Aβ Immunotherapy for Alzheimer’s Disease: Where are we?

KEYWORDS :

• Alzheimer’s disease
• amyloid-β
• immunotherapy
• new therapies
• vaccine

Alzheimer’s disease (AD) was implicated in most of the estimated 46.8 million worldwide dementia cases in 2015, with projections set to almost triple by 2050 [1]. Because current therapies are focused on ameliorating AD symptoms instead of targeting the underlying causes of the disease, it is necessary to develop disease-modifying therapies.

In accordance with the amyloid cascade hypothesis, AD is caused by the progressive aggregation of the Aβ peptide into oligomers, fibrils and amyloid plaques, which results on synaptic loss, neuronal dysfunction and cell death [2]. Accumulation of the Aβ peptide is thought to start more than a decade before the onset of clinical symptomatology, at what is known as the prodromal phase. Then, the first clinical symptoms appear as mild cognitive impairment (MCI) and the disease finally results in dementia. Actually, amyloid deposition can be visualized by PET in the prodromal phase, as well as biochemical changes measured in the cerebrospinal fluid.

Aβ immunotherapy is a promising approach to reduce Aβ burden, as illustrated by the large number of ongoing clinical trials [3]. Active Aβ-immunotherapy uses synthetic full-length Aβ peptide, or a fragment, to stimulate B cells to generate specific antibodies for sequestering amyloid from the brain in the peripheral system. The first Phase IIa clinical trial for an active AD vaccine, AN1792, contained the full-length Aβ₄₂ peptide and was performed in 2002 (ELAN, Dublin, Ireland, and Wyeth, PA, USA) [4]. Although some beneficial effects were shown by antibody responders, administrations were halted due to the development of meningoencephalitis in approximately 6% of the treated group. Similarly, T-cell meningoencephalitis was noted in two postmortem reports. It is likely that one of the excipients of the administered preparation induced the exposition to the solvent of the C-terminus of the peptide, which is thought to activate the T-helper type 2 (Th-2) response. Hence, most new-generation epitopes for active Aβ-immunotherapy avoid this region of the peptide. Currently, three drugs are being assayed: the Aβ_1–6 peptide coupled to the Qβ coat protein (CAD106), a tetra-palmitoylated Aβ_1–15 peptide liposome-based vaccine (ACI-24) and a combination of UBITh^® helper T-cell epitope (activating Th-1 response, rather than Th-2) and Aβ_1–14 (UB-311) [3]. CAD106 (Novartis, Basel, Switzerland) is in Phase II/III clinical trial, ACI-24 (AC Immune, Lausanne, Switzerland) in Phase I/II and UB-311 (United Neuroscience Ltd, Dublin, Ireland) in Phase II.

The main drawback of active immunotherapy is the difficulty of intervening whenever adverse effects occur. Passive immunotherapy, in other words, treating the patients with ex vivo produced monoclonal antibodies (mAbs), overcomes this problem. Eight Aβ-directed mAbs have been, or are being, tested in clinical trials: bapineuzumap, ponezumab, solanezumab, gantenerumab, crenezumab, aducamab, BAN2401 and SAR228810 [3].

In 2000 it was demonstrated that peripheral injection of a mAb specific for the Aβ_1–5 peptide generated the transfer of antibody to the brain, the antibody binding to amyloid plaques and the induction of fragment-crystallizable region (Fc) receptor-mediated microglial phagocytosis of Aβ deposits in PDAPP mice [5]. Bapineuzumab (Janssen, NJ, USA and Pfizer, NY, USA), which recognizes all forms of the Aβ peptide, is the humanized successor of this antibody and has reached many Phase III clinical trials [6]. However, the occurrence of Amyloid-related Imaging Abnormalities (ARIA) denoting microhemorrhage, especially in the APOE ∊4 carrier cohorts, halted the study in 2012. Some Phase I clinical trials with a redesigned mAb intended to minimize the risk of ARIA were completed in 2014, but they did not achieve safety requirements and the company discontinued its development.

Ponezumab (Pfizer) is a humanized mAb designed to recognize the C-terminus Aβ_30–40 peptide region, which allows the binding of the plasma Aβ peptide so that the hippocampal amyloid burden is diminished by efflux [7]. However, no improvement in cognitive impairment was observed in two completed Phase II trials and it was repurposed for treating cerebral amyloid angiopathy (CAA), with a Phase II trial ongoing [3].

Solanezumab (Eli Lilly and Co., IN, USA and Hoffmann-LaRoche, Basel, Switzerland) is a humanized mAb directed to the Aβ_16–24 mid-region and is able to bind plasma Aβ in PDAPP mice, so that Aβ deposits are also reduced by promoting Aβ efflux. In Phase I, nonadverse effects appeared and some biochemical markers changed. Following Phase II trials with higher doses, a Phase III trial among patients with mild AD showed 33% reduction in the rate of decline [8] and two other Phase III studies are ongoing [3]. However, it is worth mentioning that the benefit found to date is not better than that of the palliative acetylcholinesterase inhibitor drugs.

Gantenerumab (Hoffmann-La Roche) was the first fully human mAb for Aβ-immunotherapy. In a mouse model of AD, this mAb showed sustained binding to cerebral amyloid and reduced amyloid plaques by recruiting microglia and preventing new plaque formation, while plasma Aβ remained the same. Phase I clinical trials in mild-to-moderate AD patients reduced the brain amyloid load, but two patients experienced ARIA [9]. At this moment three trials are ongoing: a Phase III trial with patients in the prodromal phase, a Phase II/III with familial AD mutations carriers and a Phase III trial with mild AD patients [3].

Crenezumab (Genentech, CA, USA) is a humanized mAb against the Aβ_12–23 mid-region that was designed on an IgG4 scaffold, instead of the IgG1 for other mAbs, to avoid inflammatory effects [10]. Interestingly, crenezumab and solanezumab are cross-reactive, although two amino acidic changes in their sequence lead to the recognition of different species, in other words, monomers by solanezumab and protofIbrilar species by crenezumab. Phase I trials in mild-to-moderate AD patients presented a good safety profile and Phase II testing with higher doses has been continued into an open-label-extension trial that will run until 2017 [3].

Aducanumab (Biogen Idec, MA, USA) is a human IgG1 mAb derived from an AD patient with an unusually stable clinical course. It showed the reduction in amyloid burden by binding insoluble fibrillar Aβ in a mouse model. Similarly to bapineuzumab, aducanumab recognizes Aβ’s N-terminal residues but also a conformational epitope featuring aggregated Aβ. In a Phase I clinical trial, patients with mild AD showed reduced cognitive decline and decreased brain levels of amyloid, although ARIA occurred in some cases [11]. Dose reduction for the subsequent Phase II trial proved safe and effective in amyloid clearance, but improvement in mental decline was not achieved. Currently, two Phase III trials are recruiting participants [3].

BAN2401 (Eisai Inc., Tokyo, Japan) is a conformation-dependent humanized mAb directed against the APP Arctic mutation (E22G in Aβ), which recognizes a unique conformation in the Aβ protofibril. Phase I clinical trials showed no serious adverse events and a Phase II trial began in January 2013 among patients with MCI and early AD [12].

SAR228810 (Sanofi, Gentilly, France) is a humanized mAb, derived from an IgG4 subclass as in the case of crenezumab, that recognizes a repeating conformational epitope of prefibrillar Aβ aggregates [13]. A Phase I clinical trial with mild-to-moderate AD patients has recently been completed [3].

In summary, passive immunotherapy is more advanced than active immunotherapy but its drawbacks, such as the occurrence of ARIA, complicate its development. The main hypothesis for bapineuzumab’s failure in clinical trials is that trial participants were in advanced stages of the disease. Consequently, most of the studies currently ongoing are being performed with patients at the prodromal or MCI stages. In this vein, three consortia are working on to prevent the disease developing: the Alzheimer’s Prevention Initiative (API), the Dominantly Inherited Alzheimer’s Network (DIAN) and the Anti-Amyloid treatment in Asymptomatic Alzheimer’s (A4). API tests crenezumab in individuals from a large Colombian family which carries an AD mutation; DIAN tests immunotherapy with solanezumab or gantenerumab in adult children of a parent with the same mutation; and, finally, A4 tests solanezumab in asymptomatic elderly patients with amyloid positive PET. Thus, although these studies will take several years, it can be concluded that immunotherapy shows glimmers of promise [14,15] and it is likely we are getting closer to finding a disease-modifying drug to treat this devastating disease.

Financial & competing interest’s disclosure

Instituto de Salud Carlos III/FEDER (FIS-PI113-01330), Generalitat de Catalunya (SGR-GRC-2014-00885) and Generalitat de Catalunya/FEDER (2014-PROD00032). PIF-UAB student grants (J Güell-Bosch, L Montoliu-Gaya and G Esquerda-Canals). 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.