Immunotherapy for Alzheimers disease: from anti ...

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Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies. Alzheimer's disease (AD) is a debilitating and progressive ...
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Immunotherapy for Alzheimer’s disease: from anti-b‑amyloid to tau-based immunization strategies The exact mechanisms leading to Alzheimer’s disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular b‑amyloid (Ab), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of Ab. The most innovative of the pharmacological approaches was the stimulation of Ab clearance from the brain of AD patients via the administration of Ab antigens (active vaccination) or anti-Ab antibodies (passive vaccination). Several active and passive anti-Ab vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate Ab and an immune adjuvant, QS‑21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Ab monoclonal antibodies (bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E e4 carriers), has raised concerns on the safety of these antibodies directed against the N‑terminus of the Ab peptide. Solanezumab, a humanized anti-Ab monoclonal antibody directed against the midregion of the Ab peptide, was shown to neutralize soluble Ab species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III trials with bapineuzumab and solanezumab will tell us if monoclonal anti-Ab antibodies may slow down the rate of deterioration of AD. Based on the new diagnostic criteria of AD and on recent major failures of anti-Ab drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of AD. KEYWORDS: b‑amyloid n active immunotherapy n Alzheimer’s disease n bapineuzumab n monoclonal antibody n passive immunotherapy n polyclonal antibody n solanezumab n tau protein

Alzheimer’s disease (AD) is a debilitating and progressive neurodegenerative disease, the most common cause of dementia [1] and the leading cause of disability and death amongst older people. The 2011 figures suggest that AD affects over 5.4 million people in the USA [2] . In 2050, the incidence of AD is expected to approach nearly a million people per year, with a total estimated prevalence of 11–16 million Americans [2] . To date, there are four US FDA-approved treatments for AD (donepezil, galantamine, rivastigmine and memantine), which only provide a symptomatic benefit, with an impending urgency to find effective disease-modifying therapies [3–5] . AD is both multifactorial and heterogeneous and, thus, offering a large number of rational therapeutic targets, AD continues to be one of the most difficult human diseases to treat. In 1907, Alois

Alzheimer described the neuropathology of presenile dementia for the first time [6] , suggesting that senile plaques (SPs) and neurofibrillary tangles (NFTs) were the ‘signature’ pathological lesions of AD [7–9] . In fact, AD is characterized by the loss of neurons and several pathological hallmarks, including neurophil threads, NFTs, dystrophic neurites and SPs. Neurophil threads are usually found in distal dendrites, NFTs are found in neuronal cell bodies, and apical dendrites and dystrophic neurites are associated with SPs found in proximity to axons [10,11] . However, while there were numerous SPs in both the two original cases described by Alzheimer, only one also had a significant number of NFTs [12] . In fact, there is controversy on the significance of these two lesions; their exact relationship is still unclear and how they may cause neuronal death is still an area of intense research

10.2217/IMT.11.170 © 2012 Future Medicine Ltd

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Francesco Panza*‡, Vincenza Frisardi‡, Vincenzo Solfrizzi, Bruno P Imbimbo, Giancarlo Logroscino, Andrea Santamato, Antonio Greco, Davide Seripa & Alberto Pilotto *Author for correspondence: Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, Foggia, Italy [email protected] ‡ Authors contributed equally For a full list of affiliations please see the back page

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effort [13] . These neuropathological hallmarks of AD strongly influenced recent therapeutic approaches and involve aberrant protein processing, characterized by the presence of both intraneuronal protein clusters (the NFTs) composed of paired helical filaments (PHFs) of hyperphosphorylated tau proteins, a microtubule-associated protein (MAP) and extracellular protein aggregates (SPs).

Anti-Ab therapeutics in AD SPs consist of a proteinaceous core composed of 5–10‑nm amyloid fibrils surrounded by dystrophic neurites, astrocytic processes and microglial cells. The b‑amyloid (Ab) peptide consists of 38–42 amino acids generated by the cleavage of amyloid precursor protein (APP), a type 1 transmembrane protein, by b- and g‑secretases [14] . APP can undergo proteolytic processing via two pathways. The a‑secretase enzyme cleaves APP at amino acid 17 of the Ab domain, thus releasing the large amino-terminal fragment sAPPa, with neuroprotective activity. Further proteolysis of this fragment by g‑secretase generates the nonamyloidogenic peptide  p3. Alternatively, cleavage of APP by b‑secretase occurs at the beginning of the Ab domain and generates a shorter N‑terminus, sAPPb, as well as an amyloidogenic C‑terminal fragment, C99. Further cleavage of this C‑terminal fragment by g‑secretase generates Ab. The main form of Ab, Ab1–40, contains 40 amino acids. The 42‑residue species, Ab1–42, is formed in smaller amounts than Ab1-40 [15] , but is more prone to aggregate into fibrils and makes up the major component of SPs [16] . The �������������������������� original ‘amyloid cascade hypothesis’ suggested that the development of SPs precedes and precipitates the formation of NFTs [17] , although the exact mechanism by which the deposition of Ab leads to the formation of NFTs is unclear [18] . Ab may promote the formation of intracellular tau [19] , or alternatively, it has been hypothesized to interact synergistically between NFTs and Ab [20,21] . On the other hand, SPs and NFTs may also develop independently or may be the products rather than the causes of neurodegeneration in AD [18] . The updated version of this theory says that SPs may not be the main contributor to neuronal death, as there is consistent evidence that soluble oligomeric forms of Ab are strongly neurotoxic [22] . Indeed, recent evidence has implicated oligomeric Ab and Ab-������������ derived diffusible ligands (ADDLs) in cognitive decline [23,24] . The addition of oligomeric Ab/ADDLs to hippocampal slices inhibited long-term 214

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potentiation, a cellular model of learning and memory [25] . Furthermore, the injection of oligomeric Ab/ADDLs directly into the hippocampi of living rats resulted in deficits in learning and memory performance [25,26] . During the past 10  years, a large portion of the many therapeutic approaches currently under development for the treatment of this disease have been directed against the production and accumulation of Ab [3] . Compounds capable of interfering with the proteases that generate the Ab peptide from APP have been actively researched. However, blockage of the most biologically attractive of these proteases, the b‑secretase that performs the first cleavage step of the APP, was found to be particularly difficult to achieve, and only a few compounds have reached clinical testing so far [4] . Very recently, among inhibitors of g‑secretase, which regulates the last metabolic step generating Ab, the clinical development of LY450139 (semagacestat) has been halted [27] . Preliminary results from two ongoing long-term Phase III studies showed that semagacestat did not slow disease progression, and was associated with worsening cognition and functional status [301] . An alternative to the inhibition of the amyloidogenic enzymes in order to decrease brain Ab burden in AD patients would be to stimulate the a‑secretase processing of APP. Among a‑secretase activators, etazolate (EHT0202, ExonHit, Paris, France) has reached Phase II clinical development [28] . Furthermore, brain penetrant inhibitors of the metal-related hypothesis of Ab aggregation have also been identified, and one of such compounds, PBT‑2 (Prana Biotechnology Ltd, Parkville, Australia), recently showed cognitive improvement in a Phase II study [29,30] . Finally, strategies to eliminate excessive brain Ab by immunization have attracted greater therapeutic importance, with several active and passive immunotherapeutic procedures that have reached clinical testing in Phase II and Phase III trials [31,32] .

Tau-based therapeutic target in AD The intracellular NFTs, which contain two aggregated tau species, hyperphosphorylated PHFs of MAP tau (or tau) and straight filaments are another pathological hallmark of AD [33] . Tau is a 50–75 kDa protein with six different splice variants [34] . In the cerebrospinal fluid (CSF), increased levels of phosphorylated or total tau appeared to be reliable biomarkers of neurodegenerative disease or injury [35] . Hyperphosphorylated tau bind together and future science group

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form oligomeric tau, from dimers to octamers [36] . Both hyperphosphorylated tau by itself and oligomeric tau are involved in synaptic loss, as observed in the wild-type human tau transgenic mouse [33,37] . When oligomeric tau consists of approximately 40 molecules, possesses a b‑sheet structure and forms a granular shape, it becomes a detergent-insoluble aggregate [38] . This granular tau oligomer may be involved in neuronal loss [33,37] . Therefore, given the confirmed link existing between NFT topography and clinical phenotype [39] , therapies targeting NFTs have potential application as drug targets against neurodegeneration, although their development has lagged behind drugs targeting Ab [40] . The identification of the specific pathological, neurotoxic form of tau is of paramount importance in establishing new tau-based therapeutic strategies [41] . Ab oligomers adversely affect synaptic structure and plasticity [42] and, while NFTs represent the final stages of the pathological process, a broadly similar process of neuronal dysfunction is induced by some intermediate hyperphosphorylated, most likely soluble, tau species [43,44] . In fact, tangle-bearing neurons seem to survive for long periods of time, suggesting that NFTs might be protective [45,46] . Therapies targeting tau aim to reduce, stabilize or prevent aggregation or hyperphosphorylation of the protein [47] . In particular, several therapeutic approaches with a disease-modifying potential have been suggested [41] : ƒƒ Inhibition of tau aggregation; ƒƒ Inhibition of tau phosphorylation (with the inhibition of tau kinases or the activation of tau phosphatases); ƒƒ Increase of microtubule stabilization; ƒƒ Increase of tau clearance. Some of these approaches have actually reached the clinic. In cell-based and/or in  vitro screening assays, several classes of agents that may act to prevent tau aggregation have been identified, including polyphenols [47] , phenothiazines [48] , benzothiazoles [49] , N‑phenylamines [50] , thioxothiazolidinones (rhodanines) [51] , phenylthiazol-hydrazides [52] , anthraquinones [53] , aminothienopyridazines [54] and others [48] . However, for many of these compounds there is a lack of evidence of efficacy in vivo for inhibiting tau aggregation. However, methylene blue (chloride methylthioninium; Rember™, TauRx Therapeutics, Singapore, Republic of Singapore), a non-neuroleptic phenothiazine future science group

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used to treat malaria for quite some time [55] , has reached the clinic, also completing a Phase II trial in AD patients [56] . This drug dissolves PHFs isolated from AD brains and prevents tau aggregation in cell models, showing efficacy in tau-transgenic animal models, reversing cognitive and other behavioral defects, and reducing tau levels in the brain [57] . However, the 24‑week monotherapy trial failed to meet its prespecified end points with respect to altering cognition, although long-term observations (50  weeks) and biomarker studies suggested possible benefit [56,58] . Some of the participants underwent brain ���������������������������� imaging (single-photon emission computed tomography) during and/or after the trial. Reduced blood flow in certain brain regions associated with AD was observed in the placebo group, but not in those receiving treatment [59] . Single-photon emission computed tomography tests were confirmed by FDG‑PET tests measuring reduced glucose use in the brain [60] . Notably, methylene blue is also able to inhibit aggregation of a‑synuclein [61] , TDP‑43 [62] and Ab, decreasing Ab oligomers in vitro by increasing fibrillar but not monomeric Ab [63] . Clinical development of this compound for AD continues, along with a new form that is more bioavailable and less toxic at higher doses, called leucomethylthioninium [41] . In AD pathogenesis, hyperphosphorylated, abnormally folded tau or tau aggregates may exert direct toxic effects on neurons by decreasing tau’s affinity for microtubules and subsequently promoting microtubule network breakdown [41] . Phosphorylation of tau can occur at many unique sites of the protein and through multiple pathways [62,63] . Several tau kinases, including glycogen synthase kinase  3b (GSK‑3b), cyclin-dependent kinase 5, MAP/microtubule affinity-regulating kinase and others, have all been implicated as potential kinase targets for tau therapeutics [62] . Interactions between GSK‑3b and cyclin-dependent kinase  5 exist and will require further evaluation to optimize treatments aimed at these kinases [64,65] . Despite the challenges faced by this approach with respect to toxicity and specificity, a number of efforts are underway to develop kinase inhibitors. In particular, two GSK‑3 inhibitors, AZD1080 and NP031112, were in clinical trials for AD [5] , but in January 2008 the halt of AZD1080 development was announced, leaving only NP031112 (NP‑12, tideglusib), a drug which belongs to the thiadiazolidinone family from Neuropharma, now named Noscira (Madrid, Spain). In animal models of AD, it www.futuremedicine.com

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was shown that tideglusib improves cognitive performance and reduces amyloid deposits, hyperphosphorylation, tau aggregation, neuroinflammation and, most importantly, neuronal loss [5] . Noscira has started a Phase II clinical study (ARGO) on tideglusib in patients with AD and other tauopathies such as progressive supranuclear palsy [302] . Small and open-label studies have suggested efficacy of lithium and valproate for cognitive and behavioral symptoms in AD [66–68] , given their inhibitory actions on GSK‑3b for stabilizing tau [40,47] . Unfortunately, larger and better controlled studies did not confirm these preliminary positive findings for either lithium [69] or valproate [70] . As an alternative to kinase inhibition, activation of phosphatases has also been proposed as a strategy for reducing tau phosphorylation, especially in the case of protein phosphatase 2A (PP2A) [71] . Activating PP2A, which plays an important role in regulation of tau phosphorylation and is decreased in AD, has its own challenges. In fact, it has broad substrate specificity and a number of regulatory subunits, which makes it difficult to target the correct pool of PP2A to the correct extent [41] . However, multiple PP2As exist and inhibition of these phosphatases results in hyperphosphorylation of tau, formation of NFT-like structures and memory impairment in animal models [72,73] . Drugs increasing the activity of PP2As, probably through the endogenous proteins that inhibit their activity, have the therapeutic potential for treating AD [74,75] . Some microtubule-stabilizing agents have been proposed among tau-based anti-AD drugs, given that tau detachment from microtubules results in loss of its normal micro­tubule stabil­ izing function, probably leading to axonal transport impairment and eventually to synaptic dysfunction [41] . Some antimitotic compounds such as paclitaxel or epothilone have been used in tau transgenic animals for their microtubulestabilizing activity [76] . Among these agents, NAPVSIPQ (NAP, davunetide), an eight-amino acid peptide (with NAP representing the first three amino acids in the peptide) derived from the activity-dependent neuroprotective protein [77] , has demonstrated the potential to decrease tau phosphorylation and Ab levels in animal models [78] . An intranasal formulation of davunetide (AL‑108, Allon Theraputics, Vancouver, Canada), is currently being tested in Phase II clinical trials for both mild cognitive impairment (MCI) [303] and progressive supranuclear palsy [304] , given that intranasally administered NAP treatment can cross the blood–brain barrier 216

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(BBB) [79] . Finally, recent efforts to develop safe and efficacious anti-Ab immunotherapy using Ab peptide as an immunogen in active vaccination approaches or anti-Ab antibodies for passive vaccination may be translated to the development of a tau-based immunotherapy [40,46] . In this article, we briefly review clinical trials on active and passive anti-Ab and tau-based immunotherapeutics for the treatment of AD, with a particular focus on animal studies and clinical findings on monoclonal antibodies against Ab.

Anti-Ab & tau-based immunotherapy for AD Immunotherapies can clear potentially deleterious agents; therefore, vaccination became an attractive treatment approach for AD. Indeed, the stimulation of the Ab clearance from the brain of the AD patients thorough the administration of Ab antigens (active vaccination) or anti-Ab antibodies (passive vaccination) represent the most innovative approach of anti-AD therapy [31,32] . The pharmacological principle underlying anti-Ab vaccination is based on the elicitation of a humoral response to the administration of Ab antigens or anti-Ab antibodies [80] . Various experimental models suggested immunological strategies for SP reduction, including active immunization with the Ab peptide of first [81–83] and second generation [84] , or with Ab short immunogens [85,86] , intranasal administration of phage–peptide [87] and systemic passive immunization with monoclonal antibodies against Ab epitopes injected intraperitoneally (Table 1) [88,89] . The mechanism by which antiAb antibodies stimulate Ab clearance from the brain is not fully understood. It includes direct disassembly of Ab deposits [90] , inhibition of Ab aggregation [91] and activation of microglia by eliciting Fc-mediated phagocytosis [88] , although the Fc portion of Ab antibodies is not necessary for Ab clearance [92] , and the removal of soluble Ab from the periphery (‘sink phenomenon’) [93,94] . The first developed active vaccine, AN1792, consisted of synthetic, preaggregated Ab1–42 and an immune adjuvant (QS‑21). Pharmacological studies in transgenic mouse models of AD and human post-mortem studies in AD patients have shown that AN1792 was able to dramatically reduce brain Ab pathology. Unfortunately, in a Phase II study in mild-tomoderate AD patients, AN1792 caused meningoencephalitis in approximately 6% of the treated subjects. Based on these clinical significant adverse events and questionable clinical efficacy (if any), the vaccine was abandoned. Later, future science group

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Table 1. Overview of principal preclinical studies of active and passive immunization targeting b‑amyloid and tau protein for the treatment of Alzheimer’s disease. Authors (year)

Type of immunization

Immunogens/epitopes

Animal model

Principal findings

Schenk et al. (1999)

Systemic active

Ab1–42

PDAPP mice

Cerebral Ab reduced in young mice

Lemere et al. (2000)

Intranasal active

Ab1–40 and Ab1–42

PDAPP mice

Cerebral Ab reduced

[127]

Weiner et al. (2000)

Intranasal active

Ab1–40 and Ab1–42

PDAPP mice

Cerebral Ab reduced

[130]

Morgan et al. (2000)

Subcutaneous active

Ab1–42

APP/PS1 mice

Prevented memory loss

[82]

Bard et al. (2000)

Systemic passive

Monoclonal: 10D5 or 21F12 Polyclonal: Ab1–42

PDAPP mice

Cerebral Ab reduced

[88]

Sigurdsson et al. (2001)

Systemic active

Antibody against aggregated Tg2576 mice Ab1–42

Cerebral Ab reduced

[85]

DeMattos et al. (2001)

Systemic passive

m266

PDAPP mice

Cerebral Ab reduced by altering CNS/plasma Ab clearance

[175]

Pfeifer et al. (2002)

Systemic passive

Anti-Ab3–6 antibody

APP23 mice

Cerebral Ab reduced with cerebral microhemorrhage

[165]

Dodart et al. (2002)

Systemic passive

m266

Tg2576 mice

Reversed memory deficit

[176]

Das et al. (2003)

Systemic active and passive

Ab1–42 and anti-Ab antibody

Tg2576 x FcRg(-/-) mice

Cerebral Ab reduced

Racke et al. (2005)

Systemic passive

m266, 3D6 and 10D5

PDAPP mice

3D6 and 10D5, but not m266, increased CAA and microhemorrhage

Rosenmann et al. (2006)

Systemic active

Recombinant full-length human tau protein

Wild-type BL/6 mice Increased NFT-like structures, axonal damage, gliosis and mononuclear infiltrates

Okura et al. (2006)

Systemic active

Nonviral DNA vaccine

APP23 mice

Cerebral Ab reduced, with no inflammation

[124]

Lee et al. (2006)

Systemic passive

NAB61

Tg2576 mice

Cerebral Ab reduced, learning improved

[216]

Maier et al. (2006)

Systemic active

2 × Ab1–15

hAPP (FAD) mice

Cerebral Ab reduced, learning improved

[86]

Asuni et al. (2007)

Systemic active

Tau379–408 (pS396–pS404)

JNPL3 P301L mice

Decreased insoluble phosphorylated tau aggregates, improved performance on motor tasks

[131]

Petrushina et al. (2007)

Systemic active

Ab1–11 fused with the promiscuous T-cell epitope

Tg2576 mice

Reduced insoluble, but not soluble, cerebral Ab

[122]

Movsesyan et al. (2008)

Systemic active

pMDC-3Ab1–11–PADRE construct

3 × Tg-AD mice

Reduced cerebral Ab, no glial activation, no microhemorrhage, improved behavior

[125]

Schroeter et al. (2008)

Systemic passive

3D6 and m266

PDAPP mice

Reduced cerebral Ab but elevates vascular Ab and CAA

[182]

Yamada et al. (2009)

Systemic passive

m266

Tg2576 mice

Peripheral administration of m266 retards cerebral Ab clearance

[179]

Tau260–264 (pS262)

JNPL3 P301L mice

Decreased tau phosphorylation in dentate gyrus together with tau clearance and motor function improvement

[135]

Khrisnamurthy Systemic active et al. (2009)

Ref. [81]

[92] [166] [95]

Ab: b‑amyloid; AD: Alzheimer’s disease; APP: Amyloid precursor protein; CAA: Cerebral amyloid angiopathy; DM: Double mutant; FAD: Familial Alzheimer’s disease; hAPP: Human amyloid precursor protein; JNPL3: Mutant human tau protein; NFT: Neurofibrillary tangles; PDAPP: PDGF-driven human amyloid precursor protein; PS1: Presenilin 1.

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Table 1. Overview of principal preclinical studies of active and passive immunization targeting b‑amyloid and tau protein for the treatment of Alzheimer’s disease (cont.). Author (year)

Type of Immunogens/epitopes Animal model immunization

Principal findings

Novak et al. (2009)

Systemic active

Truncated tau protein

Delay of behavioral impairment and prevention of the development of NFTs

Wang et al. (2010)

Systemic active

SDPM1 peptide that binds APPswePSEN1(A246E) Cerebral Ab reduced without to Ab1–40/1–42-tetramers mice inflammation, and improved cognition

[83]

Boimel et al. (2010)

Systemic active

Tau195–213[p202–205] + Tau207–220[p212–214] + Tau224–238[p231]

DM-tau-Tg mice

Decreased NFT burden in the brain and spinal cord without encephalitogenicity, clinical neurological deficits, adverse effects on brain inflammatory cells or axonal damage after a long follow-up

[96]

CAD106 - Anti-Ab1–6 antibody with Qb

APP23/APP24 mice

Cerebral Ab reduced with minimal potential side effects

[84]

[89]

Wiessner et al. Second(2011) generation systemic active

Tau-Tg rat

Ref.

Cattepoel et al. (2011)

Systemic passive Anti-Ab30–42 scFv antibody

APPswe/PS1dE9 mice

Cerebral Ab reduced and CAA

Boutajangout et al. (2011)

Systemic passive Anti-tau protein antibody PHF1

JNPL3 P301L mice

Decreased tau pathology and functional impairments

[97]

[205]

Ab: b‑amyloid; AD: Alzheimer’s disease; APP: Amyloid precursor protein; CAA: Cerebral amyloid angiopathy; DM: Double mutant; FAD: Familial Alzheimer’s disease; hAPP: Human amyloid precursor protein; JNPL3: Mutant human tau protein; NFT: Neurofibrillary tangles; PDAPP: PDGF-driven human amyloid precursor protein; PS1: Presenilin 1.

several other active and passive anti-Ab immunization preparations were developed with the aim of abolishing or reducing the inflammatory adverse events observed with AN1792 [31] . During the last few years, the disappointing clinical results in late-stage clinical trials of several Ab-based pharmacological approaches, including anti-Ab immunotherapy, has proposed novel tau-based therapies (Table  1) [41] . Although tau is an intracellular protein and the deposits occur inside cells, several immunotherapeutic approaches have recently been tested in preclinical models for tau antibody-induced tau clearance, with some preliminary data indicating that this may be a viable option for clearing tau deposits in AD. Unfortunately, immunization with recombinant full-length human tau protein (unphosphsorylated) of wild-type mice led to encephalomyelitis with neurological and behavioral deficits, axonal damage and inflammation [95] . However, vaccination with tau phosphopeptides reduced the NFT burden in the brain and spinal cord, without apparent neurotoxicity [96] . An approach targeting AD-specific, misfolded, truncated forms of tau has provided some evidence for prevention of the development of NFTs and delay of behavioral impairment [97] . Therefore, it appears that targeting abnormally phosphorylated tau epitopes or perhaps specific pathological conformers could elicit antibody responses, facilitating tau clearance. More recently, a passive immunotherapy approach has 218

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also been proposed in vitro by using a site-directed monoclonal antibody with high binding constant toward the 300‑QPGGGSVQIVYKP‑312 residues within the tubulin binding domain of tau, able to completely abolish the pathological microtubule assembly promoted by misfolded tau [98,99] . Finally, similar to what has happened in the amyloid field regarding SPs and intermediate Ab oligomers, increasing evidence proposes some soluble, oligomeric tau species (prefilament, immature filaments), rather than the NFTs, as the pathogenic ones [100–102] . The importance of the accurate identification of the tau species to be targeted by immunotherapy is highlighted by the demonstration of a link between tau oligomers and brain pathology in animal models [103] .

Active immunization in AD „„ Anti-Ab strategies Active immunization is the traditional approach to systemically administer a drug or molecule of interest in order to generate an intended antibody response in patients. As seen above, based on the impressive results in preclinical testing with preaggregated Ab1–42 administered with the immune Freund’s adjuvant, an initial trial was carried out in the UK in 80 patients with mild-to-moderate AD to assess the antigenicity and toxicity of multiple-dose immunization with AN1792 [104] . During the later phases of this Phase I study, the emulsifier polysorbate future science group

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80 was added to the vaccine [105] . In a successive Phase II study involving 372 AD patients, AN1792 in the poly­sorbate 80 formulation was administered to 300  subjects. This trial was stopped early because of symptoms of acute meningoencephalitis in 18 vaccinated patients [106] . Cytotoxic T‑cell reactions surrounding some cerebral vessels as seen at autopsy suggested an excessive Th1-mediated response [107] , although the exact cause of toxicity in these patients is unknown. When stimulated in  vitro with Ab, peripheral blood mononuclear cells from most patients who showed an anti-Ab antibody response produced IL‑2 and IFN‑g suggestive of a class II (CD4 +) Th1-type response [105,108] . Interestingly, immunization with Ab resulted in the accumulation of T cells at SPs in the brain, where they induced microglia activation and efficient clearance of Ab [109] . Post-mortem histopathological examinations of a few patients showed clearance of parenchymal plaques, confirming the ability of vaccination in boosting amyloid clearance in the human brain [107,108,110,111] . Approximately only 25% of patients treated with AN1792 had an antiAb antibody response. It has been shown that patients with antibody responses had statistically significant improvement on some cognitive tests compared with baseline and a slowed rate of decline in activities of daily living compared with patients who did not form antibodies [104,112] . A subanalysis of the Zurich cohort of the AN1792 Phase IIa trial [112] indicated that antibody responders scored significantly better in composite scores of memory functions than nonresponders or placebo-treated patients [105] . This finding could be related to the small decline in cognitive function in the placebo group [106,113] . It has been suggested that AN1792 treatment could be more effective if started before the development of clinically significant AD-related pathology; this has been confirmed by the presence of tau-related path­ology in cortical areas cleared of Ab. If immunization begins at earlier stages of the disease, the Ab-lowering effects could have increased cognitive benefits [114,115] . Indeed, in transgenic mouse models of AD, early vaccination was shown to prevent the formation of both Ab deposits and hyperphosphorylated tau aggregations [116] , therefore preventing the formation of new tangles without affecting those already formed. Currently, several clinical studies of active immunization approaches are underway [117,118] . Appropriate modifications of the of the antigenic presenting Ab-peptide may favor a future science group

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humoral response also reducing the potential for a Th1-mediated response. An ideal anti-Ab vaccine should preferentially stimulate a Th2 immune response eliciting a robust anti-Ab antibody [118] . Examples of second-generation active anti-Ab vaccines include soluble Ab-derivative immunogens [119] , phage display of Ab3–6 [120] , N‑terminal Ab fragments [121,122] , HSV amplicons coding for Ab [123] , nonviral DNA Ab vaccines [124] , DNA vaccines encoding Ab N‑terminal fragments [125] and Ab ‘retroparticles’ (Table 1) [126] . Moreover, various adjuvants and routes of administration (oral, intranasal and transcutaneous) are under investigation to improve the safety, efficacy and ease of use of anti-Ab vaccines [118] . Mucosal vaccination is particularly attractive because it mainly elicits a humoral response. This is owing to the presence of lymphocytes in the mucosa of the nasal cavity and GI tract. Mucosal vaccine delivery primarily produces secretory IgA antibodies, but when the antigen is coadministered with adjuvants (cholera toxin subunit  B or heatlabile Escherichia coli enterotoxin) robust serum IgG titres can be elicited [127,128] . Interestingly, a nasal proteosome-based adjuvant alone was shown to prevent Ab deposition in young mice, and affect Ab deposition and memory function in old mice with a large amyloid load, with the mediation of peripheral activation of microglia with no apparent toxicity [129] . Indeed, nasal immunization of transgenic mice with Ab efficiently reduced amyloid burden without eliciting a cell-mediated immunological response [130] . „„ Tau-based strategies The tau-based active immunotherapy approach elicited anti-tau antibodies resulting in clearance of tau pathological species and eventually neuronal function improvement [41] . In 2007, Asuni and colleagues published the first report of active tau immunotherapy on the P301L mutant human tau protein (JNPL3 P301L) transgenic mice with a 30‑amino acid tau phosphopeptide spanning amino acids 379–408 (with adjuvant aluminum), including phospho-Ser at positions 396 and 404, two phospho‑Ser residues commonly associated with NFTs [131] . Homozygous JNPL3 P301L mutant tau-expressing mice are a tauopathy model in which aggregated tau and NFTs readily accumulate in the motor cortex, brainstem and spinal cord at the age of 5 months, with significant motor and behavioral impairment [132] . Immunohistochemical and biochemical analyses demonstrated a specific antibody response with a reduction in insoluble www.futuremedicine.com

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phosphorylated tau aggregates following multiple doses of this vaccine [131] . Behavioral analyses using the rotarod and traverse beam showed improved performance on motor tasks after immunization as compared with controls treated with adjuvant alone [131] . Immunizing young animals starting at 2 months of age led to reductions in tau histopathology at 5 or 8 months, in some brain regions by as much as 96%. This study demonstrated that antibodies against this immunogen were able to cross the BBB and bind to phosphorylated tau [131] . In the mice, the clearance of tau was associated with behavioral improvements, while the effect in preventing cognitive decline could not be determined since motor impairments interfere with common tests of learning and memory. In 2006, Rosenmann and colleagues using recombinant, full-length unphosphsorylated human tau protein as an immunogen (emulsified in complete Freund adjuvant/pertussis toxin) in wild-type mice demonstrated that it was encephalitogenic and triggered severe autoimmune response [95] . The mice vaccinated with soluble tau developed NFT-like structures, axonal damage, gliosis, mononuclear infiltrates and motor phenotypes [95] , suggesting a neurotoxic potential of tau immunization. This report demonstrates the potential dangers of using soluble tau protein as immunogen or anti­bodies recognizing epitopes on full-length tau for passive vaccination. �������������������� Interestingly, immunization with a mixture of three different tau phosphopeptides (Tau195–213 [p202/205], Tau207–220 [p212/214] and Tau224–238 [p231]) containing the AD/tauopathy-related phosphorylation epitopes, in transgenic mice overexpressing a double-mutant human tau protein (K257T/P301S) [133] , led to a 40% decrease in NFT burden in brain and spinal cord in the absence of any evidence of encephalitogenicity, clinical neurological deficits, adverse effects on brain inflammatory cells and axonal damage after a long follow-up [96] . Recently, two other studies reported positive effects after immunization with tau phosphopeptides [134,135] . The first report used the same 30‑amino acid tau phosphopeptide as the study by Asuni and colleagues [131] but on hTau/PS1 mice expressing all six wild-type isoforms of human tau on a mouse tau knockout background [136] , plus human mutant (M146L) presenilin 1 [137] . This animal model developed tau pathology primarily in the cortex and hippocampus. Animals were immunized at 2–3  months of age, boosted 2 weeks later and continued with 220

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monthly injections. Starting at 7–8  months, the mice performed three cognitive tests and were sacrificed at 8–9 months. In immunized animals, tau immunotherapy decreased tau phosphorylation and improved not only motor function but also cognitive decline [134] . In the second report, a shorter peptide (Tau260–264 [pS262]) encompassing amino acids within the tubulin-binding domain was used [135] , while the ones aforementioned were located on either side of this domain [134] . In JNPL3 P301L mice, a robust antibody response associated with a 64% reduction in tau phosphory­lation (PHF‑1) in the dentate gyrus together with tau clearance and motor function improvement was elicited by active vaccination [135] . From an intrinsically disordered soluble protein into insoluble misordered aggregates, tau undergoes multiple modifications during the process of hyperphosphorylation [41] , including phosphorylation, truncation, glycosylation and ubiquitination [43] . Using a transgenic rat model of tauopathy, immunization with recombinant misfolded truncated tau protein resulted in a delay of behavioral impairment and prevention of the development of NFTs [97] , reducing the levels of soluble misfolded tau protein well before neuronal loss is observed. Therefore, targeting abnormally phosphorylated tau epitopes or perhaps specific pathological conformers seems to elicit antibodies responses, facilitating tau clearance. New immunotherapy approaches targeting tau are being actively pursued in different animal models [138] , with a sharp focus on targeting prefilament tau species to prevent neurodegeneration and the formation of NFTs [139] .

Passive immunization in AD „„ Anti-Ab strategies Passive immunization involves the administration of an antibody generated in a host or model system, which is maximized for efficacy before administration to a patient. In AD, passive immunotherapy may be another option that permits more direct control over the extent of the immune response against Ab [140,141] . Passive transfer of exogenous monoclonal Ab antibodies seems the easiest way to avoid eliciting Th1mediated autoimmunity. AD transgenic mice treated with monoclonal Ab antibodies showed a significant decrease in brain Ab levels, reduced brain plaque pathology and improved cognition [140,142] . These beneficial effects were observed using a variety of antibodies that differed in Ab-binding properties [140,142] . The observed future science group

Immunotherapy for Alzheimer’s disease

biological effects occur within 1 day of administration, a period much shorter than one would expect if the mechanism of action was simple removal of existing brain plaques [143] . This finding suggests that immunization strategies may work through mechanisms of Ab binding not clearly related to overt SP removal. It ������������� is hypothesized that early soluble oligomeric forms of Ab may precede plaque formation and are responsible for neuronal death and the development of AD [144] . Thus, removal of such oligomeric species of Ab would be beneficial for the disease process [140] . In AD animal model systems, passive immunization appears quite safe [143] . Major safety challenges of this immuno­t herapeutic approach are brain microhemorrhage, off-target cross-reactivity and loss of the antibody to a peripheral sink phenomenon [140] . Nevertheless, at least ten clinical studies of passive immunization with various Ab antibodies are ongoing (Table 2) [141] . The most advanced passive vaccines are bapineuzumab (AAB‑001) [145–147] and solanezumab [148] , composed of humanized anti-Ab monoclonal antibodies, are currently in Phase III clinical trials for the treatment of AD. Three types of anti-Ab monoclonal antibodies binding to linear epitopes within the Ab sequence have been described: antibodies against the N‑terminal epitope (amino acids ~1–10), the central region (amino acids ~17–32) and the C‑terminal region of Ab (amino acids ~32–42) [149] . Antibodies directed to the N‑terminal region of Ab have been shown to bind to Ab aggregates triggering microglial phagocytic clearance of amyloid plaques via an Fc receptormediated mechanism [88] . They were also shown to work by inhibiting aggregation or neurotoxicity of Ab [150] . F(ab’)2 fragments that lack the Fc region of the antibody may also be effective [151,152] . ���������������������������������� Bapineuzumab represents the prototypical monoclonal antibody directed against the N‑terminus of Ab. It is a fully humanized version of the mouse monoclonal antibody 3D6 recog­nizing the Ab1–5 region [153] . Bapineuzumab does not cross-react with APP or its a‑secretase cleavage product (sAPPa) [153] . In a Phase I, single-ascending dose trial, 30 mildto-moderate AD patients received bapineuzumab infusions of 0.5, 1.5 or 5 mg/kg or placebo [154] . The highest dose of 5 mg/kg was associated with MRI abnormalities (mainly high signal abnormalities on fluid-attenuated inversion recovery sequences) consistent with vasogenic edema, all of which resolved over time [154] . Brain microhemorrhage was observed in one patient. Pharmacokinetic analysis demonstrated future science group

Review

a half-life of 21–26 days, supporting a 13‑week dosing interval for bapineuzumab. At week 16, there was a positive trend in favor of the 0.5 (p  =  0.152) and 1.5  mg/kg (p  =  0.047) doses compared with placebo on the Mini Mental State Examination (MMSE) scale. However, the highest dose group (5 mg/kg) did not show differences compared with control group [154] . A Phase II multiple-ascending dose study was conducted at 30 sites in the USA between April 2005 and March 2008 [155] . The study was designed to evaluate safety but was not powered to show efficacy [155] . The coprimary outcome measures for preliminary efficacy were the Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS‑Cog), as a measure of cognition, and the Disability Assessment for Dementia (DAD) scale, as a measure of activities of daily living. A total of 234 mild-to-moderate AD patients (aged 50–85 years with MMSE scores of 16–26) received intravenous bapineuzumab or placebo (vehicle). Patients were initially entered into three dosing cohorts: 0.5, 1.0 and 2.0 mg/kg, administered every 13 weeks for 18 months (six intravenous infusions). After the occurrence of vasogenic edema in patients enrolled in the previous Phase  I study, an additional cohort receiving 0.15 mg/kg was added. Eighty patients (65%) treated with bapineuzumab completed the study, as did 78 (71%) of placebo-treated patients [155] . There were no statistically significant effects of bapineuzumab on a modified intent-to-treat analysis carried out on patients who received at least one infusion followed by at least one assessment [155] . A post‑hoc analysis on subjects who received all injections (n = 78) showed significant improvement in favor of the pooled bapineuzumab groups compared with placebo on ADAS‑Cog, DAD, neuropsychological test battery (NTB), but not on the Clinical Dementia Rating-Sum of Boxes (CDR‑SB) and on MMSE. A further post hoc subgroup analysis suggested that the benefits of bapineuzumab might be restricted to the ApoE e4 noncarriers alone (ADAS‑Cog, NTB, MMSE and CDR‑SB, but not DAD) [155] . Twelve out of 124 bapineuzumab-treated patients developed vasogenic cerebral edema. Six of them developed clinical symptoms, including headache, confusion, vomiting and gait disturbance. Vasogenic edema was detected as areas of increased T2 signal intensity MRI, which was obtained at routine intervals throughout the study [155] . In the initial Phase  II trial, the levels of Ab and tau in CSF were measured in a small substudy of 20 bapineuzumab-treated and 15 www.futuremedicine.com

221

222

Company/ institution

Immunotherapy (2012) 4(2)

1350 patients (2009–2012) Extension of NCT00574132 [307] and NCT00575055 [305] 220 patients (2006–2013)

80 patients (2009–2013) 120 patients (2010–2014) 80 patients (2008–2010)

Janssen

Janssen

Pfizer–Janssen

Janssen–Pfizer

Wyeth (Pfizer)

18 patients (2010–2012) 8 patients (2010–2011) 198 patients (2008–2011) 36 patients (2009–2011)

Pfizer

Pfizer

Pfizer

Pfizer

1275 patients (2010–2014) Extension of NCT00905372 [316] and NCT00904683 [317]

800 patients (2009–2017) Extension of NCT00676143 [306]

Pfizer

Eli Lilly

1000 patients (2009–2018) Extension of NCT00667810 [308]

Pfizer

1000 patients (2009–2012)

1000 patients (2008–2014)

Pfizer

Eli Lilly

1000 patients (2007–2012)

Janssen–Pfizer

1000 patients (2009–2012)

800 patients (2008–2013)

Pfizer

Eli Lilly

1300 patients (2007–2012)

Janssen–Pfizer

Estimated or completed enrollment (year)

AD: Alzheimer’s disease; IvIg: Intravenous immunoglobulin; MCI: Mild cognitive impairment.

Ponezumab (PF-04360365)

Solanezumab (LY2062430)

Bapineuzumab (AAB-001)

Monoclonal antibodies

Antibody

Phase III trial (ongoing, but not recruiting) Phase III trial (in progress) Phase III trial (in progress) Phase III trial (in progress) Phase III trial (in progress by invitation only)

Carriers of the ApoE e4 allele Noncarriers of the ApoE e4 allele Noncarriers of the ApoE e4 allele Carriers of the ApoE e4 allele Carriers and noncarriers of the ApoE e4 allele

Administered intravenously, multiple doses

Administered intravenously, multiple doses

Administered intravenously, multiple doses

Administered intravenously, multiple doses

Administered intravenously every 4 weeks for 80 weeks

Administered intravenously every 4 weeks for 80 weeks

Administered intravenously every 4 weeks for 80 weeks

Administered subcutaneously

Administered subcutaneously

Administered subcutaneously

Phase II trial (completed)

Phase II trial (completed)

Phase I trial (completed)

Phase I trial (in progress)

Phase III trial (in progress)

Phase III trial (ongoing, but not recruiting)

Phase III trial (ongoing, but not recruiting)

Phase II trial (completed)

Phase II trial (recruiting)

Phase II trial (recruiting)

Phase II trial (not recruiting)

Phase III trial (in progress)

Carriers of the ApoE e4 allele

Long-term extension study in AD patients who must have completed one of the following studies: AAB-001‑201 or AAB-001‑102

Phase III trial (ongoing, but not recruiting)

Status

Noncarriers of the ApoE e4 allele

Characteristics

Table 2. Overview of clinical trials of active and passive immunization targeting b‑amyloid and tau protein for the treatment of Alzheimer’s disease.

[322]

[319]

[321]

[320]

[318]

[317]

[316]

[311]

[310]

[309]

[312]

[315]

[314]

[313]

[308]

[305]

[306]

[307]

Ref.

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future science group

Company/institution

future science group

Eisai

BAN2401

80 patients (2010–2012)

50 patients (2007–2011)

www.futuremedicine.com

Sutter Health

NewGam

50 patients with MCI (2011–2013)

58 patients (2008–2011)

AD: Alzheimer’s disease; IvIg: Intravenous immunoglobulin; MCI: Mild cognitive impairment.

Octapharma IvIg, 10%

IvIg

IvIg, 10%

Weill Medical College of Cornell University Baxter; NIH Alzheimer’s Disease Cooperative Study

24 patients (2006–2010)

IvIg, 10%

Administered intravenously, single and ascending doses

Administered intravenously, single and multiple doses

Administered intravenously, single and multiple doses

Administered subcutaneously, multiple doses

Administered intravenously, single and ascending doses

Characteristics

Baxter; NIH 390 patients (2008–2013) Alzheimer’s Disease Cooperative Study

Octagam­®

Gammagard

Intravenous polyclonal antibodies (immunoglobulins)

GlaxoSmithKline

GSK933776A

56 patients (2008–2010)

360 patients with prodromal AD (2010–2015)

Hoffmann-La Roche

Genentech

60 patients (2006–2010)

Estimated or completed enrollment (year)

Hoffmann-La Roche

Crenezumab (MABT5102A)

Gantenerumab (R1450/ RO4909832)

Monoclonal antibodies (cont.)

Monoclonal antibodies

Phase II trial (in progress)

Phase II trial (completed)

Phase II trial (completed)

Phase III trial (active, not recruiting)

Phase I trial (in progress)

Phase I trial (completed)

Phase I trial (completed)

Phase II trial (in progress)

Phase I trial (completed)

Status

Table 2. Overview of clinical trials of active and passive immunization targeting b‑amyloid and tau protein for the treatment of Alzheimer’s disease (cont.).

[331]

[329]

[328]

[330]

[327]

[326]

[323]

[324]

[325]

Ref.

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placebo-treated patients.�������������������� Bapineuzumab treatment did not influence CSF Ab levels at week 52 compared with the baseline. There was a nonsignificant trend in lower CSF tau levels in the bapineuzumab-treated subjects compared with the placebo group [155] . In the same subgroup of patients, volumetric MRI analyses showed conflicting results based on ApoE genotype. ApoE e4 noncarriers showed significantly lower brainvolume loss. In ApoE e4 carriers, bapineuzumab treatment was associated with greater ventricular enlargement but no change in whole-brain volume [155] . In a subsequent Phase II study of bapineuzumab (0.5, 1.0 and 2.0  mg/kg), a modified intent-to-treat analysis showed that bapineuzumab-treated patients (n = 19) exhibited reduced carbon-11-labeled Pittsburgh compound B (11C‑PiB) retention on PET at 18  months compared with the baseline, whereas the placebo-treated patients (n  =  7) showed more retention compared with baseline [156] . These data suggested that bapineuzumab reduced brain accumulation of Ab. Unfortunately, the reduction in brain Ab accumulation in the bapineuzumab-treated patients was accompanied with a significant cognitive, functional or clinical benefit. Thus, the usefulness of the 11C‑PiB brain uptake as biomarker of drug efficacy remains unclear, since we do not know whether a reduction in brain Ab deposits may lead to clinical benefit. Furthermore, among the 53 individuals screened, eight showed low baseline 11C‑PiB binding, thus suggesting an imperfect correlation between clinical diagnosis of probable AD and the presence of Ab pathology [157] . A pooled ana­lysis of the two Phase II studies with bapineuzumab found a statistically significant (p = 0.0270) decrease in CSF hyperphosphorylated-tau levels in bapineuzumabtreated compared with placebo-treated patients, but not of Ab1–42 levels [158] . This observation suggests that bapineuzumab treatment may alter neuro­degenerative processes that occur later in the disease process and that are more directly associated with loss of function. However, the inconsistent findings on Ab1–42 levels and the post hoc nature of the ana­lysis of two pooled small studies suggest considering this report cautiously. Phase  I and II studies with bapineuzumab indicated the occurrence of vasogenic cerebral edema at the higher doses, especially in ApoE e4 carriers [154–156] . Vasogenic cerebral edema was observed in none of the placebo-treated patients and it exhibited a clear dose dependence. The 224

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incidence of vasogenic edema in bapineuzumabtreated patients increased with increasing ApoE e4 gene dose. In the initial Phase II study, all patients with vasogenic edema recovered both clinically and radiologically. Six patients were redosed at a lower dose (0.15 mg/kg) followed by a titration up to 50% of the original dose [155] . In the second Phase II study [156] , two out of 20 bapineuzumab-treated patients (both ApoE e4 carriers) developed vasogenic edema. Interestingly, ApoE e4 carriers are also less likely to improve cognitively, highlighting the importance of understanding the interaction between ApoE genotype and drug treatment in designing clinical trials [159] . It should be noted that since vasogenic cerebral edema occurred more frequently in ApoE e4 carriers, there were fewer bapineuzumab-treated carriers than noncarriers, so some analyses may have failed to detect a cognitive effect in ApoE e4 carriers just for lack of power. Alternatively, since the e4 allele may decrease Ab transport across the BBB [160] , one could hypothesize that ApoE e4 carriers may be resistant to bapineuzumab if it acts primarily by a peripheral-sink mechanism. An increase in vascular amyloid burden may have resulted in vasogenic edema in ApoE e4 carriers [155] . However, there are data suggesting that ApoE modifies CNS inflammatory responses in an isoform-specific fashion; a potential common denominator for its role in acute and chronic neurological diseases. In particular, the ApoE polymorphism was associated with enhanced glial activation and neuroinflammatory response [161] . Thus, although the effect of the ApoE e4 allele on the development of vasogenic edema was unanticipated, it is consistent with the possibility that ApoE e4 carrier status is associated with increased and potentially dangerous neuro­ inflam­matory responses in trials of immuno­ therapies designed to promote Ab clearance. Conversely, therapies that suppress inflammatory responses, such as NSAIDs, may be useful in patients with the ApoE e4 allele [162] . The emergence of vasogenic cerebral edema did not lead in an early interruption of the bapineuzumab trials, being clinical symptoms and signs generally mild and manageable. Other adverse events of bapineuzumab were not dose dependent. The occurrence of deep venous thrombosis and pulmonary embolisms has been described and are of clinical relevance [155] . Four deaths occurred (three during and one after the study) [155] and although they all occurred in the bapineuzumab-treated group, these deaths were not related to dose, ApoE e4 future science group

Immunotherapy for Alzheimer’s disease

status or the presence of vasogenic edema, and all were considered unrelated to treatment. In the Phase I trial, brain microhemorrhages were associated with vasogenic edema in one patient [154] . Brain microhemorrhages are of clinical concern in studies of passive immunization. It has been suggested that Ab has a role maintaining vascular and BBB integrity and its removal may cause leakage of serum components into the brain, resulting in an inflammatory immune (or autoimmune) response [163] . A clinically significant consequence of such Ab removal would be the occurrence of ministrokes. Other authors believe that brain microhemorrhages are related to vascular amyloid deposits (congophilic amyloid angiopathy), which may cause degeneration of smooth muscle cells and weakening of the blood vessel wall. Congophilic amyloid angiopathy is present in almost all AD patients and in approximately 33% of cognitively healthy elderly subjects [164] . Several studies have shown an increase in microhemorrhages in transgenic mouse models of AD after passive intraperitoneal immunization with different monoclonal antibodies [165,166] . Microhemorrhages after active immunization in a transgenic mouse model were reported in one study [167] . In these animal studies, the administration of Ab antibodies prevented the deposition of vascular amyloid. Human brain autopsies from AN1792 trials also demonstrated clearance of vascular amyloid [168] . In one patient, several cortical bleeds were noted [107] . Other neuropathology studies on AN1792 led to similar conclusions [110,169] . The initial finding that vaccination with AN1792 may shrink the brain of AD patients (due to Ab removal) [106] was later integrated by the long-term observation that patients with significant antibody responses showed similar brain volumes than placebo-treated patients [170] . While neither cognitive nor functional benefit were observed in the Phase II trials on bapineuzumab [155,156] , favorable arithmetic trends in some neuropsychological measures led to Elan and Wyeth’s decision to embark in four large Phase III studies in more than 4000 patients (Table 2) [146,147] . Participants will receive bapineuzumab by intravenous injection for 18 months. Studies were stratified by ApoE e4 status in carriers [305,306] and noncarriers [307,308] to verify if allele differences affect the clinical response to the drug (Table 2) . For safety reasons, ApoE e4 carriers are only receiving the lowest dose (0.5  mg/kg) of bapineuzumab based on the occurrence of vasogenic edema in the Phase II studies in this subgroup particularly at the future science group

Review

highest drug doses [155] . However, in April 2009, Elan and Wyeth dropped the highest of the three bapineuzumab doses (2 mg/kg) in ApoE e4 noncarriers because of the occurrence of vasogenic edema; these patients are now being treated with 1  mg/kg [146] . Subcutaneous administration of bapineuzumab is being investigated in AD patients in two Phase II studies (Table 2) [309,310] . Another Phase II clinical trial on subcutaneous bapineuzumab was completed in August 2010 in 80 AD patients (Table 2) [311] , and a Phase II long-term extension study is in progress [312] in AD patients who completed one of the following studies Phase II studies: AAB-001‑201 [155] or AAB-001‑102 (Table 2) . Finally, three other openlabel Phase III extension studies are ongoing to evaluate the long-term safety and tolerability of bapineuzumab [313–315] , ApoE e4 carriers and noncarriers, who participated in previous trials (Table 2) [305–308] . The closest competitor of bapineuzumab is solanezumab (LY2062430, Eli Lilly, Indianapolis, IN, USA) [148] . Solanezumab’s mechanism of action differs from other passive immunotherapies. This humanized version of the mouse antibody m266 directed against the Ab13–28 region [171,172] , recognizes a distinct epitope in the central portion of the peptide and it is able to recognize various N‑terminal truncated species such as Ab3–42 that are known to be present in AD SPs [173] . Whereas bapineuzumab has a higher affinity for amyloid SPs than soluble Ab, solanezumab selectively binds to soluble Ab with little to no affinity for the fibrillar form [174] . Furthermore, the intraperitoneal administration of solanezumab caused a rapid increase in the level of plasma Ab, while chronic treatment with m266 even affected Ab deposition, suggesting that it changed the equilibrium of Ab levels between brain interstitial fluids and blood, thereby accelerating Ab efflux [175,176] . Therefore, the site of antibody action is in the periphery, where soluble forms of Ab are sequestrated in the peripheral circulation and thus drive an efflux of Ab from the brain to the blood plasma, providing a peripheral sink for Ab clearance [175,177] . By contrast, the increased plasma Ab levels may be attributed to a reduced clearance rate of Ab complexed to antibodies, as no amyloid reduction with m266 was observed [174] . Another observation showed that despite an increase in plasma Ab, anti-Ab antibodies did not change the levels of total Ab [178] . Yamada and colleagues demonstrated that peripheral administration of m266 actually retards the efflux transport of Ab from brain to bloodstream and increases the level www.futuremedicine.com

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of the soluble monomer form of Ab in the brain [179] . These findings suggested that solanezumab may be effective by stabilizing Ab monomers and preventing the formation of Ab oligomers and amyloid fibrils [179] . Solanezumab was examined in a small Phase I clinical trial (19 patients) to assess safety and biomarker outcomes after a single dose [172] . According to the different doses administered (0.5, 1.5, 4.0 and 10.0  mg/kg) patients were stratified into four treatment groups. Excluding infusion reactions at higher dosages, no adverse events attributed to the treatment were seen over the short course of the trial. A dose-dependent increase of Ab in plasma and CSF was observed, although changes in cognitive scores were not noted [172] . In a Phase II study of 52 patients with mild-to-moderate AD (baseline MMSE score 20.2 ± 3.8) who received one of four doses of solanezumab (n = 10–11 per dosing group), plasma and CSF biomarker assays suggested a promising drug effect. Doses of solanezumab varied based on dose (100 vs 400  mg) and frequency of administration (weekly vs every 4 weeks), and a fifth group served as the control [180] . After injection of solanezumab, distinct plasma elevations of Ab and an increase of Ab1–42 and a decrease of Ab1–40 in the CSF were reported [180] . However, no significant cognitive benefit appeared in the ADAS‑Cog in this small sample over the 12‑week treatment period, although the study was not powered to detect efficacy. Even after 1 year of follow-up no adverse effects were reported, particularly no vasogenic edema. During the Phase I and Phase II studies there was no evidence of meningoencepha­litis or vasogenic edema [172,180] . However, a first case of vasogenic edema has been recently communi­ cated by Eli Lilly during Phase  III studies. Preclinical studies indicated that mice treated with m266 are less prone to cerebral microhemorrhage than mice treated with the murine equivalent of bapineuzumab [181] . In a Phase II trial in mild-to-moderate AD patients, cognitive performance (ADAS‑Cog), CSF tau levels and brain plaques (PET‑PiB) remained unaffected in solanezumab-treated subjects [180] . On the other hand, the absence of Ab clearance with monoclonal antibodies directed against the central region of Ab has been described in some animal models [88,182] . Two large Phase III trials for solanezumab are now underway, EXPEDITION [316] and EXPEDITION2 [317] , with more than 2000 cumulative patients and a planned completion date of autumn 2012 (Table 2) [148] . In each study, subjects received 400 mg of solanezumab 226

Immunotherapy (2012) 4(2)

versus placebo intravenously every 4 weeks for 80 weeks. Concurrent psychotropic and cognition-enhancing medications are allowed, provided that the dose has not changed for at least 2 months prior to randomization. A third openlabel extension study (EXPEDITION EXT) [318] has also been organized to provide ongoing safety data for solanezumab on 1275 patients as an extension of the EXPEDITION and EXPEDITION2 trials (Table 2) [316,317] . Bapineuzumab and solanezumab have several competitors, as at least five other monoclonal anti-Ab antibodies are in various stages of development (Table 2) [141] . In fact, other monoclonal antibodies against Ab have exhibited properties distinct from bapineuzumab and solanezumab (Table 2) [145–147] . The humanized IgG2 monoclonal antibody ponezumab (PF-04360365, Pfizer, Cambridge, UK) targets the free C-terminus of Ab1-40, specifically Ab33–40 [147,149] and is, at present, in Phase  II trial (Table 2) [319] . Although two Phase I studies [320,321] and one Phase II trial [322] have been completed, only preliminary data are available [183] . Single-dose data on 37  patients were obtained and indicate that the substance is well-tolerated over a 0.1–10 mg/kg bodyweight dose range. In MRI examinations vasogenic edema did not occur. A mild central antibody penetration over the BBB is supposed as two out of eight patients in the 10 mg/kg bodyweight cohort had measurable concentrations in CSF (~0.5% of plasma values). However, no remarkable changes in cognition (ADAS‑Cog or MMSE) have been noted yet [183] . Another ������������������������������������� monoclonal antibody, crenezumab (MABT5102A, Genentech, San Francisco, CA, USA) [184] , has completed a Phase I study [323] ; although its epitope is not published, it distinguishes itself by binding to Ab monomers, oligomers and fibrils with equally high affinity (Table 2) [147] . A Phase II study on 360 individuals with prodromal AD with gantenerumab (R1450 or RO4909832, Hoffmann-La Roche, Basel, Switzerland) is presently in progress [324] , while information regarding a completed Phase I study on gantenerumab [325] and a Phase I study in progress on GSK933776A (GlaxoSmithKline, London, UK) [326] is not yet publicly available (Table 2) . Finally, BAN2401 (Eisai, Tokyo, Japan) [327] , a monoclonal antibody that selectively binds, neutralizes and eliminates soluble protofibrils, is presently in a Phase I clinical trial (Table 2) . At present, the epitopes of GSK933776A and BAN2401 are not known, while both N‑terminal and central portions of Ab were recognized by gantenerumab [149] . future science group

Immunotherapy for Alzheimer’s disease

Studies with polyclonal antibodies or oligoclonal combinations of antibodies are scarce as high regulatory hurdles exist for approval of such drugs [149] . Currently, we only have data on commercially available intravenous immunoglobulin (IvIg) preparations, which have been used in clinical trials in AD patients. IvIg is a pooled mixture of natural human immunoglobulins that include Ab antibodies (those recognizing Ab oligomers and fibrils, among others) [185] . The rationale for their use in AD stems from data that commercially available IvIg preparations contain naturally occurring autoantibodies against Ab (nAbs-Ab) [186] . nAbs-Ab were detected in the blood and CSF of healthy and diseased persons and, although there are contrasting data, the current evidence indicates that their concentration is reduced in AD patients [187,188] . The nAbs-Ab seem to have an important physiological role in the clearance of Ab [189] in healthy as well as in diseased states by interfering with the oligomerization and fibrillization of Ab [190,191] , protecting neurons against Ab-mediated toxicity [185] and interfering with Ab metabolism and hydrolysis [192] . However, based on the hypothesis that a reduced concentration of nAbs-Ab exists in AD patients, their supplementation would be a therapeutic option [149] . Further evidence for an effect of antibody-based therapy and nAbs-Ab stems from a retrospective case–control study evaluating the incidence of AD and related disorders in an IvIg-treated population with various diagnoses as indication for IvIg use, mainly humoral immunodeficiency syndromes, versus an untreated population, with a 42% lower incidence rate of dementia in patients treated with IvIg [193] . The first study on polyclonal antibodies investigated 16 patients with AD: eight patients received 140 g piracetam for 1  year only and eight patients received an additional monthly dose of 0.2 g/kg IvIg (octagam®, Octapharma, Lachen, Switzerland)) [194] . Unfortunately, the study results are only available in abstract form; however, although we did not know the outcome measures used, the authors concluded that the treatment demonstrated a significant improvement in the group of patients with the additional IvIg treatment [193] . Two pilot studies showed that IvIg (gammagard 10%, Baxter International Ltd Deerfield, IL, USA) may be efficacious in the treatment of AD [195,196] . In particular, the first study included five AD patients who were given monthly infusions (a total of 1.2 g/kg bodyweight over a 3‑day period) for a duration of 6 months. The primary outcome was the shift of Ab from the central to the peripheral pool, future science group

Review

with a significant decrease in Ab1–40 CSF concentration detected and an increase in the serum after 6 months of IvIg treatment [195] . Similar findings were reported by a US pilot trial that included eight patients with mild-to-moderate AD receiving IvIg for a total period of 18 months (6  months treatment, 3  months washout and 9 months observation) at different concentrations and infusion intervals [196] . In addition, nAbs-Ab were detected in the CSF of the patients following IvIg treatment, indicating that IvIg antibodies might cross the BBB and lower Ab levels in the brain [196] . None of the patients deteriorated during the study period, and in the US study an improvement of MMSE scores by a mean of 2.5 points was reported [196] , although the small number of patients and the lack of a control group in both studies precluded a meaningful analysis of cognitive changes. A Phase II dose finding study on IvIg was completed in 2010 in 24 mild-to-moderate AD patients for a period of 6 months (Table 2) [328] . Four different dosing regimens and two different application times (0.2 [n = 4] and 0.4 g/kg/2 weeks [n = 4]; 0.4 [n = 4] and 0.8 g/kg/4 weeks [n = 4]; and placebo [n = 8]) were applied [149] . The ADAS‑Cog difference between the control group and the treated patients was 5.27 at 6  months; however, this was not significant. The Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and the Neuropsychiatric Inventory (NPI) improved significantly in the combined group as compared with the placebo group [149] . Plasma Ab increased in a similar fashion as in the previous study. In the FDG-PET in a subgroup of the study, the glucose metabolism in mildly hypometabolic brain regions and in severely hypometabolic brain regions was preserved [149] . Recently, also another Phase II clinical trial using IvIg (octagam 10%) was completed by Octapharma as a dose-finding study with centers in the USA and Germany [329] . At present, there are two trials currently underway for IvIg in AD: a Phase III trial sponsored by Baxter International Ltd and the NIH Alzheimer’s Disease Cooperative Study [330] ; and a Phase II trial on subjects with amnestic MCI by Sutter Health (Sacramento, CA, USA) (Table 2) [331] . The Phase III trial with gammagard will recruit over 360 patients with mild-to-moderate AD and will be randomized into three treatment arms: 0.4 and 0.2 g/kg IvIg every 2 weeks for 70 weeks; and placebo. Primary outcome measures include cognition and global function. Data from this trial will be available in 2013 [149] . www.futuremedicine.com

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„„ Tau-based strategies Anti-tau oligomer antibodies similar to the ones developed for Ab [197] may be ideal candidates for passive vaccination [139] , providing exciting opportunities to validate anti-tau oligomer immunotherapeutic approaches in animal models already available for researchers [103,198,199] . Recently, circulating naturally occurring antibodies against tau (IgM and IgG) have been detected in the blood and with much lower titers in the CSF [200] . In the sera of nine AD and eight healthy individuals, and in 20 AD patients and 22 subjects suffering from other neurological disorders, Rosenmann and colleagues found antibodies against unphosphorylated as well as phosphorylated tau. Similar to naturally occurring antibodies against Ab, naturally occurring tau antibodies decrease with age [149] . A new class of monoclonal antibodies could behave as chaperones protecting targeted proteins against conformational changes [99] . Several studies have suggested that these antibodies effectively inhibit aggregation and toxicity of misfolded proteins [201–203] . More recently, a passive immunotherapy approach has also been proposed by using chaperone-like antibodies targeting misfolded tau [98,99] . These �������������������������� chaperone-like antibodies may facilitate physiological folding and prevent tau aggregation, or may reverse pathological conformations to native. Interactions between antibodies and strategic epitopes may also neutralize toxicity linked to misfolded tau [99] . The effects of antibodies on protein folding is strictly substrate specific; different from endogen chaperones that act on protein classes [99] . Antibodies directed to the first or second repeat of the microtubule-binding domain of tau protein, which is believed to be regulate PHF assembly, completely inhibited aggregation into PHFs [202,203] . However, site-directed antibodies did inhibit effects on tau-induced microtubule assembly [202,203] . It has been shown that assembly of tau proteins into fibrils depends on a b-sheet conformation generated by the sequence motif 306-VQIVYK-311 [204] . Indeed, a monoclonal site-directed antibody with high affinity for the 300-QPGGGSVQIVYKP-312 residues has been developed and was found to completely abolish the pathological microtubule assembly promoted by misfolded tau [98] . The feasibility of this approach has to be demonstrated, given that, at present, only one study reported in vivo data [205] . In fact, multiple injections of the antitau monoclonal antibody PHF1 were associated with clearance of tau pathology in homozygous JNPL3 P301L-expressing mice, also with some 228

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functional improvements [205] . Analogous to previous active tau immunization studies, tau pathology correlated well with antibody levels and behavioral outcomes [131] , further supporting the validity of this approach. PHF1 is a monoclonal antibody that recognizes phospho‑Ser in positions 396 and 404 of the tau molecule [206] , both of which are contained within the prototype phospho-tau immunogen Tau379–408 (phospho-Ser‑396 and -404), used in previous studies on active tau immunization (Table 1) [131] . Unfortunately, no further studies regarding passive immunization against tau are currently available, and this makes it hard to predict the potential problems [139] . Tau vaccination using tau conformation-specific antibodies may not cause side effects, such as cerebral amyloid angio­pathy and microhemorrhages, observed when anti-Ab antibodies were used in passive vaccination studies because, unlike Ab, tau does not bind blood vessels [139] . However, the location of tau oligomers, presumably intracellularly, could be more challenging for immunotherapy than the extracellular Ab. Importantly, antibodies can clear intraneuronal protein aggregates without entering the cells, suggesting that depletion of the extracellular pool of aggregates by the antibody will shift the equilibrium between the intra- and extra-cellular pools of aggregates [207] , hence leading to removal of the intracellular aggregates. This has been demonstrated for Ab, a‑synuclein and tau protein [131,208,209] . Moreover, antibodies against both tau and Ab can be internalized, most likely by endocytosis [131,210] . Another approach could be the use of anti-tau intra­bodies, which was effective in treating mice with Huntington disease [211] . Finally, the search for novel methods and reagents to study tau oligomers will benefit greatly from the expertise gained by studying Ab and other amyloid oligomers [207] . Very recently, LasagnaReeves and colleagues reported methods to prepare tau oligomers in vitro and described a novel anti-tau oligomer conformation-specific antibody similar to those developed against Ab oligomers [197] and shown to be effective in targeting Ab oligomers in animal models [198] . Such antibodies and intrabodies with similar specificity will provide valuable tools to target tau oligomers in mouse models by passive vaccination and to assess their role in AD and other neurodegenerative diseases.

Future perspective Research findings suggested that AD probably involves several physiological pathways, and future science group

Immunotherapy for Alzheimer’s disease

recent results of anti-Ab immunotherapy raised the question whether Ab may be an ideal target for AD therapy. In fact, while immunization with preaggregated Ab1–42 (AN1792) resulted in almost complete removal of the SPs from the brain of the AD patients, the removal of plaques did not prevent progressive cognitive or clinical decay [113] . There are several reasons why Ab immunotherapy might have been ineffective in treating AD patients. In fact, other important targets in AD are the NFTs and their precursors, composed primarily of hyperphosphorylated tau proteins. APP-overexpressing mice do exhibit memory impairment without tau pathology or neuronal loss, whereas the reduction of tau levels in APP-overexpressing mice prevents Ab-induced memory deficits [212] . Therefore, some changes in tau prior to NFT formation may be involved in memory impairment. However, these changes in tau may be insufficient to cause NFT formation and neuronal loss. Pathological changes in tau that lead to NFT formation and neuronal loss may be key to understanding why Ab removal fails to halt the clinical course of AD in humans. Therefore, it remains unclear whether therapies that only attenuate Ab pathology or tau pathology will be effective in slowing down the rate of cognitive and functional decline in AD. Incidentally, one should note that antitau target may have applications beyond AD, in a variety of neurodegenerative conditions including frontotemporal dementia, progressive supranuclear palsy and corticobasal degeneration. Immunotherapeutic approaches for the treatment of AD, whether aimed at Ab or tau, show real promise and are prime candidates for further research, though it is possible that a combination immunotherapy approach may be more beneficial than either approach alone. Furthermore, passive immunization protocols for tau could also be considered as an alternative to the active immunization approaches, although there is a lack of studies using passive immunotherapy for tau. In addition to providing an important new therapeutic avenue for AD, further tau immunotherapy studies may confirm the validity and relevance of immunization protocols aimed at intracellular proteins. Among the Ab-based therapies, the most innovative approach is represented by active and passive vaccines, which were proven to lower Ab deposits in the brain of AD patients. Furthermore, among immunotherapeutics, the passive approach with anti-Ab monoclonal antibodies is the most advanced. Bapineuzumab and solanezumab represent the cutting edge of future science group

Review

these passive immunotherapy approaches and are presently under extensive clinical testing with over 6000 AD patients in Phase III trials. Subgroup analyses of the initial Phase II studies with bapineuzumab suggest that the drug may have beneficial effects in some patients. Unfortunately, bapineuzumab treatment has been associated with the occurrence of vasogenic edema and brain microhemorrhages. It has been proposed that these risks could be mitigated during the preclinical stages of AD before massive vascular Ab deposition takes place. Indeed, the ‘prodromal’ phase of AD may represent the ideal time for bapin­euzumab intervention. A number of bapineuzumab’s direct competitors were specifically designed to decrease the risk of inflammation and vasogenic edema, increasing their potential efficacy for Ab removal. Among these new immunological approaches, solanezumab is the most clinically advanced. However, as seen above, the hypothesis that Ab is the key pathologic factor affecting the disease process is strongly questioned by the finding that the removal of SPs with anti-Ab immunotherapy failed to halt progressive neurodegeneration [113] . These negative findings have been recently echoed by the failure of semagacestat, a g‑secretase inhibitor, in two large Phase III clinical trials [25] , although the drug dramatically reduced the production of Ab in the CNS of humans [213] . Indeed, several studies have demonstrated that Ab has a physiol­ ogical role in modulating synaptic plasticity and hippocampal-mediated learning and memory [214] . Ab deposition could simply represent a host response to an upstream pathological process, or alternatively could serve as a protective chelator [214,215] . In this direction, immunotherapy selectively directed towards oligomeric Ab and ADDLs should produced beneficial cognitive effects without altering normal physiology of monomeric Ab. Indeed, conformation-specific monoclonal antibodies recognizing toxic soluble Ab oligomers and ADDLs have been designed to achieve this scope [216,217] . As discussed above, both AN1792 and bapineuzumab use has caused clinically significant adverse events in a minority of patients (5–10%), without showing impressive clinical efficacy. It remains to be understood whether the occurrence of side effects is intrinsically linked to the mechanism of action of the immunotherapy (the removal of Ab from the brain vascular wall with loss of integrity of BBB) or is antibody-specific. It is unknown if the absence of marked beneficial effects is owing to the fact www.futuremedicine.com

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that these immunotherapies have been tested in subjects with mild-to-moderate AD, rather than in earlier stages. It is also unknown if the efficacy of bapineuzumab is maximized and toxicity minimized in ApoE e4 noncarriers. After the recent failure of the g‑secretase inhibitor semagacestat, bapineuzumab and solanezumab represent the most clinically advanced chance for patients suffering from AD. ��������������� In the unfortunate case that these drugs fail, earlier intervention should probably have been attempted. In fact, the recent introduction of new diagnostic criteria for AD based on specific cognitive patterns and reliable biomarkers [218] may open a new paradigm of therapeutic intervention, based on the distinction of two preclinical states of AD in which individuals are free of cognitive symptoms [219] . One group is formed of ‘asymptomatic subjects at risk of AD’ with biomarker evidence of AD pathology. The other group is formed of ‘presymptomatic AD subjects’ carrying genetic determinants, who will eventually develop the disease [219] . This distinction may revolutionize drug intervention with increased chances of success in delaying this devastating disease. New drugs should be tested in these two populations of ‘asymptomatic’ or ‘presymptomatic’ subjects rather than in AD patients. Very recently, the National Institute on Aging and the Alzheimer’s Association set a workgroup with the task of revising the 1984 criteria for AD dementia [220] , developing criteria the for the symptomatic predementia phase of AD (MCI due to AD) [221] and defining the preclinical

stages of AD for research purposes and toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious [222] . In particular, for MCI due to AD, the workgroup developed core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or CSF ana­lysis, and research criteria that could be used in clinical research settings, including clinical trials, incorporating the use of biomarkers based on imaging and CSF measures [221] . Therefore, the stage of the mild-to-moderate AD patients in which most clinical progression trials have been run, is relatively late in the disease course, where irreversible damage to the brain may have already occurred. Newly designed clinical trials that access patients earlier in the course of the disease are in progress [223] , and new diagnostic criteria recognizing preclinical or prodromal/predementia AD will enhance the ability to test the amyloid cascade hypothesis of AD in patients that may still have the capacity to respond to treatment more fairly. Financial & competing interests disclosure This work was supported by the Italian Minister of Health IRCCS Research Program 2006–2008, Line 2: ‘Malattie di rilevanza sociale’. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary ƒƒ The two principal neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques and neurofibrillary tangles; the former being mainly composed of b‑amyloid (Ab) peptide and the latter of hyperphosphorylated tau protein. ƒƒ Although tau is an intracellularly located protein, different studies have reported successful active immunization against tau in animal models of AD, also confirming positive findings in studies on active and passive immunotherapeutics against a‑synuclein. ƒƒ Very few studies regarding passive immunization against tau protein are currently available. ƒƒ Human brain imaging studies and postmortem neuropathological studies have demonstrated the ability of both active and passive anti-Ab immunotherapies to clear brain Ab deposits. ƒƒ An active Ab vaccine (AN1792) has been used in AD patients, but the results were equivocal regarding clinical efficay and the vaccine caused meningoencephalitis in approximately 6% of subjects. Its clinical development has been discontinued. ƒƒ Second-generation active Ab vaccines and new passive Ab immunotherapies have been developed and are under clinical testing. ƒƒ Several monoclonal antibodies developed against Ab, as well as polyclonal antibodies, are currently in clinical testing. Some have already entered Phase III clinical trials. ƒƒ The most advanced of these anti-Ab monoclonal antibodies are bapineuzumab and solanezumab, which have been tested in Phase II trials, where they reduced Ab burden in the brain of AD patients. ƒƒ However, particularly in Apo E e4 carriers, the preliminary cognitive efficacy of bapineuzumab appears uncertain and vasogenic edema may limit its clinical use. ƒƒ The results of ongoing Phase III trials with 6000 AD patients on bapineuzumab and solanezumab will tell us if passive anti-Ab immunization is able to alter the course of this devastating disease. ƒƒ AD progression trials should probably include patients earlier in the course of the disease, employing recently amended diagnostic criteria for AD.

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nn

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Immunotherapy (2012) 4(2)

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Francesco Panza Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, Foggia, Italy Vincenza Frisardi Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, Foggia, Italy Vincenzo Solfrizzi Department of Geriatrics, Center for Aging Brain, University of Bari, Bari, Italy Bruno P Imbimbo Research & Development Department, Chiesi Farmaceutici, Parma, Italy Giancarlo Logroscino Department of Neurological & Psychiatric Sciences, University of Bari, Bari, Italy Andrea Santamato Department of Physical Medicine & Rehabilitation, University of Foggia, Foggia, Italy Antonio Greco Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, Foggia, Italy Davide Seripa Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, Foggia, Italy Alberto Pilotto Geriatrics Unit, Azienda ULSS 16 Padova, S Antonio Hospital, Padova, Italy and Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, Foggia, Italy

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