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Amyloid-based immunotherapy for Alzheimer’s disease in the time of prevention trials: the way forward Expert Rev. Clin. Immunol. Early online, 1–15 (2014)

Francesco Panza*1,2, Vincenzo Solfrizzi5, Bruno P Imbimbo3, Rosanna Tortelli1,2, Andrea Santamato4 and Giancarlo Logroscino1,2 1 Department of Basic Medicine, Neuroscience, and Sense Organs, Neurodegenerative Disease Unit, University of Bari Aldo Moro, Bari, Italy 2 Department of Clinical Research in Neurology, University of Bari Aldo Moro, “Pia Fondazione Cardinale G. Panico”, Tricase, Lecce, Italy 3 Research & Development Department, Chiesi Farmaceutici, Parma, Italy 4 Physical Medicine and Rehabilitation Section, “OORR” Hospital, University of Foggia, Foggia, Italy 5 Geriatric Medicine-Memory Unit and Rare Disease Centre, University of Bari Aldo Moro, Bari, Italy *Author for correspondence: [email protected]

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Both active and passive anti-b-amyloid (Ab) immunotherapies for the treatment of Alzheimer’s disease (AD) have demonstrated clearance of brain Ab deposits. Among passive immunotherapeutics, two Phase III clinical trials in mild-to-moderate AD patients with bapineuzumab, a humanized monoclonal antibody directed at the N-terminal sequence of Ab, were disappointing. Also solanezumab, directed at the mid-region of Ab, failed in two Phase III trials in mild-to-moderate AD. Another Phase III trial with solanezumab is ongoing in mildly affected AD patients based on encouraging results in this subgroup. Second-generation active Ab vaccines (CAD106, ACC-001, and Affitope AD02) and new passive anti-Ab immunotherapies (gantenerumab and crenezumab) have been developed and are under clinical testing. These new anti-Ab immunotherapies are being tested in prodromal AD, in presymptomatic subjects with AD-related mutations, or in asymptomatic subjects at risk of developing AD. These primary and secondary prevention trials will definitely test the Ab cascade hypothesis of AD. KEYWORDS: active immunotherapy . Alzheimer’s disease . cognitive disorders . dementia . gantenerumab .

monoclonal antibody

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passive immunotherapy

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solanezumab

Alzheimer’s disease (AD) is a devastating and progressive neurodegenerative disease and represents significant and increasing clinical challenge, leading to progressive cognitive decline, functional impairment and loss of independence. The 2013 figures suggested that AD affects over 5.2 million people in the USA [1]. By 2050, nearly a million new cases of AD per year are expected to develop, with a total estimated prevalence of 13.8 million. At present, available pharmacological treatments provide only symptomatic benefit, with no effective disease-modifying action [2,3]. In fact, AD appears to be very difficult to treat, given its multifactorial and heterogeneous nature, thus offering a large number of rational therapeutic targets. Senile plaques (SPs) and neurofibrillary tangles (NFTs) were the ‘signature’ neuropathological hallmarks of AD [4]. These pathological lesions of AD involve both intraneuronal protein aggregates (NFTs) composed

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of paired helical filaments of hyperphosphorylated tau protein, a microtubule-associated protein, and extracellular protein clusters (SPs) resulting from the accumulation of b-amyloid (Ab) peptide. In particular, SPs have a proteinaceous core composed of 5- to 10-nm amyloid fibrils and are accompanied by dystrophic neurites, astrocytic processes and activated glial cells. The cleavage of amyloid precursor protein (APP) by b- and g-secretases generates Ab peptide, consisting of 38–42 amino acids [5]. Ab1– 40 is the main form of Ab containing 40 amino acids, while Ab1–42, although formed in less amounts than Ab1–40 [6], is more prone to aggregate into fibrils and is one of the major component of SPs [7]. The original ‘amyloid cascade hypothesis’, first formulated in 1991, postulated that Ab deposition, given an imbalance between production and clearance of this peptide, is thought to precede and precipitate the formation of NFTs [8], although the exact

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Panza, Solfrizzi, Imbimbo, Tortelli, Santamato & Logroscino

mechanism is still unclear [9]. The deposition of Ab may lead to the formation of intracellular tau protein and therefore to NFTs [10], or Ab and NFTs may promote a synergistic interaction [11,12], or there could be an independent development of SPs and NFTs, or these two neuropathological lesions may occur as the products rather than the causes of AD neurodegeneration [9]. Since the SP number does not correlate well with the severity of dementia [13] as opposed to soluble oligomeric forms of Ab [14], the amyloid cascade hypothesis has been reformulated, positioning soluble Ab aggregates as the main contributors to neuronal death, given their strong neurotoxicity [15]. Several different Ab species with overlapping size and morphology have been described [Ab-dimers, low-molecular-weight oligomers, globulomers, Ab-derived diffusible ligands (ADDLs), protofibrils or amylospheroids] [16], and recent evidence has implicated oligomeric Ab and ADDLs in cognitive decline [17,18]. Therapeutics targeting tau pathology in AD

Hyperphosphorylated tau by itself and oligomeric tau are both involved in synaptic loss, as confirmed by studies on the wild human tau transgenic mouse [19]. Therefore, therapies targeting NFTs have potential application against neurodegeneration, given the confirmed link existing between NFT topography and clinical AD phenotype [20], although the development of these compounds has lagged behind drugs targeting Ab [21]. However, novel tau-based therapeutic strategies should be based on the identification of the specific pathological and neurotoxic forms of tau [22–24]. In fact, while NFTs represent the final stages of a pathological process, some intermediate hyperphosphorylated and most likely soluble tau species induce a process of neuronal dysfunction [25,26], similar to that induced by Ab oligomers, affecting synaptic structure and plasticity [27]. Drugs targeting tau pathology reduced, stabilized or prevented aggregation or hyperphosphorylation of the protein [21,28]. In particular, among different disease-modifying therapeutic approaches, the inhibition of tau aggregation or tau phosphorylation and the increase of microtubule stabilization or tau clearance have been suggested [21,23], with some of these approaches reaching the clinic [22]. Finally, the efforts for the clinical development of safe and efficacious anti-Ab active and passive vaccinations have opened the way for the development of possible tau-based immunotherapeutics [21,23,24]. Studies of immunotherapy targeting tau pathology appeared increasingly promising and are based on a number of studies conducted in tau transgenic mouse models, both on active [29–34] and on passive immunization [35,36]. Axon Neuroscience SE (Graz, Austria) recently began recruiting mild-to-moderate AD patients for a Phase I safety study of their active vaccine AADvac1, a synthetic peptide derived from a tau protein sequence coupled to keyhole limpet hemocyanin and designed to target misfolded tau protein (clinicaltrials.gov identifier: NCT01850238) [37]. Unfortunately, immunization with recombinant full-length human tau protein (unphosphorylated) of wild-type mice led to encephalomyelitis with neurological and behavioral deficits, inflammation and axonal damage [29]. On the other hand, vaccination with doi: 10.1586/1744666X.2014.883921

tau phosphopeptides reduced the NFT burden in the brain and spinal cord, without apparent neurotoxicity [32], although, under certain conditions, the safety of repeated phosphorylatedtau immunotherapy has been recently questioned because it may cause neuroinflammation [38]. Furthermore, targeting misfolded, truncated forms of tau suggested some therapeutic potential for the prevention of NFT development and delay of behavioral impairment in AD [39], eliciting antibody responses and enhancing tau clearance. In the last decade, lowering the burden of Ab with a strategy against the production and the accumulation of this peptide has represented a large portion of the many therapeutic approaches currently under development for the treatment of AD [3]. Several active and passive immunotherapeutic procedures have reached Phases II and III clinical development, suggesting a greater therapeutic importance of strategies aimed to eliminate excessive brain Ab by immunization [40,41]. In the present article, we reviewed clinical trials on active and passive amyloid-based immunotherapeutics for the treatment of AD, focusing on animal studies and clinical findings on anti-Ab monoclonal antibodies. This review was based on searches of US National Library of Medicine databases covering the period before November 2013. Active anti-Ab immunotherapy for AD: the current evidence

Immunization strategy, the most innovative approach of antiAD therapy, has focused on two main techniques with the administration of Ab antigens (active vaccination) or anti-Ab antibodies (passive vaccination), stimulating the Ab clearance from the AD brain [21,40,41]. Among active immunotherapeutic procedures, after the impressive results of preclinical studies with preaggregated Ab1–42 administered with the immune Freund’s adjuvant [42], the first anti-Ab vaccine (AN1792) tested in AD patients included full-length Ab1–42 peptide with an adjuvant (QS21), preferentially promoting T-cell–mediated immune responses. The first Phase I trial, involving only 24 patients, demonstrated good tolerability of AN1792 [43]. In a trial with multiple doses of AN1792, there was no significant difference of adverse effects between AN1792 and a placebo group, although one patient developed meningoencephalitis [44]. However, a Phase IIa trial on 372 mild-to-moderate AD patients was halted owing to 6% of the treated patients developing aseptic meningoencephalitis [45], thought to have been induced by an excessive Th1-mediated response suggested by cytotoxic T-cell reactions surrounding some cerebral vessels [46]. However, if patients who were treated but did not have an antibody response were excluded from the analyses, the percentage of side effects will be much higher. In a long-term observation of AD patients with significant anti-Ab antibody responses, approximately only 25% of AN1792-treated patients showed similar brain volumes than placebo-treated patients [47], while initial findings suggested that AN1792 vaccination may cause increased losses in AD brain due to Ab removal [45]. Postmortem histopathological examinations of a few patients Expert Rev. Clin. Immunol.

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Amyloid-based immunotherapy for AD in the time of prevention trials

showed clearance of parenchymal SPs, confirming the ability of vaccination in boosting Ab clearance in the AD brain [46,48,49]. The hypothesis suggesting that if AN1792 immunization begins at earlier stages of the disease, the Ab-lowering effects could have increased cognitive benefits [50,51] has been confirmed by the presence of tau-related pathology in cortical areas cleared of Ab. On the contrary, in transgenic mouse AD models, early vaccination prevented the formation of both Ab aggregates and hyperphosphorylated tau clusters [52], therefore preventing the formation of new NFTs without affecting the tangles already formed. In the 80 patients of the multiple-dose Phase I trial [44], the burden of Ab correlated inversely with antibody titer after vaccination, but with no effect on survival or progression of dementia [53]. Based on the clinically significant adverse events and questionable clinical efficacy, the vaccine was abandoned. After the failure of AN1792 vaccination, active immunotherapeutics was continued with alternative approaches. At present, several preclinical studies of anti-Ab active immunization are under investigation [21,54]. An ideal anti-Ab vaccine should elicit a robust anti-Ab antibody, stimulating a Th2 (T-helper) immune response [54]. In fact, these second-generation vaccines were designed to reduce the potential for a Th1-mediated cellular immune response and, with appropriate modifications of the antigenic presenting Ab-peptide, to favor a humoral response. A series of preclinical studies on transgenic mouse models of AD showed examples of second-generation active anti-Ab vaccines by testing alternate immunogens and adjuvants to overcome an inappropriate T-cell response, including nontoxic/nonfibrillar, soluble Ab-derivative immunogens [55]; adenovirus vector vaccines encoding Ab1–15 [56,57] and Ab3–10 [58]; phage display of epitope EFRH (Ab3–6) [59]; DNA vaccines targeting Ab [60–62], Ab ‘retroparticles’ [63] and Ab species (YM3711) [64]; short amino-terminal Ab fragments that target the B-cell epitope avoiding T-cell activation [65,66]; herpes simplex virus amplicons coding for Ab [67]; active vaccination against ankyrin G [68]; a liposomal immunogen adjuvant with an Ab antigen (EB101) [69]; oral vaccines that elicit Th2-dominant immune responses, such as recombinant AAV/Ab vaccine [70,71] and recombinant Ab rice [72], and an epitope vaccine (Lu AF20513) in which the T-helper cell epitopes of Ab1–42 were replaced by two foreign Th epitopes from tetanus toxoid— P2 and P30—and the immunodominant B-cell epitope of Ab1– 12 [73]. Moreover, various adjuvants and routes of administration (oral, intranasal and transcutaneous) are underway to improve the safety, efficacy and ease of use of anti-Ab vaccines [21,52]. After a decade from the failure of AN1792, CAD106 was developed as the second generation of active Ab immunotherapy, reaching clinical development. CAD106 comprised only a small Ab fragment (Ab1–6) that is a B-cell epitope coupled to an adjuvant carrier formed by 180 copies of the coat protein of bacteriophage Qb, providing T-cell help for the anticipated immune response. Immunization with CAD106 prevented brain SP accumulation in two transgenic AD mouse models, with reductions of up to 80% in the SP area compared with informahealthcare.com

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controls [74]. Recently, a Phase I clinical trial assessed the safety and tolerability of CAD106 showing that 67% of patients receiving 50 mg CAD106 and 82% receiving 150 mg CAD106 developed Ab antibody response meeting prespecified responder threshold. This trial reported some minor adverse effects but no cases of autoimmune meningoencephalitis [75]. However, the study was under-powered to show any clinical differences between AD patients treated with CAD106 and controls, while five Phase II clinical trials on CAD106 were recently completed and the data analyses are pending (ClinicalTrials.gov Identifiers: NCT01097096, NCT00956410, NCT00795418, NCT01023685 and NCT00733863) [76–80]. Therefore, CAD106 is one of the new peptide vaccines too short (6 amino acids long) to activate T cells, with only the parts needed for generation of Ab-specific antibodies. Two other of these B-cell–targeted peptide vaccines for active immunizations, ACC-001 (vanutide cridificar) and Affitope AD02 [81,82] are currently in Phase II clinical trials. ACC-001 is a conjugated N-terminus peptide attached to an immunostimulatory carrier protein using the surface-active saponin adjuvant QS-21, while Affitope AD02 is a synthetic 6-amino acid peptide vaccine targeting the N-terminus of Ab only, when it is free, with aluminum hydroxide as adjuvant. The response of Affitope AD02 is focused exclusively on Ab, without crossreacting with APP, and hence, may have a favorable safety profile. While AN1792 vaccine presented residues Ab15–42, the most common T-cell epitope causing Th1 lymphocyte activation, and therefore, predominantly responsible for autoimmune meningoencephalitis, these new immunogens should potentially avoid these safety concerns. Early clinical data from Phase I trials confirmed positive antibody responses for these peptide vaccines with no signs for adverse autoimmune inflammation [81,82], while further results from the ongoing Phase II trials are needed for these active immunization therapies. Passive anti-Ab immunotherapy & prevention trials for AD

Passive immunization involves the direct injection of already preformed and manufactured humanized monoclonal antibodies to AD patients without requiring the immune system to generate an antibody response, avoiding eliciting Th1-mediated autoimmunity [83,84]. AD transgenic mice treated with anti-Ab monoclonal antibodies showed a significant decrease in brain Ab levels, reduced brain SP pathology and improved cognition, beneficial effects observed using a variety of antibodies that differed in Ab-binding properties [85,86]. Among anti-Ab monoclonal antibodies, bapineuzumab and solanezumab emerged as the two leading candidates following the passive immunization route, which led to their careful evaluation in several Phase III clinical trials [87,88]. Unfortunately, these large clinical trials have failed to achieve the projected results [89]. Bapineuzumab (AAB-001) represents the prototypical fully humanized monoclonal antibody directed against the N-terminus of Ab, recognizing the Ab1–5 region [87,89]. In a Phase II clinical trial, an important negative side effect was doi: 10.1586/1744666X.2014.883921

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the occurrence of amyloid-related imaging abnormalities (ARIAs) detected by MRI [90], particularly vasogenic edema, in bapineuzumab-treated patients that increased in apolipoprotein E (APOE) e4 carriers [91]. In another Phase II trial in mild-tomoderate AD patients, bapineuzumab was shown to lower brain Ab burden, a marker of cortical fibrillar Ab load, assessed with 11C Pittsburgh compound B (11C PiB) PET amyloid imaging [92]. In Phase II clinical development, main outcomes were slight differences between treatment and placebo groups for cerebrospinal fluid (CSF) tau but not for CSF Ab [93]. However, no significant clinical benefits have been reported in two large Phase III clinical trials, leading to the discontinuation of all Phase III clinical trials and follow-on extension studies of bapineuzumab in its intravenous form in AD patients on August 6, 2012. Bapineuzumab failed to meet primary end points, which were changes in cognitive and functional performance compared to placebo, in AD patients who are APOE e4 carriers and non-carriers. Although all Phase III trials on bapineuzumab have ended, one Phase I clinical trial has been completed in mild-to-moderate AD patients to test the safety and tolerability of a more recent version of bapineuzumab (AAB-003, PF-05236812) (ClinicalTrials. Identifier: NCT01193608) [94], which was re-engineered to reduce the risk of ARIAs [84], while another Phase I trial is still ongoing (ClinicalTrials. Identifiers: NCT01369225) [95]. Solanezumab is the other anti-Ab monoclonal antibody that has progressed to Phase III clinical trials, directed against the Ab13–28 region and able to also recognize various N-terminal truncated species such as Ab3–42, which are known to be present in AD SPs [88,89]. Whereas bapineuzumab has a higher affinity for amyloid SPs than soluble Ab, solanezumab selectively binds to soluble Ab [96]. In a Phase II study of 52 patients with mild-to-moderate AD who received one of four doses of solanezumab (100 vs 400 mg and frequency of administration [weekly vs every 4 weeks]), with no subdivision into APOE e4 carriers and non-carriers, distinct plasma elevations of Ab and an increase of Ab1–42 and a decrease of Ab1–40 in the CSF were reported [97]. There were no treatment effects on cognitive performance [Alzheimer’s disease assessment scale-Cognitive subscale (ADAS-Cog)], CSF tau levels or cerebral amyloid burden imaged by 11C PiB PET scanning over the 12-week treatment period, although the study was not powered to detect efficacy [97]. Even after 1 year of follow-up, during the Phase I and Phase II studies, there was no evidence of the meningoencephalitis reported with first-generation active amyloid vaccines, ARIA associated with bapineuzumab or other significant drugrelated adverse events [97,98]. These findings encouraged the launch of two large randomized double-blind controlled Phase III trials of solanezumab, EXPEDITION1 and EXPEDITION2 (ClinicalTrials.gov Identifiers: NCT00905372 and NCT00904683) [99,100]. The EXPEDITION trials included more than 2050 patients with mildto-moderate AD in 16 countries around the world. The trials were 18 months in duration and randomized to 400 mg of solanezumab or placebo every 4 weeks for 80 weeks, with followdoi: 10.1586/1744666X.2014.883921

up open-label extension to determine the long-term safety of solanezumab (EXPEDITION-EXT, ClinicalTrials.gov Identifier: NCT01127633) [101]. On September 3, 2012, Eli Lilly announced that the two EXPEDITION trials did not meet cognitive and functional primary end points. However, while in the EXPEDITION1 trial, co-primary cognitive and functional end points were not met in overall mild-to-moderate AD patients, in the same study, a statistically significant reduction in cognitive decline was shown in prespecified secondary subgroup analyses in patients with mild AD [mini mental state examination (MMSE) score of 20 to 26]. Based on these encouraging results, for EXPEDITION2 trial, Eli Lilly specified a single primary end point of cognition in mild AD patients prior to database lock. Unfortunately, this revised primary end point did not achieve statistical significance. In addition, prespecified secondary subgroup analyses of pooled data across both studies showed a statistically significant 34% reduction in cognitive decline in patients with mild AD (MMSE score of 20 to 26), but not in patients with moderate severity (MMSE score 16 to 19) [89]. An independent analysis by the Alzheimer’s disease cooperative study (ADCS) confirmed these findings [89]. Biomarker analysis showed an increase in plasma Ab levels of AD patients, suggesting that this toxic protein was removed from the brain. There were no significant changes in other AD biomarkers including tau, phosphorylated tau, hippocampal volume, whole brain volume or amyloid burden assessed by PET imaging [89]. Adverse events of statistical significance, with an incidence of at least 1%, which occurred more in the solanezumab group than in the placebo group, were lethargy, rash, malaise (in EXPEDITION1) and angina (in EXPEDITION2). Two ongoing Phase III trials will continue as planned, the open-label extension study, EXPEDITIONEXT (ClinicalTrials.gov Identifier: NCT01127633) [102] and the EXPEDITION3 on the progression of mild AD patients (ClinicalTrials.gov Identifier: NCT01900665) [103]. Indeed, solanezumab, but not bapineuzumab, has shown to attenuate or reverse memory deficits in transgenic mouse models of AD. It should be pointed out that studies in transgenic mice have shown that solanezumab is much less effective than bapineuzumab in removing brain SPs [96]. Solanezumab recognizes epitopes located in the central region of Ab (13–28 amino acids), different from the N-terminus region targeted by bapineuzumab (1–5 amino acids). In addition, solanezumab binds more effectively than bapineuzumab to soluble forms of Ab than to those deposited in SPs [104]. It is suggested, based on solanezumab’s effects on plasma and CSF Ab levels, that solanezumab acts on peripheral amyloid, altering the equilibrium between plasma and CSF amyloid, leading to efflux of amyloid from the CNS into a ‘peripheral sink’ [105,106]. The recent failure of g-secretase inhibitors semagacestat and avagacestat and monoclonal antibody bapineuzumab and the absence of marked beneficial effects for solanezumab suggested that earlier intervention should be probably attempted. In fact, it is well established that some AD biomarkers, such as Ab deposition in brain, precede the clinical symptoms of the Expert Rev. Clin. Immunol.

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Amyloid-based immunotherapy for AD in the time of prevention trials

disease by about 20 years, and therapy to prevent or treat AD must be started before symptoms occur [107–109]. Recent studies on familial [107] and sporadic AD [108] showed a prolonged preclinical phase of more than two decades before the onset of dementia in which Ab deposition is slow and protracted, suggesting prevention trials in asymptomatic genetic forms of AD [107] and in individuals with no cognitive dysfunction suspected to be at an asymptomatic stage of sporadic AD [108]. In particular, a longitudinal study on autosomal dominant familial AD showed that the CSF Ab1–42 concentrations had already begun declining 25 years before the onset of clinical symptoms as indicators of Ab accumulation in the brain; while using PET scans, Ab deposition in the brain is already visible 15 years before clinical symptoms occur [107]. Moreover, late-onset sporadic form of AD is associated with 30% impairment in the clearance of both Ab1–42 and Ab1–40 from the brain in comparison with cognitively normal controls, while the production rates are very similar [110], suggesting that the involvement of antibodies as well as cellular components of the immune system will greatly facilitate Ab clearance in AD. Furthermore, new diagnostic criteria for AD based on specific cognitive patterns plus a core of reliable biomarkers [111] suggested new possible therapeutic interventions in individuals without cognitive symptoms in preclinical states of AD [112]. These evidences supported the idea that passive immunotherapy may be involved in a preventive way, with three upcoming trials that will investigate when exactly AD therapy has to be started to be really effective [83]. One of these secondary prevention trials called A4, Anti-Amyloid Treatment for Asymptomatic AD, beginning at the end of 2013, will test solanezumab for 3 years in 1000 people 65 years of age and older, without a dominant genetic predisposition to AD, who have positive PET scans for brain amyloid but without clinical AD symptoms [83]. Inclusion criteria will be MMSE score of 27 to 30 (education adjustment), clinical dementia rating scale of 0 and logical memory II score of 15–19 for high education. Primary outcome measure will be rate of decline on a composite cognitive score (episodic memory, free and cued selective reminding delayed recall, logical memory paragraph recall, timed executive function test, digit symbol and MMSE). Ideally, the A4 investigators will follow these subjects beyond treatment to determine the extent of the impact of monoclonal antibody on the trajectory of cognitive decline. Currently, at least five other anti-Ab monoclonal antibodies, with properties distinct from bapineuzumab and solanezumab, are in various stages of development (TABLE 1). Gantenerumab (R1450 or RO4909832, Hoffmann-La Roche, Basel, Switzerland) is the first fully human monoclonal antibody with subnanomolar affinity to a conformational epitope expressed on Ab fibrils [113], resulting in a monoclonal antibody that binds Ab monomers and fibrils. In transgenic mice, gantenerumab significantly reduced the amyloid plaque burden by recruiting microglia and preventing new SP formation without altering plasma Ab [113]. In a recent Phase I clinical trial, 16 AD patients received two to seven infusions of intravenous informahealthcare.com

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gantenerumab (60 or 200 mg) or placebo every 4 weeks [114]. Gantenerumab-treated patients showed a decrease of cerebral amyloid burden imaged by 11C PiB PET of up to 30% in a dose-dependent manner [114]. A Phase III study with gantenerumab on individuals with prodromal AD, amyloid-positive by PET imaging but not yet cognitively impaired, is presently in progress (ClinicalTrials.gov Identifier: NCT01224106) (SCarlet RoAD trial) [115]. Among prevention/early treatment trials beginning in 2012, the dominantly inherited Alzheimer network (DIAN) [107,116] will analyze patients who are carriers of autosomal dominant genetic mutations, which makes it highly likely that these individuals develop AD at early age, using two different treatment methods: solanezumab and gantenerumab (DIAN TU, ClinicalTrials.gov Identifier: NCT01760005) [102] (TABLE 1). In the DIAN trial, primary outcome measures will be the amount of fibrillar amyloid deposition as measured by 11C PiB PET scans for gantenerumab, while for solanezumab it will be the concentrations of CSF Ab species at baseline and at 2-year follow-up. The estimated enrollment is 210 individuals and principal inclusion criteria are 18–80 years of age; individuals who know they have an AD-causing mutation or are unaware of their genetic status and have a 50% chance of having an autosomal dominant AD mutation (e.g., parent or sibling with a known AD-causing mutation); and individuals who are within -15 to +10 years of their parental age of symptom onset and cognitively normal or with mild cognitive impairment (MCI) or mild dementia, clinical dementia rating scale of 0–1 (inclusive). Moreover, after the results of two Phase I clinical trials not yet being publicly available (ClinicalTrials.gov Identifiers: NCT00459550 and NCT01424436) [117,118] on GSK933776A (GlaxoSmithKline, London, UK), the development of a humanized IgG1 monoclonal antibody directed against the N-terminal of Ab was discontinued in 2011. Finally, the humanized IgG2 monoclonal antibody, ponezumab (PF-04360365, Pfizer, Cambridge, UK), targeting the free C-terminus of Ab1–40, specifically Ab33–40 [119], has been discontinued for AD after two successful Phase I trials [120,121], given the negative results with respect to clinical efficacy of two Phase II studies (ClinicalTrials.gov Identifiers: NCT00945672 and NCT00722046) [122,123]. At present, the second generation of anti-Ab monoclonal antibodies, targeting pathogenic Ab multimers rather than Ab monomers or fibrils, is in intensive clinical development [16]. Among these antibodies, crenezumab (MABT5102A, Genentech, San Francisco, CA, USA), derived from a mouse antibody binding to Ab12–23, recognizes Ab monomers, oligomers and fibrils with equally elevated affinity [124]. However, it was designed on an IgG4 backbone to reduce the risk of microglial-mediated proinflammatory effects in brain [124], and this was confirmed by a Phase 1 clinical trial, in which crenezumab-treated patients had a reduced risk of brain microhemorrhage and vasogenic edema [124]. Treatment of AD patients with crenezumab also showed promising results [124,125], and this antibody is presently in Phase II trial (ClinicalTrials. gov Identifier: NCT01723826) [126] (TABLE 1). Beginning in doi: 10.1586/1744666X.2014.883921

doi: 10.1586/1744666X.2014.883921

Ab: b-amyloid; AD: Alzheimer’s disease.

Humanized monoclonal IgG4 antibody against Ab1–42 (Ab12–23)

400 patients (2012–2016)

Patients who completed the Phase II study ABE4869g or ABE4955g

Solanezumab: 400 mg intravenous infusion every 4 weeks Gantenerumab: 225 mg subcutaneously every 4 weeks

210 patients (2012–2016)

Solanezumab (LY2062430) Gantenerumab (RO4909832) Washington University School of Medicine Eli Lilly Hoffmann-La Roche Alzheimer’s Association National Institute on Aging (NIA) Avid Radiopharmaceuticals NCT01760005 (DIAN TU)

Crenezumab (MABT5102A) Genentech NCT01723826

Subcutaneous multiple doses

770 patients with prodromal AD (2010–2016)

Fully human monoclonal IgG1 antibody against Ab1-42 (Ab3–11 and Ab19–28), not binding soluble Ab

Hoffmann-La Roche NCT01224106 (SCarlet RoAD trial)

Gantenerumab (RO4909832)

400 mg administered once every 4 weeks by intravenous infusion for 18 months

2100 patients (2013–2016)

Eli Lilly NCT01900665 (EXPEDITION3)

Characteristics

400 mg administered once every 4 weeks by intravenous infusion for 100 weeks

Estimated or completed enrollment

1275 patients (2010–2016)

Humanized monoclonal IgG1 anti-Ab1–42 antibody (Ab13–28), binding soluble Ab

Binding characteristics

Eli Lilly NCT01127633 (EXPEDITION EXT)

Solanezumab (LY2062430)

Monoclonal antibodies

Compound Company/institution ClinicalTrials.gov Identifier

[126]

[102]

Phase II/III trial (currently recruiting)

Phase II trial (currently recruiting)

[115]

[103]

Phase III trial (currently recruiting)

Phase III trial (currently recruiting)

[101]

Ref.

Phase III trial (ongoing, but not recruiting)

Status

Table 1. Phase II–III clinical trials of passive immunization targeting b-amyloid for the treatment of Alzheimer’s disease.

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[141]

Phase II/III trial (currently recruiting)

Ab: b-amyloid; AD: Alzheimer’s disease.

350 patients (2012–2014) Naturally occurring anti-Ab antibodies Albumin combined with immunoglobulin Grifols Biologicals NCT01561053

Human albumin 20% and intravenous immunoglobulin 5%

[140]

Intravenous immunoglobulin 50 patients with MCI (2011–2014) Naturally occurring anti-Ab antibodies Newgam 10% IVIg Sutter Health NCT01300728

Intravenous polyclonal antibodies (immunoglobulins)

800 patients (2012–2016) Binding large-size Ab protofibrils (>100 kDa) BAN2401 Eisai NCT01767311

Monoclonal antibodies (cont.)

informahealthcare.com

Phase II trial (ongoing but not recruiting)

[131]

Phase II trial (currently recruiting) Intravenous 2.5 mg/kg biweekly (once every 2 weeks)

Status Characteristics Estimated or completed enrollment Binding characteristics Compound Company/institution ClinicalTrials.gov Identifier

Table 1. Phase II–III clinical trials of passive immunization targeting b-amyloid for the treatment of Alzheimer’s disease (cont.).

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Amyloid-based immunotherapy for AD in the time of prevention trials

Review

2013, a secondary prevention trial with crenezumab, the Alzheimer’s Prevention Initiative (API), will be conducted in 300 individuals who are 30 years of age and older and symptomfree from the world’s largest early-onset AD kindred in Antioquia, Colombia, with a mutant gene [presenilin-1 (PS1) E280A] associated with a dominant form of early-onset AD. This mutation leads to early and robust cerebral Ab1–42 plaque deposition at a relatively young age [127], which is followed within 10– 15 years, around age 50, by a progressive decline in cognition and clinical function, which is decades earlier than the typical sporadic AD cases [128]. This extraordinary kindred, which has been followed for more than 20 years, includes about 5000 people, with a sufficient number of presymptomatic carriers in the targeted age group to make it possible to relate a treatment’s effects on both biomarker and clinical end points within 2– 5 years [129]. In the proposed API trial, with a 5-year treatment period, 100 PS1 mutation carriers will receive monthly injections of crenezumab, 100 will get placebo, plus 100 non-carriers will receive placebo to ensure that study participants will not know whether they carry the pathogenic mutation or not. Moreover, among second-generation monoclonal antibodies, BAN2401 (Eisai Inc., Tokyo, Japan) selectively binds, neutralizes and eliminates soluble protofibrils derived from the arctic mutation of Ab1–42, not able to fibrillize and thus remaining prefibrillar. After a completed Phase I clinical trial (ClinicalTrials.gov Identifier: NCT01230853) [130], BAN2401 is presently in a large Phase II clinical trial on 800 patients with early AD (ClinicalTrials.gov Identifier: NCT01767311) [131] (TABLE 1). Furthermore, BIIB037/BART (Biogen Idec, Weston, MA, USA), a humanized IgG1 monoclonal antibody that binds strongly to fibrillar Ab in plaques but less well to vascular amyloid, after a successful single ascending dose Phase I safety study (ClinicalTrials.gov Identifier: NCT01397539) [132], is in progress in a multiple-dose Phase I clinical trial on prodromal and mild AD patients (ClinicalTrials. gov Identifier: NCT01677572) [133]. Finally, SAR228810 was derived from 13C3 by immunization with polymerized synthetic Ab41–42 peptide, and therefore, is believed to recognize a conformational epitope of prefibrillar Ab aggregates [16]. At present, SAR228810 is in Phase I clinical evaluation (ClinicalTrials.gov Identifier: NCT01485302) [134]. Few studies with polyclonal antibodies or oligoclonal combinations of antibodies are available, with high regulatory hurdles existing for approval of these drugs [135]. Currently, we have some promising results in pilot and Phase II clinical trials on commercially available intravenous immunoglobulin (IVIg) preparations for the treatment of AD [136]. However, recent trials, including a Phase II 24-week trial in 58 AD patients on Octagam 10% IVIg (Octapharma, Lachen, Switzerland) [137] and a 18-month Phase III trial of Gammagard 10% IVIg in 390 mild-to-moderate AD (Baxter International Ltd Deerfield, IL, USA) (ClinicalTrials.gov Identifier: NCT00818662) [138], showed no significant slowing of AD progression. In the Phase III Gammagard trial, while the study was not powered to show statistical significance among the subgroups, the 400 mg/kg treatment arm showed a doi: 10.1586/1744666X.2014.883921

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Panza, Solfrizzi, Imbimbo, Tortelli, Santamato & Logroscino

positive, numerical difference in change from baseline versus placebo in cognition as measured by the ADAS-Cog and Modified Mini-Mental State (3MS) Examination among both moderate patients and carriers of the APOE e4 allele. These differences ranged between 16 and 29%. However, full data on this trial have not yet been published and we need to know if the apparent cognitive benefit in APOE e4 carriers is also reflected in functional and/or global measures. In addition, we need to know the numerical trends in APOE e4 non-carriers to verify if the apparent benefit in these carriers just reflects random scattering. The mechanism of action of Gammagard is not fully elucidated, but it is believed to be linked to interaction with dysfunctional microglia rather than to direct removal of Ab brain plaques or deposits [139]. Ongoing clinical trials on IVIg to be completed in 2014 include a small Phase II trial of Newgam 10% IVIg (Sutter Health, Sacramento, CA, USA) in 50 subjects with MCI (ClinicalTrials.gov Identifier: NCT01300728) [140] and a Phase III study in which 350 mild-to-moderate AD patients are being treated with a combination of albumin and IVIg (Grifols Biologicals, Inc, Los Angeles, CA, USA) (ClinicalTrials.gov Identifier: NCT01561053) [141] (TABLE 1). Expert commentary

Among the Ab-based immunotherapeutics, monoclonal antibodies are presently being preferred and in most advanced stages compared to active vaccination therapies. The recent negative overall results of bapineuzumab and solanezumab in mild-to-moderate AD patients provide evidence that amyloid-based therapies need to be used at an earlier stage of the disease process, prior to plaque formation and extensive pathological damage. The recently developed diagnostic criteria for AD may represent an important tool to verify this hypothesis because they help to identify ‘asymptomatic subjects at risk of AD’ with biomarker evidence of AD pathology and ‘presymptomatic AD subjects’ carrying genetic determinants who will eventually develop the disease. Three new secondary prevention trials on the anti-Ab monoclonal antibodies solanezumab, gantenerumab and crenezumab [83,107,116] will hopefully determine when exactly AD treatment has to be started. These trials will involve asymptomatic elderly subjects at risk of developing AD (A4 trial) or presymptomatic subjects with APP or presenilin mutations (DIAN- and API-sponsored trials). In general, it is now widely accepted that new anti-AD drugs should be tested in these two populations rather than in mild-to-moderate patients, that is, relatively too late in the disease process, where irreversible damage to the brain may have already occurred. Indeed, a workgroup of the National Institute on Aging and the Alzheimer’s Association developed criteria for research purposes and toward earlier intervention for the symptomatic predementia phase of AD (MCI due to AD) [142,143], thus defining the preclinical stages of AD when some disease-modifying therapies may be most efficacious. In particular, for MCI due to AD, the work group developed clinical criteria without PET imaging or CSF analysis for healthcare providers and research criteria for clinical research settings, including clinical trials, with the use of PET imaging and CSF biomarkers [143]. doi: 10.1586/1744666X.2014.883921

Five-year view

The finding that the removal of SPs with anti-Ab immunotherapy failed to halt progressive neurodegeneration strongly questioned the hypothesis in which Ab is the principal pathologic factor affecting AD course [51], suggesting that other processing derivatives of APP may be involved in neurodegeneration. In fact, after a- and b-cleavage, the carboxyl terminal fragments (CTFs) of APP, known as aCTF and bCTF, respectively, remain membrane-associated and will be further cleaved by g-secretase. CTF processing by g-secretase generates the harmless P3 peptide (non-amyloidogenic pathway) or Ab peptides ranging in size from 35 to 42 amino acids (amyloidogenic pathway), plus the APP intracellular domain (AICD) fragment. The amyloidogenic pathway has been shown to be the major source of AICD in vivo [144,145]. By acting as a docking site for a heterogeneous set of adaptor proteins, the AICD has been shown to be involved in a variety of signaling processes, many of which are potentially relevant to AD pathology [146–148]. The best known AICD interactor is the adaptor protein Fe65, which stabilizes the AICD and promotes its nuclear translocation [149–151]. AICD and Fe65 overexpressing mice do not show brain Ab accumulation, yet display a number of AD-like neuropathological features, including tau hyperphosphorylation, glycogen synthase kinase-3b activation, working memory deficits and neuroinflammation [146,152]. Because AICD levels were found to be elevated in human AD brains [146,153], it has been hypothesized that this C-terminal APP fragment may be causally involved in AD pathogenesis [146,148,154,155]. Indeed, neuronal apoptosis is considered a common feature of AD and the first cellular alteration that was shown to be positively regulated by the AICD [153,156]. Furthermore, conformation-specific monoclonal antibodies have been designed to be selectively directed toward oligomeric Ab and ADDLs, with the intent of producing beneficial cognitive effects without altering normal physiology of monomeric Ab [157,158]. Moreover, preclinical studies have reported beneficial effects of passive immunotherapy against other Ab-related targets, suggesting that other proteins involved in Ab binding and aggregation might also be a target for immunotherapy that may act as a seed for Ab aggregation. For example, monoclonal antibodies anti-pyroglutamate-3 Ab, a highly pathogenic Ab species found in SPs and vascular amyloid but not in CSF or plasma, reduced plaque burden in young and old AD transgenic mice, in the absence of increased vascular amyloid or microhemorrhage [159]. Anti-APOE antibodies, similar to certain anti-Ab antibodies, showed anti-amyloidogenic effects by binding to APOE in the plaques and activating microgliamediated amyloid clearance [160]. Recently, a plaque-specific antibody, targeting a modified Ab peptide (Abp3–42), showed robust clearance of pre-existing plaque without causing microhemorrhage [161]. Furthermore, in transgenic AD mice, passive anti-murine Ab immunization cleared Ab plaque pathology, including the major human Ab component, decreasing behavioral deficits and suggesting that also targeting minor endogenous brain plaque constituents can be beneficial [162]. As a final note, we want to point out that recent studies have identified Expert Rev. Clin. Immunol.

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Amyloid-based immunotherapy for AD in the time of prevention trials

innate immune system and microglia as promising therapeutic targets of AD. In the AD brain, inflammatory response is characterized by activated microglia and reactive astrocytes. Activated microglial cells may mediate neuronal damage by producing toxic cytokines, excitatory amino acids and reactive oxygen intermediates. However, inflammatory processes can also be neuroprotective and microglia may also participate in plaque phagocytosis. Based on this dual activity, the activity of microglia has been divided according to an inflammatory (M1) and a phagocytic (M2) phenotype. During the early phases of AD, initial deposition of Ab may shift the equilibrium of microglia from the M2 phagocytic to the M1 inflammatory phenotype [163]. The recent discovery that a defective mutation of a microglial phagocytic protein (TREM2) increases by three times the risk of AD [164] has renewed interested in anti-inflammatory drugs that may fine-tune microglia activity by stimulating M2 phagocytic activity and simultaneously inhibiting M1 inflammatory activity (microglial modulators). Another microglial cell-surface protein (CD33) has been genetically linked to AD and has recently been found in high amounts in the AD brain [165], suggesting that dysregulation of CD33 plays a role in disease pathogenesis. Other recent studies also link microglia to AD via the complement

Review

component receptor-1 (CR1 or CD35). Single-nucleotide polymorphisms in CR1 were reported to be associated with greater risk of AD. The rs6656401A risk allele of CR1 was also related to greater cognitive decline over time in older individuals. More recently, it has been shown that loss of CR1 modulates the impact of the APOE e4o` allele on brain fibrillar amyloid burden, indicating that microglial dysfunction can be genetically linked to AD [166]. The results of the ongoing clinical trials in subjects with ‘MCI due to AD’ or ‘prodromal AD’ together with the planned secondary prevention trials in presymptomatic subjects with familial AD or in asymptomatic biomarker-positive subjects at genetic risk of developing AD will tell us whether passive antiAb immunotherapy can indeed prevent or delay the onset of this devastating disease, providing an effective therapy for AD. Financial & competing interests disclosure

This research was supported by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale (PRIN) 2009 Grant 2009E4RM4Z. 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.

Key issues .

Senile plaques, mainly composed by the accumulation of b-amyloid (Ab) peptide, and neurofibrillary tangles, a product of the tau protein hyperphosphorylation, are the principal neuropathological lesions of Alzheimer’s disease (AD). These neuropathological hallmarks are surrounded by dystrophic neurites and microglial cells.

. .

Few therapeutic approaches based on active and passive immunization against tau protein are currently available, almost all in preclinical phase. Both active and passive anti-Ab immunotherapies demonstrated to clear Ab deposits from the brain of AD patients in neuroimaging and neuropathological studies.

.

AN1792, an active anti-Ab vaccine preparation, showed some signs of clinical efficacy in AD patients, but it has been discontinued

.

Second-generation amyloid-based active vaccines and passive anti-Ab immunotherapies are under extensive clinical investigation, with

because it caused autoimmune meningoencephalitis in a minority of subjects. several monoclonal antibodies against Ab in Phase III clinical trials. .

Bapineuzumab, a humanized monoclonal antibody recognizing N-terminus of Ab, showed in Phase III clinical trials on AD patients no

.

Solanezumab, a monoclonal antibody directed at the mid-region of Ab, has shown some beneficial cognitive effects in mildly affected

.

Some secondary prevention trials on the anti-Ab monoclonal antibodies solanezumab, gantenerumab and crenezumab will investigate

treatment benefits in cognitive and functional measures, with a high incidence of amyloid-related imaging abnormalities. AD patients. A Phase III study in mild AD patients is ongoing to confirm these potential benefits. when exactly AD treatment has to be started, focusing on therapy in asymptomatic subjects at risk of AD or presymptomatic AD subjects.

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