Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond

AN1792 was the first anti-Aβ vaccine tested clinically. It is a synthetic full-length Aβ₄₂ with QS-21 adjuvant. In a phase IIa clinical trial (NCT00021723), 19.7% of AN1792-treated patients were antibody responders with high anti-AN1792 IgG titers. However, although AN1792 treatment reduced Aβ deposition and showed positive effects in neuropsychological test battery (NTB) score and cerebrospinal fluid (CSF) tau levels, this difference was only found in the antibody responders. Moreover, AN1792 injection resulted in T cell-mediated meningoencephalitis in 6% of treated participants, which led to the termination of this clinical study [35, 36]. After that, another long-term follow-up study was conducted and found that the antibody responders defined in the previous phase IIa clinical trial maintained low but detectable, sustained anti-AN1792 antibody titers, which contributed to the less functional decline and long-term functional benefits [37].

Amilomotide (CAD106) is a vaccine that comprises N-terminal Aβ_1-6 as a B-cell epitope to generate anti-Aβ antibodies without an Aβ-specific T-cell response [38]. The phase I trial (NCT00411580) found that CAD106 had a favorable safety profile and an acceptable antibody response [38]. Phase II trials, including IIa (NCT00733863, NCT00795418, NCT00956410, NCT01023685) and IIb (NCT01097096), suggested an appropriate balance between antibody response and tolerability. However, as the first vaccine entering phase II/III trial (NCT02565511), CAD106 caused unpredicted changes in cognitive function, brain volume, and body weight, leading to early study termination.

UB-311 comprises two synthetic Aβ_1-14-targeting peptides as B-cell epitopes, each conjugated to different helper T-cell peptide epitopes (UBITh®). The Th2-biased delivery system is applied to maximize immunogenicity and minimize T-cell inflammatory reactivity [39]. Results of a phase II trial (NCT02551809) indicated that UB-311 had the potential to improve cognitive function in early-to-mild AD patients with 100% responder rate and strong on-target immunogenicity [39]. However, this clinical trial did not include a placebo group. Rather, it compared the increase of Alzheimer’s Disease Assessment Scale-Cognitive Section (ADAS-Cog) scores from baseline in the subgroup of mild AD patients (Mini-Mental State Examination [MMSE] score ≥ 20) with the moderate AD subgroup. Another phase II trial (NCT03531710) was terminated due to treatment assignment error.

Aducanumab (BIIB037) is a human IgG1 monoclonal antibody that binds to the N terminus of Aβ in an extended conformation [40]. It targets Aβ aggregates, including soluble oligomers and insoluble fibrils. The phase Ib randomized trial, PRIME (NCT01677572), showed significant reductions in amyloid positron emission tomography (PET) standard uptake value ratio (SUVRr) composite score in the aducanumab-treated patients, especially in those treated with 10 mg/kg aducanumab at 54 weeks. The brain amyloid burden decreased in a dose- and time-dependent manner in patients with prodromal or mild AD. The Clinical Dementia Rating-Sum of Boxes (CDR-SB) and MMSE scores were delayed by aducanumab treatment, indicating a positive effect on cognition and clinical progression [41].

Aducanumab achieved convincing results in PRIME, although the amyloid-related imaging abnormalities vasogenic edema (ARIA-E) occurred dose-dependently in 3%–41% of aducanumab recipients and was more common in APOE ε4 carriers [41]. The phase II study was skipped owing to the promising phase I data. Two identically designed phase III studies ENGAGE (NCT02477800) and EMERGE (NCT02484547) were conducted but both were terminated in March 2019 based on futility analysis indicating little likelihood of treatment efficacy [42]. However, a reversal occurred in October 2019. An expanded analysis revealed that EMERGE met its primary endpoint, where patients in the high-dose group showed a statistically significant reduction of clinical decline from baseline in CDR-SB scores by 22% at 78 weeks. Although ENGAGE did not achieve its primary endpoint, data from patients receiving high-dose aducanumab were consistent with the findings of EMERGE [43]. It is controversial whether the positive results of EMERGE are sufficient to establish validity in the context of the negative results of ENGAGE.

In March 2021, three members of the US Food and Drug Administration (FDA) Peripheral and Central Nervous System Drugs Advisory Committee published their opposition to aducanumab for AD treatment in a JAMA article [44]. However, aducanumab was still given official approval to treat AD based on the surrogate endpoint, i.e., removal of amyloid plaques from the brain, by the U.S. FDA through the accelerated approval pathway in June 2021. Although according to the accelerated approval provisions, a new phase III clinical trial (NCT04241068) is still needed to evaluate the efficacy and safety, aducanumab is the first new anti-AD drug to win FDA approval since memantine launched in 2003. After the approval, many researchers and drug developers considered the FDA’s decision on aducanumab is wrong and will ultimately undermine confidence in the agency. Anyway, aducanumab is now the first available therapy to target and ameliorate the fundamental disease process of AD. Meanwhile, the approval of aducanumab has brought new hope to patients in the early stage of AD and shed new light on the research and innovation to conquer the disease.

Donanemab (LY3002813) is a humanized monoclonal IgG1 antibody that binds specifically to the N-terminal pyroglutamate Aβ epitope, which is present merely in deposited Aβ. In the phase II trial, TRAILBLAZER-ALZ (NCT03367403), donanemab induced a smaller reduction of integrated Alzheimer’s disease rating scale score in patients with early-stage AD, signifying less cognitive and functional decline, although results for secondary outcomes were mixed. Moreover, results of ¹⁸F-florbetapir PET showed that patients treated with donanemab displayed a significant reduction of amyloid plaque at 76 weeks and 54.7% of the participants had an amyloid-negative status at 52 weeks [45]. The greater amyloid plaque reduction driven by donanemab treatment was highly associated with less cognitive decline and decreased tau progression at 24 weeks. Meanwhile, within 12 weeks of donanemab treatment, a rapid decline in plasma P-tau217, a biomarker for AD pathology, was observed. Due to the higher incidence of ARIA-E in the donanemab group than in the placebo group (26.7% vs 0.8%), larger and longer trials are needed to evaluate the efficacy and safety of donanemab in AD. Currently, a follow-on study, TRAILBLAZER-EXT (NCT04640077), is underway for patients enrolled in TRAILBLAZER-ALZ. And a phase III study, TRAILBLAZER-ALZ 2 (NCT04437511) with 1500 participants, is being conducted to specifically assess whether donanemab can prevent the clinical progression of patients with pathological evidence of AD but yet to show clinical symptoms. Another phase III study, TRAILBLAZER-ALZ 3 (NCT05026866) with 3300 participants with preclinical AD, has been started to further determine the safety and efficacy of donanemab.

Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody preferentially targeting soluble aggregated Aβ and possessing activity across oligomers, protofibrils, and insoluble fibrils. In the phase II trial, BAN2401-G000-201 (NCT01767311), although the 12-month primary endpoint was not met, the brain amyloid plaques were reduced, and several clinical and biomarker endpoints showed sustained clinical remission at the highest dose of 10 mg/kg biweekly. The reduction of amyloid PET SUVr value and clinical decline on Alzheimer’s Disease Composite Score (ADCOMS) and ADAS-Cog14 were dose-dependent over 18 months. A confusing finding was that the difference in CDR-SB decline between the lecanemab and placebo groups was not significant at 18 months, but significant at 12 months. According to the Bayesian sensitivity analyses, in comparison to the placebo, lecanemab at a biweekly dose of 10 mg/kg induced greater reductions of cognitive decline in APOE4 carriers versus non-carriers. CSF biomarker analyses showed an increase in Aβ₄₂ and a decrease in p-tau compared with placebo, but results on total tau were inconsistent between 12 and 18 months. It is worth noting that the ARIA-E incidence was 9.9% at 10 mg/kg in the overall population and was 14.3% in APOE4 carriers, indicating well tolerance of lecanemab [46]. A phase III study, Clarity AD (NCT03887455), is underway to evaluate the efficacy, long-term safety, and tolerability of lecanemab in early AD. Another phase III trial, AHEAD 3–45 (NCT04468659), primarily aimed to determine the change from baseline of the Preclinical Alzheimer Cognitive Composite 5 score at 216 weeks of treatment, is being conducted to assess the efficacy and safety of lecanemab in preclinical AD patients.

Solanezumab (LY2062430) is a humanized monoclonal antibody that targets the mid-domain of Aβ peptide (Aβ_13-28) to increase Aβ clearance [47]. Two completed phase III clinical trials, EXPEDITION 1 (NCT00905372) and EXPEDITION 2 (NCT00904683), failed to demonstrate efficacy of solanezumab in retarding cognitive decline and improving functional ability in patients with mild-to-moderate AD [48]. In addition, EXPEDITION EXT (NCT01127633), as an open-label extension study of EXPEDITION 1 and EXPEDITION 2, was terminated as it did not meet the primary endpoint. Meanwhile, two other phase III clinical trials, Expedition 3 (NCT01900665) and ExpeditionPRO (NCT02760602), were terminated due to the failure in improving cognitive decline. In a recent trial (DIAN-TU, NCT01760005) conducted to test the effects of solanezumab on patients with dominantly inherited AD, solanezumab treatment engaged its Aβ targets but showed no improvement and even a little aggravation of cognitive impairment compared to the control group [49]. Although these clinical trials did not show statistically significant benefits for patients with mild to moderate AD, another phase III clinical trial, A4 (NCT02008357), is underway to explore the effects of solanezumab in asymptomatic or very mild patients with amyloid plaques in the brain.

Crenezumab (RG7412) is a humanized IgG1 monoclonal antibody, targeting multiple forms of Aβ, including monomers and aggregates [50]. It has a tenfold higher affinity for oligomers [50]. Two phase III trials, CREAD (NCT02670083) and CREAD2 (NCT03114657), were terminated because a pre-planned interim analysis found unlikeliness to hit the primary endpoint of improving CDR-SB scores. The phase III trial CREAD OLE (NCT03491150) was terminated due to an interim analysis as well. Currently, a phase II clinical trial (NCT01998841) is being conducted to evaluate the efficacy and safety of crenezumab versus placebo in preclinical AD patients with presenilin 1 (PSEN1) E280A autosomal dominant mutation.

Gantenerumab (RO4909832) is a human IgG1 monoclonal antibody that binds to aggregated Aβ with high affinity and facilitates Aβ clearance via Fc receptor-mediated phagocytosis [51, 52]. In February 2020, gantenerumab was announced to fail to meet the primary endpoint in a phase II trial (DIAN-TU, NCT04623242) on patients with inherited AD. After that, another phase II trial, DIAN-TU-001 (NCT01760005), has been carried out in individuals with mutations associated with early-onset AD. Gantenerumab treatment significantly decreased Aβ plaques, CSF total tau and phospho-tau181 and attenuated the increases of neurofilament light chain, but without benefits for cognitive measurements. Amyloid-related imaging abnormalities edema was observed in 19.2% of the subjects [49]. These results led to the belief that a higher dose of gantenerumab was needed for probable clinical efficacy. Currently, two randomized, double-blind, placebo-controlled, parallel-group phase III trials, GRADUATE 1 (NCT03444870) and GRADUATE 2 (NCT03443973), are ongoing to study the safety and efficacy of gantenerumab in the broader population of people with AD not directly caused by gene mutations. In addition, two open-label, multicenter, rollover phase III trials (NCT04339413 and NCT04374253) are underway to assess the safety and tolerability of long-term administration [53].

AADvac1 is the first-generation active immunotherapy vaccine developed by Axon Neuroscience, which targets a 12-amino-acid sequence, KDNIKHVPGGGS, in the microtubule-binding region of tau protein. It is safe with rare adverse events being observed in either immunized or placebo group [63]. Besides, AADvac1 treatment resulted in less brain atrophy and reduced cognitive decline in patients with mild-to-moderate AD in phase I trial (NCT02031198) [64]. And it is exciting that AADvac1 significantly reduced the levels of two CSF biomarkers of AD, p-tau181 and p-tau217 [65]. These positive results support the transition of AADvac1 to phase II trial. Information from clinicaltrials.gov showed that AADvac1 finished a phase II trial on November 14, 2019, but no other details have been reported [63]. Another phase II trial evaluating the safety and tolerability of long-term AADvac1 treatment and the immunogenicity and efficacy of AADvac1 in slowing cognitive decline of AD patients has been completed recently [66]. The results showed that AADvac1 was safe and well tolerated, but it failed to improve cognitive function in a total of 196 patients. There is no doubt that AADvac1 makes a monumental progress in AD active immunotherapy. Nevertheless, larger stratified studies should be conducted to better assess the therapeutic efficacy of AADvac1 in clinical treatment.

ACI-35 is the other active immunotherapy vaccine designed by AC Immune to target the pathological conformers of hyperphosphorylated tau. The vaccine contains 16 copies of a synthetic tau recognizing the pathological phosphorylation residues S396 and S404 of tau. ACI-35 is still in a multicenter, double-blind, randomized phase I/II clinical trial to detect the safety and efficacy in mild-to-moderate AD patients in Finland, which is expected to complete before October 31, 2023 (NCT04445831) [67].

Semorinemab (RO705705) is a humanized anti-tau monoclonal antibody against extracellular tau with an immunoglobulin G4 isotype backbone which can bind all six human tau isoforms and protect neurons. Its safety profile has been published by AC Immune SA, but no effectiveness signals on AD were observed in clinical trials [68]. Obviously, a further suitably designed trial is required to evaluate its efficiency. A study of semorinemab in patients with moderate AD is ongoing until October 2023 (NCT03828747) [69]. In January 2021, an article published in Nature Reviews Drug Discovery reported that semorinemab does not improve AD symptoms and declared the failure of the phase II trial (NCT02754830) [70].

BIIB076 (NI-105) and gosuranemab (BIIB092) came from the same company Biogen. BIIB076 is a monoclonal IgG1 targeting the mid-domain of tau. It is still in the early stages of clinical research, and has completed a phase I trial (NCT03056729) [71]. Gosuranemab is a humanized monoclonal antibody against extracellular N-terminal of tau in the interstitial fluid (ISF) and CSF released by neurons. A phase II trial in progressive supranuclear palsy showed that the unbound N-terminal tau in CSF was decreased by 98% in the gosuranemab group and increased by 11% in the placebo group, but the N-terminal tau neutralization does not translate into clinical efficacy (NCT03068468) [72]. Recently, Kim and his colleagues examined the brain tissues of three individuals receiving gosuranemab and found that gosuranemab treatment may be associated with glial responses including accumulation of tau within astrocytic lysosomes [73]. However, the phase II study of gosuranemab in participants with early AD was terminated due to the lack of efficacy in slowing cognitive and functional impairment following the placebo-controlled period readout [74].

Tilavonemab (ABBV-8E12) is an antibody recognizing the aggregated, extracellular form of pathological tau and binding to the N-terminus of tau. This drug was developed by C2N Diagnostics and AbbVie and has been validated for its safety in a phase I trial (NCT02880956) [75, 76]. However, the phase II trial, evaluating the efficacy and safety of tilavonemab in 453 patients with early AD, did not obtain expected results and now tilavonemab is discontinued in AD treatment (NCT02880956) [76]. In addition, a phase II trial purposed to assess the long-term safety and tolerability of tilavonemab in 364 participants with early AD was finished in September 30, 2021, but its final reports are not available (NCT03712787) [77].

Bepranemab (UCB0107) is a humanized, monoclonal IgG4 antibody from company UCB S.A., targeting the mid-region of tau (amino acids 235–250). The mid-region antibodies seem to be more potential in interfering with the cell-to-cell propagation of pathogenic and aggregated tau than the N-terminal-targeting anti-tau antibodies [78]. Recently, a phase II study to test the efficacy, safety, and tolerability of bepranemab in mild AD patients is under enrollment (NCT04867616) [79]. This trial was estimated to include 450 participants and expected to be finished in November 2025.

Zagotenemab (LY3303560) is a humanized anti-tau antibody derived from MCI-1, Peter Davies' mouse monoclonal antibody against an early pathological conformation of tau. Until now, zagotenemab has completed two phase I trials on healthy participants and AD patients to examine the safety of repeated doses (NCT02754830, NCT02754830) [80, 81]. A phase II trial finished enrollment of 285 people with at least six months of gradual and progressive memory decline in August 2019 and ran until August 2021. In October 2021, Lilly announced that the trial had missed its primary endpoint, and the development of zagotenemab was terminated [82].

Several other tau antibodies are currently in the early drug development stage for AD and other tauopathies. JNJ-63733657 is a humanized IgG1 monoclonal antibody designed by Janssen. This antibody can recognize the microtubule-binding region of tau with high affinity for pThr217. JNJ-63733657 treatment has been shown to cause dose-dependent reductions of pTau in the CSF [83]. Now, JNJ-63733657 is in the phase II to evaluate its effect on cognitive decline in AD patients (NCT04619420) [84]. E2814 and Lu AF87908 are humanized, monoclonal IgG1 antibodies from Eisai Co. and Lundbeck, respectively. E2814 recognizes an HVPGG epitope in the microtubule-binding domain near the mid-domain of tau [85], while LuAF87908 targets pSer396 and pSer404. Until now, research on the two antibodies is still in the early stage, with an ongoing phase I/II trial of E2814 to assess its safety and target engagement in mild AD participants (NCT04971733) [86], and a phase I trial to investigate the safety of a single dose of Lu AF87908 in healthy subjects and AD patients under recruitment (NCT04149860) [87]. PNT001 from Pinteon Therapeutics is a monoclonal antibody to the cis-isomer of tau phosphorylated at threonine 231 and completed a phase I trial in healthy adults in 2021 while the results have not been published (NCT04096287) [88]. RG7345 (RO6926496) is another antibody against pSer422 of tau, but it has been terminated because of the inflammatory response (NCT02281786) [89].