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WO2015165961A1 - Traitement et prévention de la maladie d'alzheimer - Google Patents

Traitement et prévention de la maladie d'alzheimer Download PDF

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Publication number
WO2015165961A1
WO2015165961A1 PCT/EP2015/059331 EP2015059331W WO2015165961A1 WO 2015165961 A1 WO2015165961 A1 WO 2015165961A1 EP 2015059331 W EP2015059331 W EP 2015059331W WO 2015165961 A1 WO2015165961 A1 WO 2015165961A1
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WIPO (PCT)
Prior art keywords
vaccine
aluminium
per dose
amino acid
aluminium salt
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English (en)
Inventor
Markus Mandler
Achim Schneeberger
Frank Mattner
Walter Schmidt
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Affiris AG
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Affiris AG
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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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • 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
    • A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]

Definitions

  • AD Alzheimer's Disease
  • the present invention relates to means and methods for the treatment and the prevention of Alzheimer's Disease (AD) .
  • AD Alzheimer's Disease
  • AD is characterized by the aberrant accumulation of Amyloid- ⁇ polypeptides ( ⁇ ) resulting in ⁇ -amyloid deposition.
  • AD Alzheimer's disease
  • APP Amyloid Precursor Pro ⁇ tein
  • NFT neurofibrillary tangles
  • Hyperphosphorylation of Tau results in loss of microtubule association and subsequent disassembly of microtubules, which in turn leads to an impair ⁇ ment of axonal transport and subsequent axonal and neuronal de ⁇ generation. It is still unclear whether tau hyperphosphorylation and tangle formation are a cause or a consequence of AD.
  • AD Alzheimer's disease
  • cytokines pro ⁇ inflammatory cytokines
  • cell adhesion molecules cell adhesion molecules
  • chemokines pro ⁇ inflammatory cytokines
  • AD and related disorders could be based on immunotherapy to prevent or reduce the accumulation of neurotoxic agents like ⁇ or Tau/hyperphosphorylated Tau.
  • AD specific biomarkers such as radiologic biomarkers using PET (positron emission tomogra ⁇ phy) scans (Kozauer et al . , N. Engl. J. Med. 368 (2013), 1170- 1171) .
  • WO 94/16327 Al discloses therapeutic agents that involve an "amyloid protein ion channel".
  • this concept of amyloid protein ion channel of WO 94/16327 Al was not further prosecuted and was finally challenged scientifically (Sokolov et al . , J. Gen. Physiol. 128 (2006), 637-647; commentary by Eliezer, J. Gen. Physiol. 128 (2006), 631-633).
  • Figure 7 and 8 of this application disclose that topically applied aluminium-oxyhydroxide is able to lower cognitive decline significantly in an APP-transgenic model for Alzheimer's disease (Tg2576) without significantly changing cer ⁇ ebral ⁇ levels. This is implying an ⁇ / ⁇ independent mecha ⁇ nism underlying beneficial functional effects exerted by alumin ⁇ ium-oxyhydroxide in this AD model.
  • WO 99/27944 Al discloses AD vaccines being essentially based on the presence of an agent effective to induce an immunogenic response against ⁇ .
  • WO 2011/120924 Al refers to an ⁇ vaccine, which is essentially based on ⁇ 1-6 peptide bound to a virus ⁇ like particle.
  • WO 2006/005707 A2 , WO 2009/149486 A2 and WO 2009/149485 A2 disclose ⁇ mimotope peptides for use in vaccines for the prevention and treatment of AD.
  • Magga et al . J. Cell. Mol. Med. 16 (2012): 1060-1073
  • Magga et al . disclose monocyte gene therapy in AD APP+PS1 transgenic mice.
  • WO 2012/055981 Al sug ⁇ gests the use of a "TLR4 agonist free of endotoxin" for the pre ⁇ vention or reduction of amyloid deposition.
  • Malm et al . (GLIA 58 (2010) : 889-900) review the role and therapeutic potential of monocytic cells in AD.
  • WO 2009/105641 Al discloses the use of M-CSF for the treat ⁇ ment of amyloidosis.
  • Boissionneault et al . (Brain 132 (4) (2008) : 1078-1092) report the effects of M-CSF on amyloid depo ⁇ sition and cognitive impairment in AD.
  • Luo et al . (Neuroscience letters 367 (2) (2013) : 210-172) disclose that Colony- stimulating factor 1 receptor (CSF1R) signalling in injured neurons facilitates protection and survival.
  • CSF1R Colony- stimulating factor 1 receptor
  • AD disease modifying treat ⁇ ment
  • Available treat ⁇ ment modalities for AD include three acetylcholinesterase in ⁇ hibitors (AChEI) and one N-Methyl-D-aspartate (NMDA) antagonist. Their effects are small and only symptomatic in nature (see e.g. Corbett et al . , Nat. Rev. Drug Discov. 11 (2012), 833-846). Thus, there is a high medical need for a disease-modifying drug.
  • MRI Magnetic resonance imaging
  • the present invention provides a vaccine for use in the treatment and prevention of AD, wherein the vaccine con- tains an aluminium salt, especially aluminium oxyhydroxide, in an amount of at least 1.2 mg per dose, preferably at least 1.5 mg per dose, especially at least 1.8 mg per dose.
  • This vaccine to be improved according to the present invention is to be un ⁇ derstood as a pharmaceutical composition effective in eliciting an immune response that has been used in vaccination strategies to treat and prevent AD.
  • AD vaccines especially those that have already been disclosed in the art, are improved to gain effectiveness in the treatment and prevention of AD so as to elicit a disease-modifying effect with respect to AD.
  • the present invention provides improved vaccines with an increased amount of aluminium salt, especially aluminium oxyhydroxide. Therefore, the present invention also provides a vaccine for use in the treatment and prevention of AD, wherein the vaccine contains an aluminium salt, especially aluminium ox ⁇ yhydroxide, in an amount of at least 2.2 mg per dose, preferably at least 2.5 mg per dose, especially at least 2.8 mg (given as AI 2 O 3 equivalent) per dose.
  • the present invention also provides a vaccine for use in the treatment and prevention of AD, wherein the vaccine contains an aluminium salt, especially aluminium ox ⁇ yhydroxide, in an amount of at least 3.0 mg per dose, preferably at least 3.5 mg per dose, more preferred at least 4.0 mg per dose, especially at least 5.0 mg (given as AI 2 O 3 equivalent) per dose.
  • the amount of aluminium salt for Alhydrogel is given as AI 2 O 3 equivalent in line with the strength as stated by the manu ⁇ facturer (i.e. 2% Alhydrogel equates to 2% AI 2 O 3 , i.e. 20 mg/mL) .
  • This concentration is directly convertible into the re ⁇ spective concentration of aluminium by using the respective mo ⁇ lecular masses (20 mg/mL AI 2 O 3 (Mw 101,96) corresponds to 10.6 mg/mL aluminium (molecular mass 26, 98)) .
  • this value can easily be converted into the necessary amount/concentration of a different aluminium salt (it is clear that these values are based solely on the amount of aluminium (salt) , and other aspects, such as the contribution of the par ⁇ ticulate nature of Alhydrogel is not taken into account.
  • aluminium salts especially aluminium oxyhydrox ⁇ ide
  • the present invention therefore provides a breakthrough technology for this disease.
  • a significant disease modifying effect could be detected in AD pa ⁇ tients.
  • the present invention has also turned out to be effective without the significant side effects reported in other clinical trials for AD medication, especially in the field of AD immunotherapy.
  • the present invention has achieved a sta ⁇ tistically significant disease modifying effect in AD patients with respect to MRI scans of the volume of the (right) hippocam ⁇ pus.
  • the correlation of a clinical biomarker and a radiologic biomarker has been shown in the course of clinical trials performed for the present invention.
  • Structural MRI has been highlighted as a significant biomarker, in the most recent scientific literature (Risacher et al . , Annu . Rev. Clin. Psychol. 9 (2013), 621-648; Vermuri et al . , Neurology 73 (2009), 287-293 and 294-301; Weiner et al . , Alzh. Dememt . 9 (2013), elll-94; Frisoni et al . , Nat. Rev. Neurol. 6 (2010), 67- 77; Fox et al . , Arch. Neurol. 57 (2000), 339-344).
  • MRI provides great power to effect cross-sectional groupwise discrimination and better correlation with general cognition and functional status cross-sectionally .
  • MRI reflects clinically de ⁇ fined disease stage even better than various CSF biomarkers tested (Vermuri et al . , Neurology 73 (2009), 287-293 and 294- 301).
  • Numerous studies have demonstrated significantly reduced hippocampal and entorhinal cortex (EC) volume, as well as re ⁇ cuted cortical thickness in the medial and lateral temporal cor ⁇ tex, parietal lobe, and frontal lobes, in patients destined to convert from MCI to probable AD (MCI-converters) , up to two years prior to clinical conversion (Risacher et al . , 2013) .
  • this biomarker was investigated in the course of the clinical trials performed for the present invention in parallel with the standard clinical parameters (monitoring func ⁇ tional and cognitive function of AD patients) .
  • AD patients a significant improvement in the development of AD patients compared to the usual development of AD patients (gradual cognitive, functional and behavioural de ⁇ cline) can be achieved so as to satisfy the long-felt need of providing a disease-modifying treatment of AD.
  • This improvement according to the present invention is achieved by combining the disease-modifying effect of aluminium salts with the immunotherapy approach for AD.
  • Active or passive amyloid-targeted immunotherapy is a strategy that has been pursued with con ⁇ siderable effort, yet without significant breakthrough, however, with numerous drawbacks, such as the failure of the first active vaccine (AN1792, consisting of preaggregate ⁇ and an immune ad ⁇ juvant, QS-21) that was abandoned because it caused meningoen ⁇ cephalitis in approximately 6% of treated patients.
  • Further studies have identified significant risks in the immunotherapy based on native antigens, such as ⁇ 42.
  • the passive immuno ⁇ therapy approach has not yet resulted in positive results from clinical trials. As also noted above, reports from clinical tri ⁇ als of bapineuzumab and solanezumab were disappointing as well.
  • the active and passive vaccination approach for AD is combined with the clinical breakthrough of administration of an immune stimulating pharmaceutical composition comprising aluminium salts, especially aluminium oxyhydroxide (Alhydrogel) .
  • aluminium salts especially aluminium oxyhydroxide
  • Alhydrogel aluminium oxyhydroxide
  • Either the vac ⁇ cines can be mixed with aluminium salts, especially aluminium oxyhydroxide, so as to obtain a pharmaceutical composition that is both, an active or passive vaccine and an immune stimulating pharmaceutical composition, or the aluminium salts, especially aluminium oxyhydroxide, can be administered separately from the vaccine.
  • alu ⁇ minium salts especially aluminium oxyhydroxide
  • aluminium salts especially aluminium oxyhydroxide
  • doses of 2 mg have been successfully applied to AD patients to obtain a stop in disease progression, measured by classical functional and/or cognitive clinical pa ⁇ rameters .
  • a preferred embodiment of the present invention is the combination of an active or passive vaccine against ⁇ , especially ⁇ 1-42, and/or against tau, especially hyperphosphor- ylated tau with an effective amount of an aluminium salt.
  • aluminium salts according to the present invention are specifically highlighted when an ad ⁇ ministration dose of at least 1.2 mg aluminium salt, especially alhydrogel/dose is applied. If the aluminium salt component of the present invention is combined with the active or passive vaccine in a single pharmaceutical composition, it is, however, preferred to use higher doses, because of the protein binding property of aluminium salts (also depending on the p i of the protein and the pH of the pharmaceutical preparation) .
  • the aluminium salt may therefore be ad ⁇ sorbed by the polypeptides and proteins (or (antigenic) polypep ⁇ tides bound by (carrier) proteins) present in such vaccines.
  • the aluminum salt concentrations are preferably in ⁇ creased when proteins or polypeptides are present in the pharma ⁇ ceutical preparation to be administered to a patient.
  • aluminium phosphate (Adju-Phos) has a maximal binding capacity (in mg protein/mg aluminum at pH 7.4) to Lyso- zyme (p i 11.0) of 1.4 ⁇ 0.1; aluminium oxyhydroxide (Alhydrogel) to Ovalbumin (p i 4.6) of 1.6 ⁇ 0.1 and to BSA (p i 4.9) of 2.2 ⁇ 0.1 (Jones et al . , JBC 280, (2005), 13406-13414).
  • aluminium salt In order to account for the aluminium that is bound to such proteins, more aluminium salt has to be provided in such admixed pharmaceutical preparations than in preparations that contain the aluminium salt as the single effective ingredient or - at least in the ab ⁇ sence of proteins or polypeptides in the pharmaceutical prepara ⁇ tion.
  • a pharmaceutical composition according to the present invention should provide the effectiveness of a dose of 2 mg aluminium salt, especially aluminium oxyhydroxide, and contains a specific amount of proteins or polypeptides (antigens or antibodies) which binds to the aluminium salt, an amount equal to the aluminium salt portion binding to such proteins has to be additionally included in the pharmaceutical preparation to provide 2 mg "free" aluminium salt.
  • the amount of the aluminium salt portion binding to such proteins can easily be determined for a given protein/polypeptide at the conditions in the pharma ⁇ ceutical composition/vaccine planned, e.g. by the method dis ⁇ closed by Jones et al . , 2005) . It may therefore be necessary to provide considerably more than 2 mg Alhydrogel into such a pro ⁇ tein (or polypeptide) containing vaccine, e.g. at least 2.5 mg, preferably at least 3 mg, more preferred at least 3.5 mg, espe ⁇ cially at least 4 mg, of aluminium salt, especially Alhydrogel (as further explained below, the mg amounts of aluminium salts, especially aluminium oxyhydroxide are always given as AI 2 O 3 equivalent) .
  • the vaccine according to the present invention is an active or passive vaccine against ⁇ , especially ⁇ 1-42, and/or against tau, especially hyperphosphorylated tau.
  • the active vaccine is preferably containing an antigen that elicits an immune response against ⁇ , ⁇ aggregates, especially oligomeric ⁇ aggregates, tau protein, phospho-tau protein, ag ⁇ gregated tau protein, hyperphosphorylated tau protein or a natu ⁇ rally occurring fragment thereof, preferably ⁇ 1-40/42, ⁇ 2- 40/42, ⁇ 3-40/42, ⁇ 4-40/42, ⁇ 1-38, or ⁇ 1-39.
  • the antigen may also be an ⁇ or tau antigen containing modifications, pref ⁇ erably racemisation of aspartate and serine residues, isomerisa- tion of aspartate residues, and pyroglutamate formation at the glutamate residues.
  • the “aggregate” contained in the active vaccine according to the present invention refers to the aggregate as such, but also to preparations containing the aggregate, especially prepara ⁇ tions suitable for diagnostic purposes in human medicine, i.e. preparations made according to GMP and standardised procedures.
  • the aggregate-forming Tau protein variant and the aggregate-forming ⁇ 1-42 variant are, independently of each other, selected from the following groups:
  • Hyperphosphorylated Tau abnormally phosphorylated Tau (as referred to and defined in Shahani et al . J. Neurosci. 26 (2006), 6103-6114), Tau protein variants that have marker func ⁇ tion for a disease (either isoform of all 6 naturally occurring isoforms (Tau441, Tau412, Tau411, Tau383, Tau381, Tau352) or mutant forms thereof (e.g.
  • P301L, P301S, V337M, etc. forms preferably simultaneously phosphorylated at amino acids 181, 202, 205, 212, 214, 231, 396 and, optionally at additional resi ⁇ dues present in Tau like 18, 153, 175, 189, 235, 262, 394, 404 and 422, of Tau441, Tau412, Tau410, Tau383, Tau381, Tau352 (a more detailed analysis of Tau phosphorylation is disclosed e.g. in Hanger et al . , Trends in Mol. Med.
  • truncated form of the ⁇ -1-40- or the ⁇ - ⁇ -42-peptide wherein the truncation is at amino acid positions other than amino acids 16 to 35 and wherein the truncation is at least one amino acid and at most 20 amino acids;
  • combinations thereof especially combinations of at least one mutation and at least one truncation of the ⁇ -1-40- or the ⁇ - ⁇ -42-peptide .
  • the aggregate has a size of 50 nm to 15 ym, preferably from 100 nm to 10 ym, especially from 200 nm to 5 ym.
  • the aggregate is obtainable by incubating the protein species at a pH of 2 to 9 for at least 20 min, prefera ⁇ bly at least 1 h, especially at least 4 h (see also: e.g. WO 2013/050249 Al) .
  • Preferred passive vaccines to be improved according to the present invention are vaccines containing monoclonal antibodies directed against the ⁇ and tau proteins and variants listed above.
  • Preferred monoclonal antibodies are selected from the group consisting of solanezumab, bapineuzumab, gantenerumab, crenezumab, ponezumab, and aducanumab. Although these antibodies have not been successful in clinical trials yet, their potential is, at least partially, still believed to be present.
  • the pre ⁇ sent invention is a strategy to provide to such antibodies clin ⁇ ical efficiency in humans, if combined with an effective amount of the aluminium salt, especially aluminium oxyhxdroxide (Alhy- drogel) .
  • the combination of the active or passive vaccine with the aluminium salt according to the present invention can be provided in a single vaccine preparation. It can also be applied by a combination of separated agents (as a "kit") so that both compo ⁇ nents can be administered separately to a patient.
  • a preferred embodiment of the present invention is a vaccine comprising two components,
  • an active or passive vaccine against ⁇ especially ⁇ 1-42, and/or against tau, especially hyperphosphorylated tau
  • an immune stimulating pharmaceutical composition comprising an aluminium salt, especially aluminium oxyhydroxide, (given as AI 2 O 3 equivalent) .
  • the two components may be provided together (as "kit of parts", optionally together with other components, such as ad ⁇ ministration devices, especially syringes, instructions for use, diluents, mixing devices (for mixing dried components with dilu ⁇ ents) , etc.) or separately. They may be administered in paral ⁇ lel, subsequently or alternating.
  • Suitable active and passive vaccines are well available in the art and have also been subject to intensive clinical testing (such as ACC-001 and AN-1792 with a vaccine against ⁇ ) .
  • Pre ⁇ ferred vaccines to be improved according to the present inven ⁇ tion for the treatment and prevention of AD are disclosed in many patent documents, such as WO 1993/011231 A, WO 1995/017429 A, US 2009/0238831, WO 99/27944 A, WO 00/72880 A, WO 01/62801 A, WO 02/46237 A, WO 02/088306 A, WO 02/088307 A, WO 00/77178 A, WO 03/070760 A, WO 03/016466 Al, WO 2007/068429 A, EP 2 009 104 A, US 2012/0244146 Al, WO 2014/008404 A, EP 0 772 634 A, (monoclo ⁇ nal antibodies, especially humanised and human antibodies bind ⁇ ing to
  • the vaccine to be improved is an active vaccine containing pep ⁇ tides eliciting an immune response against a relevant form of ⁇ (or other proteins/polypeptides proposed for active vaccination for the treatment of AD) .
  • ⁇ peptide or - preferably - a mimotope vaccine contains the peptide or the mimotope peptide preferably bound to an immunogenic carrier, especially an immu ⁇ nogenic protein, non-toxic diphtheria toxin mutant, keyhole lim ⁇ pet hemocyanin (KLH) , diphtheria toxin (DT) , tetanus toxid (TT) and Haemophilus influenzae protein D (protein D) .
  • an immunogenic carrier especially an immu ⁇ nogenic protein, non-toxic diphtheria toxin mutant, keyhole lim ⁇ pet hemocyanin (KLH) , diphtheria toxin (DT) , tetanus toxid (TT) and Haemophilus influenzae
  • Suitable epitope comprises an amino acid sequence selected from the group consisting of DAEFRH, EFRHDSGY, pEFRHDSGY, EVHHQKL, HQKLVF and HQKLVFFAED.
  • Mimotopes of the amyloid-beta-peptide are well known to the person skilled in the art (see e.g. WO 2006/005707 A, WO 2009/149485 A, WO 2009/149486 A, WO 2009/149487 A, WO 2013/164357 A) .
  • ⁇ is G or an amino acid with a hydroxy group or a negatively charged amino acid, preferably glycine (G) , glutamic acid (E) , tyrosine (Y) , serine (S) or aspartic acid (D) ,
  • X2 is a hydrophobic amino acid or a positively charged amino acid, preferably asparagine (N) , isoleucine (I), leucine (L) , valine (V) , lysine (K) , tryptophane (W) , arginine (R) , tyrosine (Y) , phenylalanine (F) or alanine (A) ,
  • X3 is a negatively charged amino acid, preferably aspartic acid (D) or glutamic acid (E) ,
  • X4 is an aromatic amino acid or a hydrophobic amino acid or leucine (L) , preferably tyrosine (Y) , phenylalanine (F) or leu ⁇ cine (L) ,
  • X5 is histidine (H) , lysine (K) , tyrosine (Y) , phenylalanine
  • XQ is not present or serine (S) , threonine (T) , asparagine (N) , glutamine (Q) , aspartic acid (D) , glutamic acid (E) , argi ⁇ nine (R) , isoleucine (I), lysine (K) , tyrosine (Y) , or glycine
  • G preferably threonine (T) , asparagine (N) , aspartic acid (D) , arginine (R) , isoleucine (I) or glycine (G) ,
  • X7 is not present or any amino acid, preferably proline (P) , tyrosine (Y) , threonine (T) , glutamine (Q) , alanine (A) , histi ⁇ dine (H) or serine (S) ,
  • the at least one mimotope comprises or consists of the amino ac ⁇ id sequence
  • X2' is tryptophan (W) or tyrosine (Y) ,
  • X3' is threonine (T) , valine (V) , alanine (A) , methionine (M) , glutamine (Q) or glycine (G) ,
  • X ' is proline (P) , alanine (A) , tyrosine (Y) , serine (S) , cysteine (C) or glycine (G) ,
  • X5' is proline (P) , leucine (L) , glycine (G) or cysteine
  • ⁇ ,' is cysteine (C) ,
  • n, m and o are, independently, 0 or 1
  • IRWDTP C
  • VRWDVYP C
  • IRYDAPL C
  • IRYDMAG C
  • IRWDTSL C
  • IRWDQP C
  • IRWDG C
  • IRWDGG C
  • the at least one mimotope comprises or consists of the amino acid sequence
  • X3'' is alanine (A), histidine (H) , lysine (K) , leucine (L) , tyrosine (Y) or glycine (G) ,
  • X '' is proline (P) , histidine (H) , phenylalanine (F) or glutamine (Q) or Cysteine
  • X5'' is cysteine (C)
  • n' and m' are, independently, 0 or 1
  • the at least one mimotope comprises or consists of an amino acid sequence selected from the group consisting of
  • MYFPH C
  • TYFSHSL C
  • HEPLFSH C
  • SLMRHSS C
  • EFLRHTL C
  • ATPLFRH C
  • QELKRYY C:
  • THTDFRH C
  • LHIPFRH C
  • NELFKHF C
  • LQFKHS (C ) , ATFRHS (C: ), TGLMFKH (C) , AEFSHWH (C) , QSEFKHW (C) ,
  • AEFMHSV C
  • ADHDFRH DGLLFKH
  • C DGLLFKH
  • C IGFRHDS
  • SNSEFRR C
  • SNFRHSV C
  • APIQFRH C:
  • AYFPHTS C
  • NSSELRH C
  • TEFRHKA C
  • the at least one mimotope preferably comprises or consists of the amino acid sequence
  • X2a is serine (S) , threonine (T) , glutamic acid (E) , aspar- tic acid (D) , glutamine (Q) or methionine (M) ,
  • X3a is isoleucine (I), tyrosine (Y) , methionine (M) or leu ⁇ cine (L) ,
  • X a is leucine (L) , arginine (R) , glutamine (Q) , tryptophan (W) , valine (V), histidine (H) , tyrosine (Y) , isoleucine (I), lysine (K) methionine (M) or phenylalanine (F) ,
  • X5a is alanine (A) , phenylalanine (F) , histidine (H) , aspar- agine (N) , arginine (R) , glutamic acid (E) , isoleucine (I), glu ⁇ tamine (Q) , aspartic acid (D) , proline (P) or tryptophane (W) , glycine (G)
  • X6a is an Y amino acid residue
  • X7a is cysteine (C) .
  • n' ' and n' ' are, independently, 0 or 1
  • the at least one mimotope comprises or consists of the amino ac ⁇ id sequence
  • X2b is glutamine (Q) , threonine (T) or methionine (M) ,
  • X3b is lysine (K) or arginine (R) ,
  • X b is leucine (L) , methionine (M) ,
  • X5b is tryptophane (W) , tyrosine (Y) , phenylalanine (F) or isoleucine ( I ) ,
  • X3 ⁇ 4b is asparagine (N) , glutamic acid (E) , alanine (A) or cysteine (C) ,
  • X7b is cysteine (C) .
  • n' ' ' and m' ' ' are, independently, 0 or 1,
  • SHTRLYF C
  • HMRLFF C
  • SHQRLWF(C) SHQRLWF(C)
  • HQKMIFA C
  • HMRMYFE C
  • THQRLWF C
  • HQKMIF C
  • the at least one mimotope preferably comprises or consists of an amino acid sequence selected from the group consisting of AIPLFVM(C), KLPLFVM (C) , QLPLFVL (C) or NDAKIVF (C) .
  • the mimotope comprises 4 to 30, preferably 4 to 20, more prefer ⁇ ably 4 to 16 amino acid residues. It is also preferred that the mimotopes are provided in the vaccine according to their se ⁇ quence (i.e. without other amino acids N- or C-terminally, ex ⁇ cept linking amino acids, such as cysteine (C) or glycine (G) or combinations thereof , such as CG-, CGG-, -GC and -GGC.
  • se ⁇ quence i.e. without other amino acids N- or C-terminally, ex ⁇ cept linking amino acids, such as cysteine (C) or glycine (G) or combinations thereof , such as CG-, CGG-, -GC and -GGC.
  • the mimotope comprises or consists of an amino acid sequence se ⁇ lected from the group consisting of DKELRI, SWEFRT, SEFKHG, ILFRHG, TLHEFRH, GAEFRFT, DWEFRD, SLEFRF, GREFRN, IRWDTP and HQKMIFA.
  • the mimotopes may comprise at the C- and/or N-terminal end a cysteine residue.
  • the vaccine according to the present invention contains at least one mimotope of an ⁇ epitope, and wherein said at least one mimotope is coupled or fused to a pharmaceuti ⁇ cally acceptable carrier protein selected from the group con ⁇ sisting of a non-toxic diphtheria toxin mutant, keyhole limpet hemocyanin (KLH) , diphtheria toxin (DT) , tetanus toxid (TT) and Haemophilus influenzae protein D (protein D) .
  • KLH keyhole limpet hemocyanin
  • DT diphtheria toxin
  • TT tetanus toxid
  • protein D Haemophilus influenzae protein D
  • epitope refers to an immunogenic region of an antigen (e.g. ⁇ or tau) which is recognized by a particular antibody molecule.
  • An antigen may possess one or more epitopes, each capable of binding an antibody that recognizes the particular epitope.
  • the term "mimotope" re ⁇ fers to a molecule which has a conformation that has a topology equivalent to the epitope of which it is a mimic.
  • the mimotope binds to the same antigen-binding region of an antibody which binds immunospecifically to a desired antigen.
  • the mimotope will elicit an immunological response in a host that is reactive to the antigen to which it is a mimic.
  • the mimotope may also act as a competitor for the epitope of which it is a mimic in in vitro inhibition assays (e.g. ELISA inhibition assays) which involve the epitope and an antibody binding to said epitope.
  • in vitro inhibition assays e.g. ELISA inhibition assays
  • a mimotope of the present invention may not necessarily prevent or compete with the binding of the epitope of which it is a mimic in an in vitro inhibition assay although it is capable to induce a specific immune response when administered to a mammal.
  • the compounds of the present invention comprising such mimotopes (also those listed above) have the advantage to avoid the for ⁇ mation of autoreactive T-cells, since the peptides of the com ⁇ pounds have an amino acid sequence which varies from those of naturally occurring amyloid-beta peptide.
  • the mimotopes of the present invention can be synthetically produced by chemical synthesis methods which are well known in the art, either as an isolated peptide or as a part of another peptide or polypeptide.
  • the peptide mimotope can be produced in a microorganism which produces the peptide mimo ⁇ tope which is then isolated and if desired, further purified.
  • the peptide mimotope can be produced in microorganisms such as bacteria, yeast or fungi, in eukaryote cells such as a mammalian or an insect cell, or in a recombinant virus vector such as ade ⁇ novirus, poxvirus, herpesvirus, Simliki forest virus, baculovi- rus, bacteriophage, Sindbis virus or sendai virus.
  • Suitable bac ⁇ teria for producing the peptide mimotope include E.coli, B.subtilis or any other bacterium that is capable of expressing peptides such as the peptide mimotope.
  • Suitable yeast types for expressing the peptide mimotope include Saccharomyces cere- visiae, Schizosaccharomyces pombe, Candida, Pichia pastoris or any other yeast capable of expressing peptides. Corresponding methods are well known in the art. Also methods for isolating and purifying recombinantly produced peptides are well known in the art and include e.g. as gel filtration, affinity chromatog ⁇ raphy, ion exchange chromatography etc.
  • a fusion polypeptide may be made wherein the peptide mimotope is transla- tionally fused (covalently linked) to a heterologous polypeptide which enables isolation by affinity chromatography.
  • Typical heterologous polypeptides are His-Tag (e.g. His6; 6 histidine resi ⁇ dues), GST-Tag (Glutathione-S-transferase) etc..
  • His-Tag e.g. His6; 6 histidine resi ⁇ dues
  • GST-Tag Glutathione-S-transferase
  • the fusion polypeptide may comprise a cleavage site at the junction between the peptide mimotope and the heterologous polypeptide.
  • the cleavage site consists of an amino acid sequence that is cleaved with an en ⁇ zyme specific for the amino acid sequence at the site (e.g. pro ⁇ teases) .
  • the mimotopes of the present invention may also be modified at or nearby their N- and/or C-termini so that at said positions a cysteine residue is bound thereto.
  • the mimotopes according to the present invention preferably are antigenic polypeptides which in their amino acid sequence vary from the amino acid sequence of ⁇ or of fragments of ⁇ .
  • the inventive mimotopes may not only comprise amino acid substitutions of one or more naturally occurring ami ⁇ no acid residues but also of one or more non-natural amino acids (i.e. not from the 20 "classical” amino acids) or they may be completely assembled of such non-natural amino acids.
  • inventive antigens which induce antibodies directed and binding to ⁇ 1-40/42, ⁇ 3-40/42, AB3-40/42, ⁇ -40/42, ⁇ 11-40/42 and AB14-40/42 may be assembled of D- or L- amino ac ⁇ ids or of combinations of DL- amino acids and, optionally, they may have been changed by further modifications, ring closures or derivatisation .
  • Suitable antibody-inducing antigens may be provided from commercially available peptide libraries.
  • these peptides are at least 7 amino acids, and preferred lengths may be up to 16, preferably up to 14 or 20 amino acids (e.g. 5 to 16 amino acid residues) . According to the invention, however, also longer peptides may very well be employed as antibody- inducing antigens.
  • the mimotopes of the present in ⁇ vention may also be part of a polypeptide and consequently com ⁇ prising at their N- and/or C-terminus at least one further amino acid residue.
  • These vaccines according to the present invention comprises the peptide epitopes or the mimotopes according to the invention in an amount of from 0.1 ng to 10 mg, preferably 10 ng to 1 mg, in particular 100 ng to 100 yg, or, alternatively, e.g. 100 fmol to 10 pmol, preferably 10 pmol to 1 pmol, in particular 100 pmol to 100 nmol.
  • the vaccine may also contain auxiliary substances, e.g. buffers, stabilizers etc.
  • the composition of the present invention may also comprise auxiliary substances, e.g. buffers, stabilizers etc.
  • auxiliary substances e.g. a pharmaceutically acceptable excipient, such as water, buffer and/or stabilisers, are contained in an amount of 0.1 to 99 % (weight), more pre ⁇ ferred 5 to 80% (weight) , especially 10 to 70 % (weight) .
  • the aluminium salt espe ⁇ cially aluminium oxyhydroxide is preferably provided in a higher amount as 1.2 mg/dose (mainly because of the protein binding ca ⁇ pacity of the aluminium salts) .
  • a preferred em ⁇ bodiment is characterised by the vaccine containing the alumini ⁇ um salt in an amount of 1.2 to 10.0 mg per dose, preferably 1.5 to 8 mg per dose, especially 1.8 to 5 mg per dose (given as AI 2 O 3 equivalent) .
  • an improved vaccine having the aluminium salt in an amount of 1.9 to 9.0 mg per dose, preferably 2.5 to 8.0 mg per dose especially 3.0 to 7.0 mg per dose (given as AI 2 O 3 equivalent) .
  • Another preferred embodiment is characterised by the vaccine containing the alu ⁇ minium salt in an amount of 1.2 to 4.0 mg per dose, preferably 1.5 to 3 mg per dose, especially 1.8 to 2.5 mg per dose (given as AI 2 O 3 equivalent) .
  • the vaccine contains the alu ⁇ minium salt in an amount of 2.5 to 10.0 mg per dose, preferably 3.5 to 8 mg per dose, especially 4.5 to 7.5 mg per dose (given as AI 2 O 3 equivalent) . Since passive vaccines usually have a high ⁇ er protein content, passive vaccines should contain higher amounts of the aluminium salts according to the present inven ⁇ tion, compared to active vaccine preparations.
  • the alumin ⁇ ium salt is provided in an amount of 1.5 to 2.5 mg per dose, preferably of 1.9 to 2.1 mg per dose, especially 2.0 mg per dose (given as AI 2 O 3 equivalent) .
  • the vaccine may further contain adjuvants, preferably con ⁇ tains a proteasome adjuvant.
  • the vaccine is provided in lyophilised, dried or frozen form, preferably in a prefilled syringe (or kit compris ⁇ ing a pair of prefilled syringes) .
  • the present invention also re ⁇ lates to a kit for use in the treatment and prevention of demen ⁇ tias associated with ⁇ -amyloid deposition, preferably AD, com ⁇ prising
  • an immune stimulating pharmaceutical composition comprising an aluminium salt, especially aluminium oxyhydroxide, wherein the an aluminium salt is present in an amount of at least 1.2 mg per dose, preferably at least 1.5 mg per dose, especially at least 1.8 mg (given as AI 2 O 3 equivalent) per dose (given as AI 2 O 3 equiv ⁇ alent) .
  • the active or passive vaccine is then provided and adminis ⁇ tered separately from the immune stimulating pharmaceutical com ⁇ position containing the aluminium salt, especially aluminium oxyhydroxide .
  • the most preferred embodiment of the present invention comprises the effective administration of alu ⁇ minium oxyhydroxide (particularly as Alhydrogel) to AD patients (separately or combined with an active or passive AD vaccine) .
  • Aluminium salts have a long-standing use as adjuvants in vaccines, however, during the years the pharmaceutical use of such salts has been reduced to mostly two suspension prepara ⁇ tions, namely Alhydrogel (aluminium-oxyhydroxide) and AdjuPhos (aluminiumhydroxyphosphate) , onto which antigens are adsorbed for vaccine preparations (reviewed in E. B. Lindblad (2004) Vac ⁇ cine 22, 3658-3668; E. B. Lindblad (2004) Immunology and Cell Biology 82, 497-505; R. K. Gupta (1998) Adv. Drug Delivery Rev. 32, 155-172) .
  • Alhydrogel aluminium-oxyhydroxide
  • AdjuPhos aluminiumhydroxyphosphate
  • Alhydrogel forms a depot at the injection side has turned out to be only one part of a multi-faceted story (reviewed in C. Exley, P. Siesjo, H. Eriksson (2010) Trends Immunol. 31, 103-109; S. L. Hem, H. HogenEsch (2007) Expert Rev. Vaccines 6, 685-698; P. Marrack, A. S. McKee, M. W. Munks (2009) Nature Rev. Immunol. 9, 287-293; S. G. Reed, M. T. Orr, C. B. Fox (2013) Nat. Med. 19, 1597-1608) .
  • aluminium adjuvants used in humans are aluminium hydroxide (or aluminium oxyhydroxide) and aluminium phosphate. Both presentations are usually prepared by expos ⁇ ing a soluble aluminium salt (historically potassium alum, i.e. KA1 (SO 4 ) 2 ⁇ 123 ⁇ 40, was often used) to alkaline conditions, upon which a suspension is formed. Characterisation with X-ray crystallography and IR spectroscopy revealed a boehmite-like struc ⁇ ture (aluminium oxyhydroxide) for aluminium hydroxide and an amorphous structure corresponding to aluminium hydroxyphosphate for aluminium phosphate.
  • a soluble aluminium salt historically potassium alum, i.e. KA1 (SO 4 ) 2 ⁇ 123 ⁇ 40, was often used
  • Preferred aluminium salts according to the present invention have the general formula Me a + Al b 3+ An c ⁇ -nH20, wherein
  • Me + is Na + , K + , Li + , Rb + , Cs + or NH 4 + ;
  • a 0, 1, 2, or 3;
  • b is 1 or 2 ;
  • c is 1, 2, 3, 4, 5, or 6;
  • n 0 to 48.
  • aluminium salts are those that have been studied, examined and verified in and for human use, such as aluminium hydroxide, aluminium oxyhydroxide, aluminium phosphate, aluminium sulphate, or any kind of "alum” (wherein “al ⁇ um” is usually referred to a class of chemical compounds, includ ⁇ ing the "classical alum", a hydrated potassium aluminium sulfate (potassium alum) with the formula KA1 (SO 4 ) 2 '123 ⁇ 40, and - more gen ⁇ erally double sulfate salts, with the formula AA1 (SO 4 ) 2 '123 ⁇ 40, where A is a monovalent cation such as potassium or ammonium) .
  • A is a monovalent cation such as potassium or ammonium
  • aluminium salts ac ⁇ cording to the present invention are selected from aluminium hydroxide, aluminium oxyhydroxide, aluminium phosphate, or alumin ⁇ ium sulphate, especially aluminium oxyhydroxide, which has been intensively investigated in the course of the present invention, since it is the preferred adjuvant in human use (as Alhydrogel adjuvant in various vaccines) .
  • Aluminium oxyhydroxide preparations have a point of zero charge at a pH of ⁇ pH 11, while aluminium hydroxyphosphate might have a point of zero charge as low as pH 4 (depending on the phosphate content) . Therefore aluminium oxyhydroxide and al ⁇ uminium hydroxyphosphate have an opposite surface charge at neu ⁇ tral pH, with the latter being negatively charged. It has to be mentioned, however, that the surface charge may change depending on the exact buffer composition, especially phosphate ions have the capacity to lower the surface charge of aluminium oxyhydrox ⁇ ide .
  • the preparation is devoid of an ⁇ ions such as sulphates, nitrates, or chlorides and has a speci ⁇ fied heavy metal content of less than 20 ppm.
  • the suspension of aluminium oxyhydroxide has a particle size distribution between 2 ym and approximately 10 ym, which are aggregates composed of smaller fibers of ⁇ 2nm x 4.5 nm x lOnm.
  • the current in ⁇ vention relates to the use of European Pharmacopoeial grade (Al- uminium-oxyhydroxide, monograph 1664), more specifically to the product manufactured by Brenntag Biosector (2% Alhydrogel) test ⁇ ed towards EP compliance.
  • Alhydrogel is available in three vari ⁇ eties: Alhydrogel 1.3%; Alhydrogel 2% and Alhydrogel "85". Alhy ⁇ drogel 2% was elected as the International Standard Preparation for aluminium hydroxide gels.
  • the pharmaceutical preparation of Alhydrogel to be used according to the present invention is aseptically formulated into a suitable buffer, preferably an isotonic phosphate buffer (ImM to 100 mM) , preferably at a con ⁇ centration of ⁇ 1.0 mg/ml Alhydrogel (given as AI 2 O 3 equivalent; this metric (Al as "AI 2 O 3 equivalent”) is used generally for the present invention; accordingly, all doses and amounts referred to in the present application, as far they are relating to alu ⁇ minum salts (especially as far as they are relating to aluminium oxyhydroxide) refer to AI 2 O 3 equivalents (of aluminium oxyhydrox ⁇ ide (Alhydrogel) ) ) , even more preferably at a concentration of ⁇ 1.5 mg/ml Alhydrogel (given as AI 2 O 3 equivalent), most preferable at a concentration of ⁇ 2.0 mg/ml Alhydrogel (given as AI 2 O 3 equivalent) .
  • Alhydrogel 2% is an alumin ⁇ ium oxyhydroxide wet gel suspension.
  • the aluminium salt to be administered to the patient is an alumini ⁇ um oxyhydroxide suspension, preferably European Pharmacopoeia grade aluminium-oxyhydroxide (monograph 1664), especially Alhy ⁇ drogel.
  • the aluminium oxyhydroxide is administered together with the active or passive vaccine in an amount effective to achieve an AD ameliorating effect, as defined by the EMEA Guideline on medical products for the treatment of AD and other dementias (Document Ref. CPMP/EWP/553/95 Rev.l of 24 July 2008).
  • any administration procedure or dosage regimen for the aluminium salt formulation, especially aluminium-oxyhydroxide formulation, according to the present invention that is suitable to achieve the AD modifying effect as provided by the present invention is subject to the present invention.
  • the preferred strategy for ad ⁇ ministration is by administration of doses, for example by subcutaneous injection.
  • the administration dose of aluminium oxyhydroxide is of at least 0.5, preferably at least 0.8, more preferred at least 1.0 mg, especially at least 1.2 mg, to an AD patient, specifically if administered separate ⁇ ly.
  • the amount of aluminium salt corresponds to the effective amount (whereas in the case the al ⁇ uminium salt is combined with proteins/polypeptides, part of this amount is bound and therefore not effective in the meaning of the present invention) .
  • a preferred range of amount to be ad ⁇ ministered to a patient (if administered separately) is an amount of aluminium oxyhydroxide of 1.2 mg to 5.0 mg.
  • the AD ameliorating effect of aluminium oxyhydroxide administration is even more pronounced at an amount of at least 1.5 mg.
  • aluminium oxyhydroxide is admin ⁇ istered in an amount of 1.5 mg to 5.0 mg, preferably 1.5 to 3.0 mg, especially 1.5 to 2.5 mg, to an AD patient.
  • Another pre ⁇ ferred embodiment comprises administration of aluminium oxyhydroxide in an amount of 1.6 mg to 2.5 mg, preferably 1.8 to 2.2 mg, especially 1.9 to 2.0 mg, to an AD patient.
  • the aluminium ox ⁇ yhydroxide is provided in the pharmaceutical preparation to be administered to in an amount of 2.2 mg or higher, specifically, if administered in combination (i.e. admixture) with the active or passive vaccine.
  • This amount is even higher as prescribed in the US general biological products standards (U.S.C. 21 CFR 610.15 (as of 1 April 2013)).
  • Such preferred higher ranges of aluminium oxyhydroxide are i.a. 2.2 to 10 mg, 2.2 to 8 mg, 2.2 to 5 mg, and 2.2 to 4 mg for one administration dose.
  • the aluminium salt preparation according to the present invention may (if administered separately from the active or pas ⁇ sive vaccine) contain various auxiliary substances that have no specific clinical effect but are useful in the dosage form to be administered, be it for administration purposes, storage purpos ⁇ es, or other purposes.
  • the aluminium oxyhydroxide preparation to be applied according to the present invention contains a pharmaceutically acceptable carrier, diluent or excipient, for example water for injection.
  • the aluminium oxyhydroxide preparation according to the present invention additionally contains one or more stabili- sators, especially thiomersal, detergents, antioxidants, com- plexing agents for mono- or divalent metal ions, especially eth- ylenediaminetetraacetic acid (EDTA) , sugars, sugar alcohols, glycerol, and/or buffer substances, especially TRIS or phosphate buffer substances.
  • stabili- sators especially thiomersal, detergents, antioxidants, com- plexing agents for mono- or divalent metal ions, especially eth- ylenediaminetetraacetic acid (EDTA) , sugars, sugar alcohols, glycerol, and/or buffer substances, especially TRIS or phosphate buffer substances.
  • EDTA eth- ylenediaminetetraacetic acid
  • the dosage form to be administered to the patients can be provided in any convenient volume, preferably as injectable sus ⁇ pension, e.g. with a volume of between 0.1 and 10 ml, more pre ⁇ ferred of 0.2 to 5 ml, especially of 0.4 to 3 ml. Specifically preferred volumes are 0.5, 1, 1.5 and 2 ml.
  • the pharmaceutical preparations according to the present invention are produced ac ⁇ cording to pharmaceutical Good Manufacturing Practice (GMP) , as required and defined by the European and/or US Pharmacopeia.
  • GMP Good Manufacturing Practice
  • the aluminium oxyhy- droxide is administered to a patient in a suspension (optionally together with the active or passive vaccine) with a pH of 4 to 10, preferably of 5 to 9, more preferred of 6 to 8, especially from 7.0 to 7.5.
  • the suspension is an isotonic sus ⁇ pension .
  • the aluminium salt (optionally together with the active or passive vaccine) is administered by a route that is as convenient as possible for the AD patient but is still effective to achieve an AD modifying effect.
  • Most effective treatment routes of aluminium oxyhydroxide (optionally together with the active or passive vaccine) according to the present invention are subcutaneous, intranodal, intradermal, or intramuscular ad ⁇ ministration, especially subcutaneous administration.
  • Subcutane ⁇ ous administration is performed as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, espe ⁇ cially in the fatty tissue in the subcutis.
  • Administration regimes can be optimised individually for each patient, depending on the treatment success, as measured by various parameters, especially by cognitive and functional per ⁇ formances and by biomarkers, especially MRI scans concerning hippocampus volume (see below) .
  • at least monthly ad ⁇ ministrations of aluminium oxyhydroxide to an AD patient have proven to be successful in ameliorating AD.
  • at least monthly ad ⁇ ministrations should be continued for at least three months, es ⁇ pecially at least six months.
  • Administration of the aluminium salt (optionally together with the active or passive vaccine) according to the present in ⁇ vention may also be performed at least twice a month (for exam ⁇ ple bi-weekly or weekly) ; also in such a dosage regimen, aluminium oxyhydroxide should be administered to an AD patient at least for a period of three months, preferably for at least six months, more preferred for at least twelve months, especially at least 24 months.
  • the administration of the aluminium salt is performed separately from the active or passive vaccine, such separate administration may be performed at the same session as the administration of the active or passive vaccination; howev- er, it may be preferred to alternate the administrations (week ⁇ ly, bi-weekly or monthly) or at least have at least one day, preferably two days, especially at least one week between the administration of the active or passive vaccine and the alumini ⁇ um salt.
  • the aluminium salt is administered first, then the active or passive vaccine follows in a week and then the next aluminium administration follows in another week or a month later (and so on), or vice versa.
  • aluminium oxyhydroxide is administered to an AD patient (optionally together with the active or passive vaccine) subcutaneously in the (outer area of the) upper arm, preferably alternating in the left and in the right upper arm (i.e. administering the first dose (or the ac ⁇ tive/passive vaccine) into the right (or left) upper arm and the second dose (the aluminium salt) into the left (right arm) , and so on), or vice versa.
  • the dose(s) to be administered can also be split into two (or more) split doses that are administered sim ⁇ ultaneously (at the same physician date; at least at the same day) to the AD patient.
  • a dose of 2 mg may be split to split doses of 1.8 and 0.2 mg, 1.7 and 0.3 mg, 1.5 and 0.5 mg, 1.34 and 0.76 mg, 1.0 and 1.0 mg, 1.05 and 0.95 mg, 1.0, 0.5 and 0.5 mg, 0.6, 0.6 and 0.7 mg, 0.2, 0.5, and 1.3 mg, 0.5, 0.5, 0.5 and 0.5 mg, 0.2, 0.3, 0.5 and 1.0 mg, etc..
  • the split doses may be administered at different administration sites or, pref ⁇ erably, at the same site of administration.
  • the "same site of administration" is within an area of 10 cm 2 of the skin, preferably within an area of 5 cm 2 of the skin, especially within 1 cm 2 of the skin.
  • Preferred split doses contain aluminium oxyhydrox ⁇ ide in an amount of 0.8 to 5.0 mg, preferably of 1.0 to 3.0, es ⁇ pecially from 1.0 to 1.5 mg.
  • the treatment according to the present invention is performed for longer than one year.
  • the aluminium salt is ad ⁇ ministered at least monthly for at least two years, preferably at least four years, especially at least 8 years, to an AD pa ⁇ tient .
  • Administration of the active or passive vaccine and the alu ⁇ minium salt, especially the aluminium oxyhydroxide, according to the present invention may be performed by any suitable admin ⁇ istration device.
  • the vaccines accord ⁇ ing to the present invention are administered by an injection device, especially a syringe, to an AD patient.
  • passive immunisation is also often performed by way of infusion (which makes the use of separate administration of passive vaccine and aluminium salt often a preferred embodiment) .
  • the pharmaceutical preparations for use in the present invention can be provided in any suitable form. Preferably, they are provided in a storage stable form. Storage stability can be assured by various means, such as sterilisation, addition of stabilisers, freezing, lyoph- ilisation, etc.
  • combinations of such means are used to enhance storage stabilities of such preparations.
  • alumi ⁇ num-salt containing agents such as aluminium oxyhydroxide con ⁇ taining pharmaceutical formulations
  • an aggregation of adjuvant particles during processing may be observed.
  • Alhydrogel aluminium ox ⁇ yhydroxide
  • compositions to be applied to patients according to the present invention are manufactured (and fin ⁇ ished) into suitable containers, and sold for example in sealed vials, ampoules, cartridges, flexible bags (often constructed with multi-layered plastic) , glass or polypropylene bottles or, preferably, in syringes, especially in prefilled (ready-to-use or ready-to-reconstitute) syringes.
  • the aluminium oxyhydroxide is administered (optionally to ⁇ gether with the active or passive vaccine) in an amount of at least 1.8 mg to an AD patient.
  • AD pa ⁇ tients who are early stage patients, including those patients that are often also referred to as "patients with mild cognitive impairment” (MCI) .
  • MCI mild cognitive impairment
  • the concept of MCI was developed in the 1990s to capture patients with early clinical signs of Alzheimer dis ⁇ ease (AD) who did not yet fulfil the criteria for dementia.
  • the amnestic variant of MCI features the following: memory com ⁇ plaints, preferably qualified by an informant; memory impairment for age, as indexed by low cognitive performance in one or more neuropsychological tests that tap into learning abilities (for example, prose recall, word list) ; preserved general cognitive function (for example, Mini-Mental State Examination score of 24 out of 30 or above) ; intact activities of daily living; and no dementia.
  • memory impairment for age as indexed by low cognitive performance in one or more neuropsychological tests that tap into learning abilities (for example, prose recall, word list) ; preserved general cognitive function (for example, Mini-Mental State Examination score of 24 out of 30 or above) ; intact activities of daily living; and no dementia.
  • cognitive impairment for example, depression or age-related cognitive impairment
  • Proposed new diagnostic cri ⁇ teria for AD developed in 2007 (Dubois et al . , Lancet Neurol. 6 (2007), 734-746) suggested that the disease can be recognized at the MCI stage if the patient is positive for at least one of the following four markers: medial temporal atrophy on MRI; temporo ⁇ parietal cortical hypometabolism on 18F-fluorodeoxyglucose PET; abnormality of cerebrospinal fluid markers (tau, amyloid ⁇ 42 or phospho-tau) ; and positivity on amyloid imaging with PET.
  • This patient population is not only included in the AD patients to be treated according to the present invention, it is a specifically preferred group of patients for which the treatment method ac ⁇ cording to the present invention is specifically effective. This is in line with the revised criteria for AD clinical trials adopted by the US-FDA (Aisen et al . , 2013; Kozauer et al . , 2013) . Accordingly, it is preferred to treat patients in an ear ⁇ ly state of AD, as defined by a relatively high MMSE (mini- mental state examination or Folstein test) score.
  • MMSE mini- mental state examination or Folstein test
  • the AD patient to be treated according to the present invention is a patient with an MMSE score of between 23 and 30 (30 being the maximum), preferably between 24 and 30, more preferably between 25 and 29, especially between 26 and 29.
  • Other preferred patient groups are patients greater than or equal to 27 points (indicat ⁇ ing a normal cognition) , 25 to 27 (slightly below normal cognition) or 19 to 24 (mild points cognitive impairment) .
  • Early stage AD patients can also be selected by other scores, preferably scores that combine cognitive and functional parameters (and numerical limits) for limiting AD population to be (effectively treated), such as ADAS-cog, etc.
  • the present invention provides for the first time an AD treatment that is disease modifying.
  • the effectiveness of the treatment according to the present invention is proven by the parameters required by the drug authorisation authorities, espe ⁇ cially the EMEA and the US-FDA.
  • the EMEA guideline for AD treatment requires primary endpoints reflecting the cog ⁇ nitive and the functional domain. Accordingly, a combined (Com ⁇ posite) score is used for the clinical assessment of the present invention.
  • This composite score combines two established scores, one for the cognitive function (ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) ) and one for the functional ability (ADCS-ADL (Alzheimer's Disease Co-operative Study - Ac ⁇ tivities of Daily Living Inventory) ) .
  • the adapted ADAS-cog com ⁇ bines items that assess cognitive function.
  • the adapted ADCS-ADL includes items that are sensitive to functional ability. Cogni ⁇ tive skills are expected to decline toward the beginning of the disease and one's ability to perform basic functions are ex ⁇ pected to decline later in the disease.
  • the combined primary outcome (Composite score according to the present invention) combines both the adapted ADAS-cog and adapted ADCS-ADL to cre ⁇ ate a composite that is sensitive to decline in cognitive and basic functions.
  • the following equation is used to derive the combined primary outcome, i.e. combined composite:
  • AD biomarkers were observed with the present invention that are characteristic for AD development.
  • EMEA and FDA criteria recommend newer techniques, such as MRI, especially atrophy of entorhinal or (para-) hippocampal cortex.
  • MRI was applied. More specifically, volume of right hippocampus (important for learning and memory of material that is difficult to verbalise) is used according to the present invention as significant AD biomarker for treatment success.
  • a clinical effect in AD treatment can be observed which can be measured by a reduction in cognitive and/or functional decline (over a treatment period of about one year) by at least 30 % (calculated by the score de ⁇ cline) , preferably by at least 50 %, especially by at least 70 %, compared to a normal development of decline in AD patients.
  • cognitive and functional parameters remain essen ⁇ tially unchanged during treatment.
  • Fig. 1 shows the results of the clinical trial according to the present invention with respect to the change in Composite score composed of (partial) Adapted ADL change and Adapted ADAS- cog change for all patients who have received the 2 mg and 1 mg aluminium oxyhydroxide treatment.
  • Fig. 2 shows a comparison of the mild population of patients (the mild population is defined by a baseline MMSE score of 24 and higher) of both groups showed that this effect is most pro ⁇ nounced in the cohort of patients in earlier disease stages.
  • Fig. 3 shows slowing of disease progression apparent in the 2 mg and 1 mg aluminium group as evidenced by Adapted ADAS-cog (ADAS-cog items only; Least Squares Means) for the 1 mg and 2 mg aluminium oxyhydroxide group compared to the historical control (p-values: 1 mg vs. HC-ADNI , S , HC : ⁇ 0.0001; 2 mg vs. HC- ADNI , S , HC : ⁇ 0.0001) .
  • Fig. 4 shows development of volume (in mm 3 ) of right hippo ⁇ campus for 2 mg and 1 mg aluminium oxyhydroxide treatment group of the mild population of patients (the mild population is de ⁇ fined by a baseline MMSE score of 24 and higher) , showing that this effect is most pronounced in the cohort of patients in ear ⁇ lier disease stages.
  • Fig. 5 shows the Quality of Life-Alzheimer's disease (QOL- AD) for caregivers.
  • Caregivers completed the measure as a ques ⁇ tionnaire about their patients' QOL .
  • the measure consisted of 13 items, rated on a 4 point scale, with 1 being poor and 4 being excellent. Outcomes are shown as the change over time using a least squares means from a mixed model.
  • SeqID 1-KLH Alum + SeqID 2-KLH Alum reduces the relative area covered by amyloid deposits compared to KLH- Alum controls significantly (diffuse and dense cored amyloid; *..p ⁇ 0.05, **..p ⁇ 0.01). A slight but insignificant reduction in ⁇ deposition is detectable in Alum only treated vs. KLH-Alum treated animals, (ns) Arrowhead in C indicates unspecific fluo ⁇ rescence from a cerebral vessel. Scale bar: 200 ⁇ ; pictures tak ⁇ en at lOx magnification.
  • Data supporting the invention are derived from a randomized clinical trial in early AD patients.
  • the study (AFF006; Eudract: 2009-016504-22) randomized early AD patients into 5 treatment arms. Patients of 2 study arms received either 1 mg aluminium or 2 mg aluminium. In total, 99 early AD patients were enrolled in ⁇ to the 2 study arms. Participation of a given patient lasted 18 months .
  • AFF006 was conducted as a randomized, placebo-controlled, parallel group, double-blind, multi-center phase II study and assessed the clinical and immunological activity as well as the safety and tolerability of repeated s.c. administrations of i.a. aluminium (different doses) in patients with early AD, as de ⁇ fined in the protocol. It was performed in a total of 6 coun ⁇ tries: Austria, France, Germany, Slovakia, Czech Republic and Republic .
  • the clinical trial comprised 10 regular outpatient visits and 6 telephone interviews. Up to four weeks before start of treatment, a screening visit (Visit 1) was performed to ensure suitability of the patients for the clinical trial and to estab ⁇ lish the patients' baseline characteristics. Following screen ⁇ ing, eligible patients were randomly allocated to the treatment groups. After randomization at week 0, patients received 6 in ⁇ jections with either 1 or 2 mg aluminium. Injections were applied s.c. by the investigator at weeks 0, 4, 8, 12, 40 and 65 (Visit 2, 3, 4, 5, 7 and 9) .
  • FCSRT Free and Cued Selective Reminding Test
  • Injections were applied to the subcutaneous tissue (s.c). Special care was taken to avoid intravasal application by care ⁇ ful aspiration before each injection. All administrations were performed at the trial site.
  • Hippocampus (left and right) , and whole lateral ventricle ROIs were delineated on an anatomical MRI template in order to generate the atlas for volumetric measures.
  • the volumes of the hippocampus and lateral ventricles for each subject were deter ⁇ mined using a fully-automated method which combines transfor ⁇ mations derived from the nonlinear registration of the atlas la ⁇ bels to individual subject scans and subject-specific image in ⁇ formation (Collins et al . , J. Comput . Assist. Tomogr., 18: 192- 205, 1994). Lateral ventricle and hippocampal segmentations that failed post-processing QC review were manually corrected.
  • the total intracranial volume (TIV) was estimated from the brain mask generated during pre-processing and the average TIV (TIV avg ) for each subject was determined by averaging the estimated TIV across visits.
  • the normalization factor (TIV t em P iate/TIV avg _subj ect ) was used to normalize the hippocampal and ventricular volumes for each subject in order to account for differences in head size .
  • AEs adverse events
  • SAEs serious adverse events
  • the primary efficacy variables are the change from baseline (CFB) in cognition as measured by an adapted ADAS-cog, CFB in function as measured by an adapted ADCS-ADL and a combination of CFB in cognition and function as measured by a combined compo ⁇ site:
  • ADAS-cog and other items included in the adapted ADAS-cog were measured at Visits 1, 2, 3, 5, 6, 7, 8, 9 and 10 or EDV.
  • ADCS-ADL were measured at Visits 2, 5, 6, 7, 8, 9 and 10 or EDV.
  • Items that contributing to the combined primary outcome were measured at Visits 2, 5, 6, 7, 8, 9 and 10 or EDV.
  • the primary efficacy outcomes all range from 0 to 100.
  • a lower score indicates better performance.
  • some items included in a scale may be op ⁇ posite in direction, i.e. a higher score indicates better performance.
  • An item is reversed in score by subtracting the observed value from the maximum possible value for the item. This reverses the scale of the items so that a lower score now indicates better perfor ⁇ mance.
  • the following items included in the adapted ADAS-cog and combined composite require reverse scoring: Verbal PAL, NTB Cat ⁇ egory Fluency and CogState ONB.
  • QOL Quality of Life
  • QOL caregiver is a brief, 13-item questionnaire designed to specifically obtain a rating of the QOL of the patient from the caregiver's perspective. Questions cover relationships with friends and family, concerns about finances, physical condition, mood, and an overall assessment of life quality. All items are rated on a four-point scale, with 1 being poor and 4 being ex ⁇ cellent. The total score is the sum of all items, which can range from 13 to 52. QOL caregiver values are presented here as the change from baseline. Outcomes were measured at Visits 1,6, 8, and 10.
  • Demographic information assessed was age, gender, racial group, smoking habits, level of education, height and weight. Subject demographics was summarized by treatment for the Safety, ITT and Per Protocol populations.
  • the primary, secondary and exploratory efficacy outcomes were analyzed by comparing change over time between the groups.
  • the efficacy analyses utilized the mixed model described below.
  • the mixed model analysis compared the estimated change from baseline between the 3 vaccine and the 2 aluminium groups in all efficacy outcome scores at each visit.
  • the model used separate repeated measures longitudinal models for each efficacy end- point. This analysis assessed whether or not there is a differ ⁇ ence in estimated CFB values between treatment groups.
  • SAS ⁇ PROC MIXED was used to fit a mixed model with repeated measures (MMRM) , with CFB of each of the efficacy outcomes (e.g., Adapted ADAS-cog) as the response variable and the fol ⁇ lowing covariates and fixed effects:
  • the covariance structure for the model was first-order het ⁇ erogeneous autoregressive (ARH[1]).
  • Least-squares means were es ⁇ timated at each visit in the study.
  • the LS mean at a particular visit was interpreted as the expected CFB in the efficacy out ⁇ come at that time point (Visit) when the specified treatment was administered.
  • Least squares means and standard errors were esti ⁇ mated from the mixed model at each visit and are shown for the various groups.
  • the adapted ADAS-cog combines items that assess cognitive function.
  • the adapted ADCS-ADL includes items that are sensitive to functional ability. Cognitive skills are expected to decline toward the beginning of the disease and one's ability to perform basic functions are expected to decline later in the disease.
  • the combined primary outcome (referred to herein as "Composite score") combines both the adapted ADAS-cog and adapted ADCS-ADL to create a Composite score that is sensitive to decline in cog ⁇ nitive and basic functions. The following equation is used to derive the combined primary outcome, i.e. combined Composite score : Combined Composite score:
  • AFF006 recruited a study population reminiscent of early AD patients based on demographic data (Table 2) and data showing the baseline characteristics of the study groups (Table 3) .
  • ADAS-cog 2 was created which used the same weightings as the adapted ADAS-cog for the ADAS-cog items, but did not include the NTB and CogState items (1.67*Word recall + 1.35*Orientation + 1.42*Word Recognition + 0.55*Recall Instructions + 0.81*Spoken Language + 1.01*Word Finding) .
  • the adapted ADAS-cog2 shows substantially more decline in the historical control group than the 1 and 2 mg aluminium oxyhydroxide treated groups from the AFF006 study ( Figure 3) .
  • the p-values were: 1 mg vs. HC-ADNI, NS, HC: ⁇ 0.0001; 2 mg vs. HC-ADNI, NS, HC : ⁇ 0.0001.
  • MRI radiologic biomarker
  • Fig. 4 shows that the patients treated according to the pre ⁇ sent invention showed almost no AD related reduction in hippo ⁇ campus volume over a period of 18 months whereas the rate of brain atrophy per year in AD patients is in the range of 3 to 6 % per year (Risacher et al . , 2013, Table 2; the rate in healthy elderly individuals is usually in the range of 0.5 to 2.2 (see also this table 2 in Risacher et al . ) .
  • Fig. 5 shows that caregivers of patients treated according to the present invention rated the QOL of the patient as signif ⁇ icantly improved over a period of 18 months following 2mg com ⁇ pared to lmg Alum and other groups (not shown) .
  • Table 2 Patient Population and Disposition
  • Asian / Pacific Islan0 ( 0.0%) 1 ( 2.0%) der
  • Injection Site Inflammation 0 ( 0.0%), 0 0 ( 0.0%), 0
  • Tissue Disorders Pain in Ex ⁇ 0 ( 0.0%), 0 1 ( 2.0%), 1 tremity
  • Psychiatric Disorders Tension 0 ( 0.0%), 0 0 ( 0.0%), 0
  • Vascular Disorders Haematoma 0 ( 0.0%), 0 0 ( 0.0%), 0
  • Standard enzyme-linked immunosorbent assay (ELISA) technolo ⁇ gy was used to measure levels of vaccine-induced antibodies in plasma and CSF (Mandler M et al. (2012) J Alzheimers Dis 28: 783-794.).
  • Substrates used include human (BACHEM, CH) ⁇ 1-40/42 (at 5 ⁇ g/ml) , KLH ( ⁇ g/ml) and peptide-Bovine serum albumin (BSA) conjugates (SeqID 1 and SeqID 2, ⁇ ) .
  • Optical density (OD) was measured at 405nm using a micro-well reader (Tecan, CH) . ODmax/2 was calculated.
  • CFC Context fear conditioning
  • AnyMaze software Stoelting Co, USA
  • mice were placed in the conditioning chamber (AFFiRiS AG, Austria) , allowed to habituate for 2 min. and received three 0.8mA foot-shocks in 2 min intervals plus 30s rest.
  • IF Immunofluorescence analysis was done as described pre ⁇ viously (Mandler M et al . (2012) J Alzheimers Dis 28: 783-794).
  • ⁇ -specific IF-staining brain sections of immunized Tg2576 were processed for analysis of amyloid load using mAb 3A5 (AF ⁇ FiRiS AG, Austria) . All secondary reagents used were obtained from Vector Labs (USA) .
  • IF sections were mounted and coun- terstained using DAPI-containing VECTASHIELD-HardSet Mounting Medium. Sections were examined using MIRAX-SCAN (Carl Zeiss AG, Germany) .
  • AD-like pathology in animals was assessed by determin ⁇ ing the relative cerebral area occupied by amyloid deposits us ⁇ ing a semi-automated area recognition program (eDefiniens Archi ⁇ tect XD; www . definiens . com, Mandler M. et al (2015) PLoS ONE 10(1): e0115237.). For analysis three slides/animal and ⁇ five individual sections/slide were assessed. Sections carrying tis ⁇ sue artifacts or aberrant staining were excluded. To assess the number of ⁇ -positive vessels, 3A5 stained sections (3 slides/animal covering cortex and hippocampus and up to five in ⁇ dividual sections per slide) have been analysed. ⁇ -positive vessels were manually counted in sub-regions of the cortex as well as in the hippocampus. Number of positive vessels per mm 2 was determined.
  • Tg2576-mice were inject ⁇ ed 6x, s.c, at 4-week intervals with either conjugate-vaccine containing 30yg net peptide, equivalent doses of KLH formulated with Alum or Alum only.
  • Alum doses used were equivalent to 2mg/ml.
  • Figs. 7 and 8 also disclose that topically applied al- uminium-oxyhydroxide is able to lower cognitive decline signifi ⁇ cantly in an APP-transgenic model for Alzheimer's disease (Tg2576) without significantly changing cerebral ⁇ levels. This is implying an ⁇ / ⁇ independent mechanism underlying beneficial functional effects exerted by aluminium-oxyhydroxide in this AD model and further evidences the lack of scientific plau ⁇ sibility of the "amyloid channel hypothesis".
  • the present invention also refers to an immune stimulating pharmaceutical composition comprising an effective amount of an aluminium salt, especially aluminium oxyhydroxide, for use in the treatment of AD, independently of the combination with ac- tive or passive vaccines (embodiment 1), as well as to the fol ⁇ lowing preferred embodiments concerning this separate immune stimulating pharmaceutical composition for the treatment and prevention of AD comprising or consisting essentially of the aluminium salt, especially aluminium oxyhydroxide.
  • Me + is Na + , K + , Li + , Rb + , Cs + or NH 4 + ;
  • a 0, 1, 2, or 3;
  • b is 1 or 2 ;
  • c is 1, 2, 3, 4, 5, or 6;
  • n 0 to 48.
  • Aluminium salt according to embodiment 1 or 2 wherein the aluminium salt is selected from aluminium hydroxide, aluminium oxyhydroxide, aluminium phosphate, or aluminium sulphate.
  • Aluminium salt according to any one of embodiments 1 to 4, contained in a pharmaceutical preparation contained in a pharmaceutical preparation.
  • auxiliary substances especially stabilisators , detergents, antioxidants, complexing agents for mono- or diva ⁇ lent metal ions, carbohydrates and/or buffer substances.
  • Aluminium salt according to any one of embodiments 1 to 9, wherein the aluminium salt is present in a medicament as single effective ingredient (active substance) .
  • the aluminium salt is an aluminium oxyhydroxide suspension, preferably European Pharmacopoeia grade aluminium- oxyhydroxide (monograph 1664), especially Alhydrogel.
  • the aluminium salt preferably aluminium oxyhydroxide
  • the aluminium salt preferably aluminium oxyhydroxide
  • aluminium salt preferably aluminium oxyhydroxide
  • the aluminium salt additionally contains one or more stabilisators , especially thi- omersal, detergents, antioxidants, complexing agents for mono- or divalent metal ions, especially ethylenediaminetetraacetic acid (EDTA) , sugars, sugar alcohols, glycerol, and/or buffer substances, especially TRIS or phosphate buffer substances.
  • stabilisators especially thi- omersal, detergents, antioxidants, complexing agents for mono- or divalent metal ions, especially ethylenediaminetetraacetic acid (EDTA) , sugars, sugar alcohols, glycerol, and/or buffer substances, especially TRIS or phosphate buffer substances.
  • EDTA ethylenediaminetetraacetic acid
  • the aluminium salt preferably aluminium oxyhydroxide
  • the aluminium salt preferably aluminium oxyhydroxide
  • the aluminium salt preferably aluminium oxyhydroxide
  • the aluminium salt preferably aluminium oxyhydroxide
  • the aluminium salt preferably aluminium oxyhydroxide
  • Aluminium salt for use according to any one of embodiments 1 to 32 contained in a pharmaceutical preparation wherein said preparation is a suspension of aluminium oxyhydroxide and has a particle size distribution between 2 ym and approximately 10 ym, said particles being aggregates, composed of smaller fibers of preferably about 2 nm x 4.5 nm x lOnm.
  • the in ⁇ vention discloses the following preferred embodiments:
  • Vaccine for use in the treatment and prevention of Alzhei ⁇ mer's Disease (AD), wherein the vaccine contains an aluminium salt, especially aluminium oxyhydroxide, in an amount of at least 1.2 mg per dose, preferably at least 1.5 mg per dose, es ⁇ pecially at least 1.8 mg (given as AI 2 O 3 equivalent) per dose.
  • AD Alzhei ⁇ mer's Disease
  • Vaccine for use in the treatment and prevention of AD wherein the vaccine contains an aluminium salt, especially alu ⁇ minium oxyhydroxide, in an amount of at least 2.2 mg per dose, preferably at least 2.5 mg per dose, especially at least 2.8 mg (given as AI 2 O 3 equivalent) per dose.
  • an aluminium salt especially alu ⁇ minium oxyhydroxide
  • Vaccine for use in the treatment and prevention of AD wherein the vaccine contains an aluminium salt, especially alu ⁇ minium oxyhydroxide, in an amount of at least 3.0 mg per dose, preferably at least 3.5 mg per dose, more preferred at least 4.0 mg per dose, especially at least 5.0 mg (given as AI 2 O 3 equiva ⁇ lent) per dose.
  • the vaccine is an active or passive vaccine against ⁇ , especially ⁇ 1-42, and/or against tau, especially hyperphosphor ⁇ ylated tau.
  • Vaccine for use according to any one of embodiments 1 to 4, wherein the vaccine contains an antigen that elicits an immune response against ⁇ , ⁇ aggregates, especially oligomeric ⁇ ag ⁇ gregates, tau protein, phospho-tau protein, aggregated tau pro ⁇ tein, hyperphosphorylated tau protein or a naturally occurring fragment thereof, preferably ⁇ 1-40/42, ⁇ 2-40/42, ⁇ 3-40/42, ⁇ 4-40/42, ⁇ 1-38, or ⁇ 1-39.
  • Vaccine for use according to any one of embodiments 1 to 6, wherein the vaccine comprises two components,
  • an immune stimulating pharmaceutical composition comprising an aluminium salt, especially aluminium oxyhydroxide.
  • Vaccine for use according to any one of embodiments 1 to 11, wherein the vaccine contains an epitope comprising an amino acid sequence selected from the group consisting of DAEFRH, EFRHDSGY, pEFRHDSGY, EVHHQKL, HQKLVF and HQKLVFFAED.
  • Vaccine for use according to any one of embodiments 1 to 12, wherein the vaccine contains at least one mimotope comprising the amino acid sequence
  • Xi is G or an amino acid with a hydroxy group or a negatively charged amino acid, preferably glycine (G) , glutamic acid (E) , tyrosine (Y) , serine (S) or aspartic acid (D) ,
  • X 2 is a hydrophobic amino acid or a positively charged amino acid, preferably asparagine (N) , isoleucine (I), leucine (L) , valine (V) , lysine (K) , tryptophane (W) , arginine (R) , tyrosine (Y) , phenylalanine (F) or alanine (A) ,
  • X 3 is a negatively charged amino acid, preferably aspartic acid (D) or glutamic acid (E) ,
  • X 4 is an aromatic amino acid or a hydrophobic amino acid or leucine (L) , preferably tyrosine (Y) , phenylalanine (F) or leu ⁇ cine (L)
  • X 5 is histidine (H) , lysine (K) , tyrosine (Y) , phenylalanine
  • Xe is not present or serine (S) , threonine (T) , asparagine (N) , glutamine (Q) , aspartic acid (D) , glutamic acid (E) , argi ⁇ nine (R) , isoleucine (I), lysine (K) , tyrosine (Y) , or glycine
  • G preferably threonine (T) , asparagine (N) , aspartic acid (D) , arginine (R) , isoleucine (I) or glycine (G) ,
  • X7 is not present or any amino acid, preferably proline (P) , tyrosine (Y) , threonine (T) , glutamine (Q) , alanine (A) , histi ⁇ dine (H) or serine (S) ,
  • Vaccine for use according to any one of embodiments 1 to 13, wherein the vaccine contains at least one mimotope comprising the amino acid sequence
  • X 2' is tryptophan (W) or tyrosine (Y) ,
  • X3' is threonine (T) , valine (V) , alanine (A) , methionine (M) , glutamine (Q) or glycine (G) ,
  • X 4' is proline (P) , alanine (A) , tyrosine (Y) , serine (S) , cysteine (C) or glycine (G) ,
  • X 5' is proline (P) , leucine (L) , glycine (G) or cysteine
  • ⁇ ' is cysteine (C)
  • n, m and o are, independently, 0 or 1
  • IRWDTP C
  • VRWDVYP C
  • IRYDAPL C
  • IRYDMAG C
  • IRWDTSL C
  • IRWDQP C
  • IRWDG C
  • IRWDGG C
  • Vaccine for use according to any one of embodiments 1 to 14, wherein the vaccine contains at least one mimotope comprising the amino acid sequence
  • X3" is alanine (A), histidine (H) , lysine (K) , leucine (L) , tyrosine (Y) or glycine (G) ,
  • X 4" is proline (P) , histidine (H) , phenylalanine (F) or glu- tamine (Q) or Cysteine
  • X 5" is cysteine (C)
  • n' and m' are, independently, 0 or 1
  • Vaccine for use according to any one of embodiments 1 to 15, wherein the vaccine contains at least one mimotope comprising an amino acid sequence selected from the group consisting of
  • MYFPH C
  • TYFSHSL C
  • HEPLFSH C
  • SLMRHSS C
  • EFLRHTL C
  • ATPLFRH QELKRYY (CI ), THTDFRH (C) , LHIPFRH (C) , NELFKHF (C) ,
  • LQFKHS ATFRHS (C; ), TGLMFKH (C) , AEFSHWH (C) , QSEFKHW (C) ,
  • AEFMHSV ADHDFRH (C] ), DGLLFKH (C) , IGFRHDS (C) , SNSEFRR (C) ,
  • Vaccine for use according to any one of embodiments 1 to 16, wherein the vaccine contains at least one mimotope comprising the amino acid sequence ( Xla ) m' ' GX2a3 ⁇ 4a3 ⁇ 4aFX5aX 6a C&la) n ' (Formula IV) , wherein X ia is serine (S) , alanine (A) or cysteine (C) ,
  • X2a is serine (S) , threonine (T) , glutamic acid (E) , aspar- tic acid (D) , glutamine (Q) or methionine (M) ,
  • X 3a is isoleucine (I), tyrosine (Y) , methionine (M) or leu ⁇ cine (L) ,
  • X 4a is leucine (L) , arginine (R) , glutamine (Q) , tryptophan (W) , valine (V), histidine (H) , tyrosine (Y) , isoleucine (I), lysine (K) methionine (M) or phenylalanine (F) ,
  • X5 a is alanine (A) , phenylalanine (F) , histidine (H) , aspar- agine (N) , arginine (R) , glutamic acid (E) , isoleucine (I), glu ⁇ tamine (Q) , aspartic acid (D) , proline (P) or tryptophane (W) , glycine (G)
  • X6a is any amino acid residue
  • X 7a is cysteine (C) .
  • n' ' and n' ' are, independently, 0 or 1
  • Vaccine for use according to any one of embodiments 1 to 17, wherein the vaccine contains at least one mimotope comprising the amino acid sequence
  • X2b is glutamine (Q) , threonine (T) or methionine (M) ,
  • X 3b is lysine (K) or arginine (R) ,
  • X 4b is leucine (L) , methionine (M) ,
  • Xs b is tryptophane (W) , tyrosine (Y) , phenylalanine (F) or isoleucine ( I ) ,
  • X6b is asparagine (N) , glutamic acid (E) , alanine (A) or cysteine (C) , X 7b is cysteine (C) ,
  • n' ' ' and m' ' ' are, independently, 0 or 1,
  • SHTRLYF C
  • HMRLFF C
  • SHQRLWF C
  • HQKMIFA C
  • HMRMYFE C
  • THQRLWF C
  • HQKMIF C
  • Vaccine for use according to any one of embodiments 1 to 18, wherein the vaccine contains at least one mimotope comprising an amino acid sequence selected from the group consisting of AIPLFVM(C), KLPLFVM (C) , QLPLFVL (C) or NDAKIVF (C) .
  • Vaccine for use according to any one of embodiments 1 to 19, wherein the vaccine contains at least one mimotope selected from the group of DKELRI, SWEFRT, SEFKHG, ILFRHG, TLHEFRH, GAEFRFT, DWEFRD, SLEFRF, GREFRN, IRWDTP and HQKMIFA.
  • Vaccine for use according to any one of embodiments 1 to 20, wherein the vaccine contains at least one mimotope of an ⁇ epitope, and wherein said at least one mimotope is coupled or fused to a pharmaceutically acceptable carrier protein selected from the group consisting of a non-toxic diphtheria toxin mu ⁇ tant, keyhole limpet hemocyanin (KLH) , diphtheria toxin (DT) , tetanus toxid (TT) and Haemophilus influenzae protein D (protein D) .
  • KLH keyhole limpet hemocyanin
  • DT diphtheria toxin
  • TT tetanus toxid
  • protein D Haemophilus influenzae protein D
  • Vaccine for use according to any one of embodiments 1 to 21, wherein the vaccine contains a proteasome adjuvant.
  • the vaccine, preferably containing aluminium oxyhydrox- ide is administered subcutaneously, intranodally, intradermal- ly, or intramuscularly, especially subcutaneously, to an AD pa ⁇ tient .
  • an immune stimulating pharmaceutical composition comprising an aluminium salt, especially aluminium oxyhydroxide,
  • an active or passive vaccine is administered at least one day, preferably two days, especially at least one week before or after the immune stimulating pharmaceutical composi ⁇ tion comprising an aluminium salt.
  • Vaccine for use according to embodiment 31 or 32 wherein the active or passive vaccine is administered into the right (upper) arm and the immune stimulating pharmaceutical composi ⁇ tion comprising an aluminium salt into the left (upper) arm, or vice versa.
  • Vaccine for use according to any one of embodiments 1 to 33 wherein the active or passive vaccine is administered at a dif ⁇ ferent site than the immune stimulating pharmaceutical composi ⁇ tion comprising an aluminium salt, wherein site of administration is selected from the group (upper) arm, just above and be ⁇ low the waist (except the area right around the navel (a 2-inch circle) ) , the upper area of the buttock, preferably just behind the hip bone, the front of the thigh, midway to the outer side, 4 inches below the top of the thigh to 4 inches above the knee.
  • site of administration is selected from the group (upper) arm, just above and be ⁇ low the waist (except the area right around the navel (a 2-inch circle) ) , the upper area of the buttock, preferably just behind the hip bone, the front of the thigh, midway to the outer side, 4 inches below the top of the thigh to 4 inches above the knee.
  • an immune stimulating pharmaceutical composition comprising an aluminium salt, especially aluminium oxyhydroxide,
  • the immune stimulating pharmaceutical composition comprising an aluminium salt, especially aluminium oxyhydroxide, is administered in split doses to an AD patient, especially at the same site of administration.
  • Vaccine for use according to embodiment 1 to 35 wherein split doses of 0.8 to 5.0 mg, preferably of 1.0 to 3.0, espe ⁇ cially from 1.0 to 1.5 mg, (given as AI 2 O 3 equivalent) are admin- isterd to an AD patient.
  • Kit for use in the treatment and prevention of dementias as ⁇ sociated with ⁇ -amyloid deposition, preferably AD, comprising
  • an immune stimulating pharmaceutical composition comprising an aluminium salt, especially aluminium oxyhydroxide, wherein the aluminium salt is present in an amount of at least 1.2 mg per dose, preferably at least 1.5 mg per dose, especially at least 1.8 mg (given as AI 2 O 3 equivalent) per dose (given as AI 2 O 3 equiv ⁇ alent) .
  • Kit according to embodiment 41, wherein the active or pas ⁇ sive vaccine and the immune stimulating pharmaceutical composi ⁇ tion comprising an aluminium salt are defined as in any one of embodiments 1 to 40.

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Abstract

L'invention concerne un vaccin destiné à traiter et à prévenir la maladie d'Alzheimer, ledit vaccin contenant un sel d'aluminium en une quantité d'au moins 1,2 mg par dose, de préférence au moins 1,5 mg par dose, en particulier au moins 1,8 mg (exprimé en équivalent d'Al2O3) par dose.
PCT/EP2015/059331 2014-04-29 2015-04-29 Traitement et prévention de la maladie d'alzheimer Ceased WO2015165961A1 (fr)

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WO2019152627A1 (fr) * 2018-01-31 2019-08-08 Olatec Therapeutics Llc Procédé de prévention ou de traitement de la maladie d'alzheimer
EP3545312A1 (fr) * 2016-11-28 2019-10-02 Distretto Tecnologico Sicilia Micro e Nano Sistemi S.C.A.R.L. Mimotopes conformationnels de détection d'anticorps spécifiques
WO2022031342A1 (fr) * 2020-08-07 2022-02-10 Othair Prothena Limited Vaccins anti-tau pour le traitement de la maladie d'alzheimer
US11434283B2 (en) 2020-07-23 2022-09-06 Othair Prothena Limited Anti-abeta antibodies
US12247056B2 (en) 2020-05-19 2025-03-11 Othair Prothena Limited Multi-epitope vaccine for the treatment of Alzheimer's disease

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