WO2005014041A2 - Substances et procedes pour le traitement des amyloses - Google Patents

Substances et procedes pour le traitement des amyloses Download PDF

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Publication number
WO2005014041A2
WO2005014041A2 PCT/EP2004/008286 EP2004008286W WO2005014041A2 WO 2005014041 A2 WO2005014041 A2 WO 2005014041A2 EP 2004008286 W EP2004008286 W EP 2004008286W WO 2005014041 A2 WO2005014041 A2 WO 2005014041A2
Authority
WO
WIPO (PCT)
Prior art keywords
amyloid
dna vaccine
amyloid beta
beta
beta dna
Prior art date
Application number
PCT/EP2004/008286
Other languages
English (en)
Other versions
WO2005014041A3 (fr
Inventor
Yoh Matsumoto
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Publication of WO2005014041A2 publication Critical patent/WO2005014041A2/fr
Publication of WO2005014041A3 publication Critical patent/WO2005014041A3/fr

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Classifications

    • 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
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6056—Antibodies

Definitions

  • the present invention relates to methods and materials for the treatment of diseases involving the abnormal accumulation of normally soluble proteins or peptides, in particular Alzheimer's Disease (AD), cerebrovascular amyloidosis, prion diseases and other degenerative diseases.
  • AD Alzheimer's Disease
  • cerebrovascular amyloidosis cerebrovascular amyloidosis
  • prion diseases and other degenerative diseases.
  • AD Alzheimer's disease
  • A/ amyloid ?-peptide
  • amyloid beta protein Using a cDNA clone of the gene encoding amyloid beta protein as a genetic probe, it was shown that the gene is located on chromosome twenty-one and is expressed in many tissues of the body (D. Goldgaber et al, Science, 235, p. 777-780 (1987)). Quantitation of amyloid beta protein expression, as seen by its mRNA levels using the cDNA probe, has revealed that its level of expression in brain tissue of Alzheimer's patients was not above that seen for other tissues outside the central nervous system. Such a finding was of interest to researchers when noting that amyloid plaque formation only occurs in the brain (R. E. Tanzi et al, Science, 235, p. 880-884 (1987)).
  • US 5,753,624 describes a method for alleviating the symptoms of disease states associated with plaque formation such as AD or Parkinson's Disease comprising the step of administering to a patient in need thereof an effective amount of amyloid protein.
  • the method described in US 5,753,624, generally comprises the administration of an adjuvant together with the vaccine.
  • the present invention relates to a method for treatment and/or prevention of neurological and vascular disorders related to beta-amyloid generation comprising the step of administering to a warm-blooded animal, including a human patient, in need thereof an effective amount of an amyloid beta DNA vaccine.
  • a ⁇ DNA vaccines After administration of A ⁇ DNA vaccines, corresponding A ⁇ peptide is produced at a relatively slow rate for a longer period of time compared with the A ⁇ peptide vaccination described in US 5,753,624 so that anti-A ⁇ antibodies, which are essential for reduction of the A ⁇ deposition in the brain, is also be raised gradually.
  • DNA vaccination can be performed without use of any adjuvant.
  • neurodegenerative diseases like AD, Down's Syndrome, memory and cognitive impairment, dementia, amyloid neuropathies, brain inflammation, nerve and brain trauma, vascular amyloidosis, or cerebral haemorrhage with amyloidosis.
  • the method of the present invention can also be employed to treat other degenerative diseases where abnormally aggregated proteins play a role in the disease process, such as prion diseases (Creutzfeld-Jacobs, Gerstmann-Straussler-Scheinker a.o.), Parkinsons disease or peripheral amyloidoses (TTR, SAA a.o.) by appropriate selection of the corresponding DNA sequences to create a DNA vaccine.
  • prion diseases Creutzfeld-Jacobs, Gerstmann-Straussler-Scheinker a.o.
  • Parkinsons disease or peripheral amyloidoses (TTR, SAA a.o.) by appropriate selection of the corresponding DNA sequences to create a DNA vaccine.
  • amyloid beta DNA vaccines suitable to be used in the present invention.
  • amyloid beta DNA vaccine as used herein relates to a vaccine comprising DNA coding for amyloid beta or a fragment thereof.
  • Figure 1 shows the number of amyloid plaques in the cerebral cortex of treated and untreated transgenic mice expressing human APP.
  • the abbreviations used have the following meanings.
  • No Tx denotes untreated animals; emp denotes animals treated with empty vector;
  • a ⁇ denotes animals treated with A ⁇ vaccine,
  • IgL denotes animals treated with IgL-A ⁇ vaccine,
  • Fc denotes animals treated with the IgL-A ⁇ -Fc vaccine.
  • the statistical significance of the results is as follows: Fc vs. emp and no Tx, p ⁇ 0.01 ; IgL vs emp and no Tx, p ⁇ 0.01; A ⁇ vs. emp, NS; A ⁇ vs. p ⁇ 0.05.
  • Figure 2 shows the numbers of positive pixels in the cerebral cortex of treated and untreated transgenic mice expressing human APP as determined from microphotographs using NIH image software.
  • the abbreviations used have the meanings as for figure 1.
  • the statistical significance of the results is as follows: Fc vs. emp and no Tx, p ⁇ 0.01 ; IgL vs emp and no Tx, p ⁇ 0.01; Ab vs emp and no Tx, p ⁇ 0.01.
  • amyloid beta DNA vaccine results in the beneficial effects described herein.
  • the person skilled in the pertinent art is fully enabled to select a relevant test model to prove such beneficial effects.
  • the pharmacological activity of an amyloid beta DNA vaccine may, for example, be demonstrated in a clinical study or in a test procedure as essentially described hereinafter.
  • amyloid beta DNA vaccines in the treatment and/or prevention of neurological and vascular disorders related to beta-amyloid generation can be confirmed, e.g., by clinical studies. Suitable clinical studies are, e.g., randomized, double-blind, placebo- controlled, parallel studies in patients with a history of AD.
  • the disease status can be evaluated in AD patients using a battery of objective tests designed to measure cognitive ability. These include the mini-mental State Examination, the Verbal Fluency Task Examination (word name task and category task), evaluation on the Demattis Dementia Rating scale, and the Word-Association Task Examination of the Wechsler Memory Scale- Revised.
  • the evaluation of the patients should preferably occur in regular time periods, e.g., every 4, 6 or 8 weeks.
  • amyloid beta DNA vaccine can result, e.g., • in an improved ability of the patient to answer questions, to place names with faces, and to complete sentences, to dress himself or to communicate, • in an increased confidence of the patient in physical actions, • in an increased score in the Mini-Mental State Exam, • in improvement primarily in areas of attention and conceptualization, or • in an improvement of the short term memory.
  • the amyloid beta DNA vaccine consists of the cDNA coding for amyloid beta 1-42 or a fragment thereof and a suitable expression vector.
  • the amyloid beta DNA vaccine comprises additionally a further DNA sequence coding for at least one " unit selected from (a) a leader sequence increasing the efficacy of extracellular secretion of the translated peptide and (b) a peptide that stabilizes the produced protein such as Immunoglobulin Fc portion (see, e.g., P. S. Linsley et al, J Exp Med 1991, 173:721 ; A. Ashkenazi, et al, Proc. Natl. Acad. Sci. USA 1991, 88:10535). It could be confirmed in an in vitro assay that cells transfected with amyloid beta DNA vaccines possessing the leader sequence IgL added to the N terminus as disclosed herein release a certain amount of amyloid beta peptide to the culture medium.
  • Suitable expression vector include, but are not limited to, plasmids, eukaryotic vectors, and prokaryotic vectors, such as, for example, bacterial vectors.
  • the present invention relates to a pharmaceutical composition suitable for enteral and parenteral administration to mammals (warm-blooded animals), including man, which comprises an amyloid beta DNA vaccine and optionally a pharmaceutically acceptable carrier.
  • a pharmaceutical dosage unit of the present invention for the delivery of amyloid beta DNA vaccine in a low concentration comprises a liquid or solid carrier and an effective amount of amyloid beta DNA vaccine.
  • the amyloid beta DNA vaccine is administered through standard methods, such as enteral, e.g. oral or rectal, and parenteral administration, including sublingual, intrathecal, subcutaneous and transdermal routes, and in dosage units that are either liquid or solid.
  • the amyloid beta DNA vaccine may be administered with conventional excipients to permit ease of administration and accurate dosage, delivery.
  • one or more of the active ingredients are administered intraveniously.
  • the amyloid beta DNA vaccine can also be delivered by intrathecal injection (i.e. injection into the spinal fluid which bathes the brain and spinal chord tissue).
  • Intrathecal injection of amyloid beta DNA vaccine into the spinal fluid can be performed as a bolus injection or via minipumps which can be implanted beneath the skin, providing a regular and constant delivery of amyloid beta DNA vaccine into the spinal fluid.
  • Compositions and formulations for intrathecal administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.
  • a solution of the vaccine or of an empty vector e.g. at a dose of 100 ⁇ g, in phosphate-buffered saline (PBS), e.g. about 100//!, can be injected intramuscularly at the anterior tibialis muscle.
  • PBS phosphate-buffered saline
  • the vaccine can also be administered intradermally using a fine needle or a gene gun and intra-lymph node after making a small incision of the skin over the lymph node.
  • compositions according to the invention can be prepared in a manner known per se.
  • the effective dosage of amyloid beta DNA vaccine employed in human patients may vary depending on the particular amyloid beta DNA vaccine or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated.
  • the dosage regimen of the amyloid beta DNA vaccine is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
  • a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, counter or arrest the progress of the condition treated.
  • Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of the active ingredients.
  • the dosage of the DNA vaccine to be applied to human patients is typically in the range of 10 to 5000 ⁇ g/injection.
  • Another aspect of the present invention relates to a method for identifying an amyloid beta DNA vaccine suitable for the treatment and/or prevention of neurological and vascular disorders related to beta-amyloid generation, the method comprising the steps of: a) vaccinating a rodent expressing amyloid precursor protein with a test amyloid beta DNA vaccine; and b) determining whether the test amyloid beta DNA vaccine reduces the number of plaques formed in the cerebral cortex or in the hippocampus. Rodents suitable for such methods are disclosed in EP 0920495 A.
  • the invention provides a method for alleviating the symptoms of disease states associated with abnormal accumulation of and/or molecular organization of amyloid protein or amyloid plaques, which comprises administration of an effective amount of an active fragment of the amyloid beta DNA vaccine described herein to a patient in need thereof.
  • the DNA fragment codes for at least six amino acids.
  • amyloid beta DNA vaccines used herein can be obtained, e.g., according to the methods described in the publications listed below, which are incorporated by reference into the present patent application:
  • the Ig-Ab sequence (see above) was connected with the 801-1499 sequence of the Fc portion of human immunoglobulin heavy chain.
  • the nucleotide sequence of this region is deposited in Gene Bank (Accession No. Y14737).
  • PBS phosphate-buffered saline
  • Immunohistochemical staining with anti-A ⁇ (6F/3D) (6F/3D; Dako, Tokyo, Japan) and house- radish peroxidase (HRP)-labeled VECTSTAIN Elite ABC Kit (Vector, Burlingame, CA) is performed using 6 ⁇ m paraffin-embedded sections. Sections are pretreated with formic acid for 3 min. Quantitative analysis is performed by counting amyloid plaques in the cortex of treated and untreated tg mice. In addition, microphotographs including plaques (5-7 fields) are taken and analyzed using a NIH image software (a free software provided by US National Institute for Health) to estimate the size of the plaques and extent of small granular deposition.
  • NIH image software a free software provided by US National Institute for Health
  • Anti-A ⁇ antibodies in the sera of Tg mice are measured by anti-A ⁇ ELISA.
  • ELISA plates are coated with A ⁇ 1-40 peptide (Peptide Institute, Inc., Osaka, Japan) and the titer of the antibodies are detected using biotin-anti mouse IgG (Vector) and the ABC complex.
  • the antibody titer is defined as the reciprocal of the greatest dilution of sera that gives half- maximal binding to A ⁇ that is determined by dividing the highest OD 450 value in the dilution range of each sample by 2.
  • a ⁇ DNA vaccination can be a therapeutic tool for the treatment and prevention of human Alzheimer's disease.

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  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
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  • Epidemiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Cette invention se rapporte à des procédés servant au traitement et à la prévention des troubles neurologiques et vasculaires liés à la production de bêta-amyloïdes, notamment la maladie d'Alzheimer, le syndrome de Down, les insuffisances de mémoire et de la fonction cognitive, la démence, les neuropathies amyloïdes, les inflammations cérébrales, les traumatismes neurologiques et cérébraux, l'amylose vasculaire ou les hémorragies cérébrales avec amylose, ces procédés consistant à administrer un vaccin à base d'ADN de bêta-amyloïde, en particulier un vaccin à base d'ADN de bêta-amyloïde comprenant un ADNc codant la bêta-amyloïde 1-42 ou un fragment de celle-ci ; à des substances, telles que des compositions pharmaceutiques, comprenant ce vaccin à base d'ADN de bêta-amyloïde, à un procédé de préparation de ce vaccin à base d'ADN de bêta-amyloïde ; et à des procédés permettant d'identifier un vaccin à base d'ADN de bêta-amyloïde utilisable pour le traitement et/ou la prévention des troubles neurologiques et vasculaires liés à la production de bêta-amyloïde.
PCT/EP2004/008286 2003-07-24 2004-07-23 Substances et procedes pour le traitement des amyloses WO2005014041A2 (fr)

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7479550B2 (en) 2006-06-02 2009-01-20 The Board Of Regents Of The University Of Texas System Amyloid β gene vaccines
US7700751B2 (en) 2000-12-06 2010-04-20 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize β-amyloid peptide
US7790856B2 (en) 1998-04-07 2010-09-07 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
WO2010110408A1 (fr) 2009-03-26 2010-09-30 財団法人東京都医学研究機構 Vaccin à adn pour maladie d'alzheimer
US7871615B2 (en) 2003-05-30 2011-01-18 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US7893214B2 (en) 1997-12-02 2011-02-22 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
US8003097B2 (en) 2007-04-18 2011-08-23 Janssen Alzheimer Immunotherapy Treatment of cerebral amyloid angiopathy
US8034339B2 (en) 1997-12-02 2011-10-11 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidogenic disease
US8128928B2 (en) 2002-03-12 2012-03-06 Wyeth Llc Humanized antibodies that recognize beta amyloid peptide
EP2522351A1 (fr) 2007-06-13 2012-11-14 Research Development Foundation Procédés pour le traitement et la prévention de tauopathies et de l'amyloïdose de bêta-amyloïde en modulant la signalisation de récepteur CRF
US8349293B2 (en) 2007-03-22 2013-01-08 Guerbet Use of metal nanoparticles in the diagnosis of Alzheimer's disease
US8613920B2 (en) 2007-07-27 2013-12-24 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
US8784810B2 (en) 2006-04-18 2014-07-22 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
US8916165B2 (en) 2004-12-15 2014-12-23 Janssen Alzheimer Immunotherapy Humanized Aβ antibodies for use in improving cognition
US9067981B1 (en) 2008-10-30 2015-06-30 Janssen Sciences Ireland Uc Hybrid amyloid-beta antibodies
US9173928B2 (en) 2009-03-26 2015-11-03 Yoh Matsumoto DNA vaccine for Alzheimer's disease
WO2017069182A1 (fr) * 2015-10-22 2017-04-27 免疫療法開発株式会社 Vaccin à adn contre l'amyloide-β et tau
US9644025B2 (en) 2007-10-17 2017-05-09 Wyeth Llc Immunotherapy regimes dependent on ApoE status
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8535673B2 (en) 1997-12-02 2013-09-17 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidogenic disease
US8034339B2 (en) 1997-12-02 2011-10-11 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidogenic disease
US8642044B2 (en) 1997-12-02 2014-02-04 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidogenic disease
US8034348B2 (en) 1997-12-02 2011-10-11 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidogenic disease
US9051363B2 (en) 1997-12-02 2015-06-09 Janssen Sciences Ireland Uc Humanized antibodies that recognize beta amyloid peptide
US7893214B2 (en) 1997-12-02 2011-02-22 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
US7790856B2 (en) 1998-04-07 2010-09-07 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US7700751B2 (en) 2000-12-06 2010-04-20 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize β-amyloid peptide
US8128928B2 (en) 2002-03-12 2012-03-06 Wyeth Llc Humanized antibodies that recognize beta amyloid peptide
US7871615B2 (en) 2003-05-30 2011-01-18 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US8916165B2 (en) 2004-12-15 2014-12-23 Janssen Alzheimer Immunotherapy Humanized Aβ antibodies for use in improving cognition
US8784810B2 (en) 2006-04-18 2014-07-22 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
US7479550B2 (en) 2006-06-02 2009-01-20 The Board Of Regents Of The University Of Texas System Amyloid β gene vaccines
US8349293B2 (en) 2007-03-22 2013-01-08 Guerbet Use of metal nanoparticles in the diagnosis of Alzheimer's disease
US8003097B2 (en) 2007-04-18 2011-08-23 Janssen Alzheimer Immunotherapy Treatment of cerebral amyloid angiopathy
EP2522351A1 (fr) 2007-06-13 2012-11-14 Research Development Foundation Procédés pour le traitement et la prévention de tauopathies et de l'amyloïdose de bêta-amyloïde en modulant la signalisation de récepteur CRF
US8613920B2 (en) 2007-07-27 2013-12-24 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
US9644025B2 (en) 2007-10-17 2017-05-09 Wyeth Llc Immunotherapy regimes dependent on ApoE status
US9067981B1 (en) 2008-10-30 2015-06-30 Janssen Sciences Ireland Uc Hybrid amyloid-beta antibodies
JP5701747B2 (ja) * 2009-03-26 2015-04-15 陽 松本 アルツハイマー病に対するｄｎａワクチン
US9173928B2 (en) 2009-03-26 2015-11-03 Yoh Matsumoto DNA vaccine for Alzheimer's disease
WO2010110408A1 (fr) 2009-03-26 2010-09-30 財団法人東京都医学研究機構 Vaccin à adn pour maladie d'alzheimer
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
JPWO2017069182A1 (ja) * 2015-10-22 2018-07-05 免疫療法開発株式会社 アミロイドβ及びタウに対するＤＮＡワクチン
WO2017069182A1 (fr) * 2015-10-22 2017-04-27 免疫療法開発株式会社 Vaccin à adn contre l'amyloide-β et tau
US11351234B2 (en) 2015-10-22 2022-06-07 Immunotherapy Development Inc. DNA vaccine against amyloid-β and tau
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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