide compounds which mimic the structural or the functional properties of a peptide
  • amyloid related diseases includes diseases associated with the accumulation of amyloid which can either be rest ⁇ cted to one organ, “localized amyloidosis", or spread to several organs, “systemic amyloidosis” Secondary amyloidosis may be associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis), including a familial form of secondary amyloidosis which is also seen in Familial Mediterranean Fever (FMF) and another type of systemic amyloidosis found in long-term hemodialysis patients Localized forms of amyloidosis include, without limitation, diabetes type II and any related disorders thereof, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt-Jakob disease, Alzheimer's disease, Cerebral Amyloid Angiopathy, and p
  • the A ⁇ (16-21) site is known to play an important role in initiating the harmful process of A ⁇ peptide amyloidogenesis It is also known that when these peptides are made from D-amino acids, they retain their ability to interact with the natural all-L-homologous sequence, thereby preventing amyloidogenesis
  • amyloid proteins which may be used in the present invention include, without limitation, IAPP, ⁇ 2-m ⁇ croglubehne, amyloid A protein, and p ⁇ on-related proteins
  • the vaccine of the present invention prepared from all-D-A ⁇ (16-21), D-A ⁇ (lO-l ⁇ ), D-A ⁇ (l-40), D-A ⁇ (l-42) or the C-terminal region of D-A ⁇ (l-42), is believed to elicit an immune response in the host or in producing antibodies that recognize the naturally occurring target
  • all-D includes peptides having > 75%, > 80%, > 85%, > 90%, > 95%, and 100% D-conftguration ammo acids
  • the vaccine of the present invention does not present the drawbacks of using "self" proteins and does not need to be aggregated to induce an immune response.
  • the antibodies raised against the all-D-A ⁇ (16-21) peptide can be expected to recognize the all-L-A ⁇ (16-21) peptide sequence.
  • the elicited antibodies present in the host having received the vaccine of the present invention bind at the A ⁇ (16-21) site or other sites such as the C-terminal region of A ⁇ and have the same or even greater ability to prevent amyloidogenesis as do the short peptides themselves.
  • the vaccine of the present invention causes the generation of effective antiamyloidogenic antibodies in the vaccinated host.
  • a suggested immunization procedure is as follows: a) prepare a vaccine from an all-D peptide having a sequence substantially the same as that of a naturally occurring ⁇ amyloid peptide, namely A ⁇ (all-L).
  • the all-D peptide includes a full length A ⁇ (1-42, all-D), a peptide derived from an immunogenic fragment of A ⁇ (1-42, all-D), and a related peptidomimetic;
  • Suitable pharmaceutically acceptable carriers include, without limitation, any non- immunogenic pharmaceutical adjuvants suitable for oral, parenteral, intravascular (IV), intraarterial (IA), intramuscular (IM), and subcutaneous (SC) administration routes, such as phosphate buffer saline (PBS).
  • IV intravascular
  • IA intraarterial
  • IM intramuscular
  • SC subcutaneous
  • PBS phosphate buffer saline
  • the pharmaceutical carriers may contain a vehicle, which carries antigens to antigen-presenting cells.
  • vehicles are liposomes, immune-stimulating complexes, microfluidized squalene-in-water emulsions, microspheres which may be composed of poly(lactic/glycolic) acid (PLGA).
  • Particulates of defined dimensions include, without limitation, oil-in-water microemulsion (MF59) and polymeric microparticules.
  • the carriers of the present invention may also include chemical and genetic adjuvants to augment immune responses or to increase the antigenicity of antigenic immunogens. These adjuvants exert their immunomodulatory properties through several mechanisms such as lymphoid cells recruitment, cytokine induction, and the facilitation of DNA entry into cells.
  • Cytokine adjuvants include, without limitation, granulocyte-macrophage colony-stimulating factor, interleukin-12, GM-CSF, synthetic muramyl dipeptide analog or monophosphoryl lipid A.
  • Other chemical adjuvants include, without limitation, lactic acid bacteria, Al(OH) 3 , muramyl dipeptides and saponins.
  • the peptide may be coupled to a carrier that will modulate the half-life of the circulating peptide. This will allow the control on the period of protection.
  • the peptide-carrier may also be emulsified in an adjuvant and administrated by usual immunization route.
  • the vaccine of the present invention will, for the most part, be administered parenterally, such as intravascularly (IV), intraarterially (IA), intramuscularly (LM), subcutaneously (SC), or the like. In some instances, administration may be oral, nasal, rectal, transdermal or aerosol, where the nature of the vaccine allows for transfer to the vascular system. Usually a single injection will be employed although more than one injection may be used, if desired.
  • the vaccine may be administered by any convenient means, including syringe, trocar, catheter, or the like.
  • the administration will be intravascularly, where the site of introduction is not critical to this invention, preferably at a site where there is rapid blood flow, e.g., intravenously, peripheral or central vein.
  • Other routes may find use where the administration is coupled with slow release techniques or a protective matrix.
  • the use of the vaccine of the present invention in preventing and/or treating Alzheimer's disease and other amyloid related diseases can be validated by raising antibodies against the corresponding all-D peptide and testing them to see if they can effectively inhibit or prevent the fibrillogenesis of the natural amyloid peptide (all-L).
  • the compounds used to prepare vaccines in accordance with the present invention have the common structure of Formula I:
  • P is an all-D peptide interacting with at least one region of an amyloid protein, e.g., ⁇ sheet region and GAG-binding site region, A ⁇ (1-42, all-D), immunogenic fragments thereof, immunogenic derivatives thereof, protein conjugates thereof, immunogenic peptides thereof, and immunogenic peptidomimetics thereof;
  • R' is an N-terminal substituent selected from the group consisting of: ⁇ hydrogen;
  • ⁇ lower alkyl groups e.g., acyclic or cyclic having 1 to 8 carbon atoms, without or with functional groups, e.g., carboxylate, sulfonate and phosphonate;
  • acyl groups e.g., alkylcarbonyl, arylcarbonyl, sulfonyl and phosphonyl groups
  • R" is a C-terminal substituent, e.g., hydroxy, alkoxy, aryloxy, unsubstituted or substituted amino groups.
  • R' and R" may be identical or different; the alkyl or aryl group of R' and R" may further be substituted with organic functionalities selected from the group of halides (F, Cl, Br, and I), hydroxyl, alkoxyl, aryloxyl, hydroxycarbonyl, alkoxylcarbonyl, aryloxycarbonyl, carbamyl, unsubstituted or substituted amino, sulfo or alkyloxysulfonyl, phosphono or alkoxyphosphonyl, and the like.
  • the preferred compounds are selected from the full-length peptide, A ⁇ (1-42, all-D), and its lower homologues consisting of A ⁇ (1-40, all-D), A ⁇ (1-35, all-D), and A ⁇ (1-28, all-D).
  • the preferred compounds are selected from a group of short peptides, e.g., A ⁇ (1-7, all-D), A ⁇ (10-16, all-D), A ⁇ (16-21, all-D), A ⁇ (36-42, all-D).
  • the peptides can be shortened further by removing one or more residues from either end or both ends.
  • the preferred compounds may also be all-D peptides derived from the peptides above by substitution of one or more residues in the naturally occurring sequence.
  • the preferred compounds are peptidomimetics of the above-said peptides.
  • the preferred compounds may be coupled with a carrier that will modulate the biodistribution, immunogenic property and the half-life of the compounds.
  • the compounds listed above may be modified by removing or inserting one or more amino acid residues, or by substituting one or more amino acid residues with other amino acid or non-amino acid fragments.
  • Thi, Cha and Pgly are intended to mean thienylalanine, cyclohexylalanine and phenylglycine, respectively.
  • the present invention encompasses various types of immune responses triggered using the vaccine of the present invention, e.g., amyloid therapies using the vaccine approach.
  • a vaccine which triggers a preferential TH-2 response or a TH-1 response, according to the type of immunization used.
  • anti-inflammatory cytokine production such as IL-4, 11-10 and TGF- ⁇ , as well as the production of IgG 1 and IgG 2b antibody classes, are favored.
  • Such type of response would be preferred, as a major inflammatory response in the brain of the patients with AD would be avoided.
  • a pro-inflammatory response with a production of inflammatory cytokines such as IL- 1, 11-6, TNF and IFN gamma would be favored. This type of response would more likely trigger activation of the macrophage population. These macrophages would then phagocytose any particulate deposits (such as plaques) via a complement-activated process as well as via antibody-mediated process. This approach would be beneficial to clear already organized senile plaques and prevent the formation of new fibrillary deposits.
  • the antigen used could be the peptides which contain regions responsible for cellular adherence, i.e., region 10-16, regions responsible for the GAG binding site, i.e., 13-16, regions responsible for the ⁇ sheet 16-21 or regions for 40-42. These peptides could be presented in such a way that either a preferential TH-1 or TH-2 response is obtained, depending on the type of adjuvant used, or depending on the route of administration of the vaccine. For example, a mucosal immunization via nasal administration is possible, since it is known that such a route of administration would favor a TH-2 response.
  • EXAMPLE I An in vitro validation procedure to test the effectiveness of all-D peptide vaccines derived from fibrillogenic proteins was performed in rabbits or mice to demonstrate that antibodies can be raised against A ⁇ 16-21 (all-D) (see FIG. 7). The antibodies produced were tested to prove that they effectively prevent the fibrillogenesis of natural A ⁇ (l-40, all-L) in vitro. Standard assays for fibrillogenesis were used to evaluate activity, such as those based on Thioflavine T, circular dichroism and solubility.
  • This approach could also be used to establish which areas of the A ⁇ peptide are most effective when used in the form of all-D peptides to prepare antifibrillogenic vaccines.
  • One way this could be performed is as follows: a) rabbits or mice are immunized with a series of overlapping all-D peptides generated from the A ⁇ (l-42) sequence, e.g., A ⁇ (l-6), A ⁇ (2-8), A ⁇ (4-10), etc. b) antisera are prepared from the immunized rabbits or mice. c) these antisera are tested to see which parts of the A ⁇ sequence produce antisera which most effectively prevents fibrillogenesis in the standard assays for fibrillogenesis mentioned above.
  • Antibodies raised against the D- and L- forms of KLVFFA were capable of blocking the fibrillogenesis process as seen either by the Thioflavin T assay (ThT) (FIGs. 2 and 3) and by EM (FIGs. 4A to 4C).
  • ThT Thioflavin T assay
  • EM EM-FIGs. 4A to 4C
  • fibril formation is monitored by the increase in fluorescence with time.
  • the antibodies were capable of inhibiting such an increase in fluorescence, proving that these antibodies were inhibiting fibrillogenesis.
  • the vaccine of the present invention 1) prevents A ⁇ from organizing itself into a fibril and 2) prevents an inflammatory response being triggered by such an antibody binding to an insoluble form, since the antibody is not able to bind to aggregated A ⁇ .

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Abstract

La présente invention concerne un vaccin à antigène « non-soi » à base stéréochimique, destiné à la prévention et/ou au traitement de la maladie d'Alzheimer et d'autres maladies associées aux substances amyloïdes. Le vaccin destiné à la prévention et/ou au traitement de la maladie d'Alzheimer et d'autres maladies associées aux substances amyloïdes selon cette invention surmonte les inconvénients associés à l'utilisation de peptides, de protéines et d'immunogènes naturels.
PCT/CA2000/001413 1999-11-29 2000-11-29 Vaccin destine a la prevention et au traitement de la maladie d'alzheimer et d'autres maladies associees aux substances amyloides WO2001039796A2 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EP00981111A EP1235587A2 (fr) 1999-11-29 2000-11-29 Vaccin destine a la prevention et au traitement de la maladie d'alzheimer et d'autres maladies associees aux substances amyloides
KR1020027006845A KR20020073341A (ko) 1999-11-29 2000-11-29 알츠하이머 및 아밀로이드 관련 질병의 예방 및 치료용 백신
BR0016022-9A BR0016022A (pt) 1999-11-29 2000-11-29 Vacina para a prevenção e tratamento da doença de alzheimer e doenças relacionadas ao amilóide
JP2001541528A JP2004500354A (ja) 1999-11-29 2000-11-29 全ｄ体ペプチドを含む、アルツハイマー病およびアミロイド関連疾患の予防および処置のためのワクチン
AU18473/01A AU784312B2 (en) 1999-11-29 2000-11-29 Vaccine for the prevention and treatment of alzheimer's and amyloid related diseases
MXPA02005576A MXPA02005576A (es) 1999-11-29 2000-11-29 Vacuna para la prevencion y tratamiento de la enfermedad de alzheimer y otras enfermedades relacionadas con amiloides.
IL14992400A IL149924A0 (en) 1999-11-29 2000-11-29 Vaccine for the prevention and treatment of alzheimer's and amyloid related diseases
CA002388559A CA2388559A1 (fr) 1999-11-29 2000-11-29 Vaccin destine a la prevention et au traitement de la maladie d'alzheimer et d'autres maladies associees aux substances amyloides
NO20022531A NO20022531L (no) 1999-11-29 2002-05-28 Vaksine for forebyggelse og behandling av Alzheimer- og amyloidrelaterte sykdommer
HK03100407.4A HK1049279A1 (zh) 1999-11-29 2003-01-16 預防及治療阿爾茨海默病(早老性痴呆)及澱粉樣蛋白有關的病之疫苗

Applications Claiming Priority (4)

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US16859499P 1999-11-29 1999-11-29
US60/168,594 1999-11-29
US72484200A 2000-11-28 2000-11-28
US09/724,842 2000-11-28

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WO2001039796A2 true WO2001039796A2 (fr) 2001-06-07
WO2001039796A3 WO2001039796A3 (fr) 2001-12-06

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US10464976B2 (en) 2003-01-31 2019-11-05 AbbVie Deutschland GmbH & Co. KG Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof
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US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
US6743427B1 (en) 1997-12-02 2004-06-01 Neuralab Limited Prevention and treatment of amyloidogenic disease
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US8067372B2 (en) 2005-11-10 2011-11-29 Alzheimer's Institute Of America, Inc. Modulation of angiogenesis by A-beta peptide fragments
US10208109B2 (en) 2005-11-30 2019-02-19 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US10538581B2 (en) 2005-11-30 2020-01-21 Abbvie Inc. Anti-Aβ globulomer 4D10 antibodies
US10323084B2 (en) 2005-11-30 2019-06-18 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US8906370B2 (en) 2005-12-12 2014-12-09 Hoffmann-La Roche Inc. Antibodies against amyloid beta 4 with glycosylation in the variable region
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US8784810B2 (en) 2006-04-18 2014-07-22 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
US8796439B2 (en) 2006-07-14 2014-08-05 Ac Immune S.A. Nucleic acid molecules encoding a humanized antibody
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US9951125B2 (en) 2006-11-30 2018-04-24 Abbvie Inc. Aβ conformer selective anti-Aβ globulomer monoclonal antibodies
US8003097B2 (en) 2007-04-18 2011-08-23 Janssen Alzheimer Immunotherapy Treatment of cerebral amyloid angiopathy
US8623374B2 (en) 2007-04-20 2014-01-07 The Chemo-Sero-Therapeutic Research Institute Method for enhancing immune response with peptide
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US9403902B2 (en) 2007-10-05 2016-08-02 Ac Immune S.A. Methods of treating ocular disease associated with amyloid-beta-related pathology using an anti-amyloid-beta antibody
US9644025B2 (en) 2007-10-17 2017-05-09 Wyeth Llc Immunotherapy regimes dependent on ApoE status
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US9067981B1 (en) 2008-10-30 2015-06-30 Janssen Sciences Ireland Uc Hybrid amyloid-beta antibodies
US9011862B2 (en) 2009-07-11 2015-04-21 Rheinische Friedrich-Wilhelms-Universität Bonn Inhibitors of the nitration of amyloid β peptides and their uses in the diagnosis and treatment of Alzheimer's disease
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US9822171B2 (en) 2010-04-15 2017-11-21 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
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US11905318B2 (en) 2015-11-09 2024-02-20 The University Of British Columbia Cyclic compound/peptide comprising an A-beta13-16 peptide and a linker that is covalently coupled to the n-terminus residue and the c-terminus residue of the A-beta13-16 peptide
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BR0016022A (pt) 2002-08-06
AU784312B2 (en) 2006-03-09
CN1433321A (zh) 2003-07-30
KR20020073341A (ko) 2002-09-23
IL149924A0 (en) 2002-11-10
WO2001039796A3 (fr) 2001-12-06
NO20022531L (no) 2002-07-12
AU1847301A (en) 2001-06-12
JP2004500354A (ja) 2004-01-08
NZ540564A (en) 2007-04-27
HK1049279A1 (zh) 2003-05-09
KR20080059676A (ko) 2008-06-30
CA2388559A1 (fr) 2001-06-07

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