What is the research progress of immunotherapy for Alzheimer’s disease?
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What is the research progress of immunotherapy for Alzheimer’s disease?
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What is the research progress of immunotherapy for Alzheimer’s disease?
Alzheimer’s disease ( AD ) is a heterogeneous neurodegenerative disease and the most common cause of Alzheimer’s disease.
The incidence of AD is increasing worldwide, and there is still no effective cure.
Furthermore, aging is considered the most critical risk factor for AD because of its considerable impact on the immune system.
Recent studies have shown an intricate link between the immune system and the central nervous system that may be out of balance to mediate neuroinflammation and AD.
Therefore, active and passive immunotherapy for AD may rebalance the immune system of AD patients to achieve the ultimate goal of treating AD.
Pathological Hypotheses of AD
AD is characterized by the accumulation of amyloid beta ( Aβ ) formed by neuritic plaques and neurofibrillary tangles ( NFTs ).
Neuropathological changes associated with AD include positive pathological changes due to accumulation of deposits in the brain and negative pathological changes due to atrophy of nerves and synapses.
The hallmark pathological proteins of AD include Aβ and pathological tau, which are potential biomarkers of AD pathogenesis.
Studies have shown that abnormal amyloid deposits can lead to rapid cognitive decline, progressive atrophy, and poor metabolism.
Tau pathology is another contributing factor in AD pathogenesis.
The essential function of tau protein is to facilitate the interaction and stability of microtubules and tubulin in neural networks.
In AD, however, tau mutations may inhibit these important functions.
Microglia, Aβ, and tau appear to be interconnected in the formation of neuritic plaques, with the response between Aβ and microglia leading to tau accumulation.
Pathological tau proteins that contribute to AD progression mainly form misfolded, aggregated and hyperphosphorylated forms that spread throughout the brain in a prion-like manner, and hyperphosphorylated tau proteins form neurofibrillary tangles within axons and dendrites junction, resulting in neuronal loss.
Over time, the toxicity of tau increases due to changes in the kinases or phosphatases that target tau, thereby inhibiting and silencing more neurons.
In addition, genetics can influence the risk of developing AD.
Variants of the APOE gene include ε2, ε3, and ε4 alleles, of which the APOEε4 subtype is an important genetic risk factor with a significant adverse effect on the development of AD.
APOEε4 was associated with a lower age at onset and higher incidence of AD compared with non-ε4 carriers.
The role of immune cells in brain homeostasis
In the parenchyma of the brain, microglia, a limited but significant number of NK cells, B cells, T cells and dendritic cells, can be found.
Various studies have established that CD4+ T cells play an important role in maintaining behavioral and cognitive abilities in naive mice.
Under steady state conditions, both TH1 ( IFN-γ producing ) and TH2 ( IL-4 producing ) CD4+ T cells grow in the meninges.
IFN-γ assists key neural circuits for social behavior by regulating BDNF expression in meningeal dendritic cells and stimulating astrocytes.
Therefore, T cells and the cytokines they secrete play a key role in maintaining brain homeostasis.
The choroid plexus is an epithelial tissue found in the ventricle of the brain.
The choroid plexus forms the blood-cerebrospinal fluid barrier and plays a key role in maintaining brain homeostasis by secreting neurotrophic factors into the cerebrospinal fluid, participating in aβ clearance and transporting leukocytes.
When looking at naive mice, the stroma of the choroid plexus was found to contain more than 50% of the CD4+ and CD8+ T cells in the brain.
Most of these T cells have effector memory phenotypes, including TH1, TH2, and Tregs, and have the ability to recognize CNS antigens.
It was found that aging causes the choroid plexus to display a distorted TH1 to TH2 balance ratio, resulting in increased CCL11 chemokine expression, and the effects of IL-4 and IFN-γ on choroid plexus epithelial cells lead to decreased leukocyte permeability and hinder recognition.
AD and the immune system
In AD pathology, observation of the brain can reveal microglia differentiation into a novel form associated with neurodegenerative disease, including altered molecular expression profiles and restricted phagocytic capacity.
Aberrant variants of the trigger receptor ( TREM2 ) expressed on myeloid cells-2 have also been observed to increase the incidence of AD models by at least two-fold.
Furthermore, in addition to upregulation within the central nervous system, TREM2 mRNA and protein also showed high expression in peripheral leukocytes of AD patients, which was associated with hippocampal atrophy and cognitive deficits.
Neutrophils are the most abundant myeloid cells in human peripheral blood.
Neutrophils have a key role in the innate immune system and are present in the brain parenchyma of 5xFAD and 3xTg AD mice.
In the brain parenchyma of these mice, neutrophils appeared to contribute to cognitive decline, amyloid plaques and tau tangles.
However, further studies showed that 10 months of treatment of 3xTg AD mice with TNF-α modulating drugs increased neutrophil infiltration into the brain, along with decreased amyloid and tau pathology and enhanced memory.
Therefore, further studies are necessary to elucidate the characteristics of infiltrating neutrophils in AD pathogenesis.
In adaptive immunity, the phenomenon of Aβ antibody production by B cells has been extensively studied over the past two decades.
To date, anti-Aβ antibodies have been found to circulate at varying levels in human blood, leading to consideration of B cell-mediated immune responses as a therapeutic strategy, as studies have shown that Aβ immunization has the potential to prevent amyloidosis in PDAPP mice Plaque progression and gliosis and neuroinflammatory dystrophy.
However, as demonstrated in the AN1792 clinical human trial, approximately 6% of subjects developed encephalitis leading to trial termination.
Nonetheless, there are passive immunotherapies showing mixed results, and numerous clinical trials continue.
Immunotherapy for AD
Active immunotherapy
In 1999, the first active Aβ immunotherapy study was conducted using the PDAPP mouse model, in which full-length human Aβ peptide and adjuvant were injected into young and old PDAPP mice.
In young PDAPP mice, immunization-produced Aβ antibodies completely prevented plaque formation and neuroinflammatory dystrophy, whereas in older PDAPP mice, the extent of amyloid deposition was significantly reduced.
Based on the PDAPP mouse model, AN-1792 is the first human Aβ active immunotherapy consisting of synthetic full-length human Aβ42 and adjuvants.
The Phase 1 clinical study of AN-1792 included 372 patients with mild to moderate AD.
Results from the Phase 1 trial showed that the vaccine induced an antibody response to Aβ42 and cleared plaque in the brain.
However, in the phase II trial, the clinical trial was suspended because the patient developed meningitis.
Despite the side effects of the AN-1792 clinical trial, the results of this study encourage the development of new active anti-Aβ immunotherapy approaches.
Currently, CAD106, ABVac40, ACI-24 and UB-311 are active anti-Aβ vaccines in Phase II trials.
Other effective anti-Aβ immunotherapies include the peptide vaccine V950, Vanutide cridificar (ACC-001) and Lu AF20513.
The CAD106 vaccine, developed by Novartis, reduces amyloid beta plaques by inducing antibody production.
The vaccine consists of truncated β-amyloid fragments ( Aβ1-6 ) to avoid T cell activation.
There were no signs of meningitis during the 52 weeks of the Phase 1 trial. The vaccine is currently undergoing safety trials, while antibody responses to beta-amyloid plaques are being measured during a phase 2 trial.
The ABvac40 vaccine was developed by Araclon Biotech and its structure targets the C-terminus of Aβ40. The vaccine consists of a short C-terminal fragment of Aβ40 adjuvanted with aluminum hydroxide.
During the Phase 1 trial, patients with mild to moderate AD were recruited and the vaccine was tested for safety, immunogenicity and tolerability.
As of now, ABvac40 has entered a Phase 2 trial, which is expected to end in December 2022.
The ACI-24 vaccine, developed by AC Immune, contains Aβ1-15 epitopes, excluding T cell epitopes, to avoid T cell responses.
In preclinical trials in transgenic mice, improvements in cognition and reduction in Aβ were obtained.
ACI-24 is currently undergoing a Phase II trial to test the safety, immunogenicity and tolerability of the injection in patients with mild AD.
The UB-311 vaccine, developed by United Biomedical, contains the Aβ1-14 epitope linked to a helper T cell peptide epitope.
The peptide cocktail will induce B cell responses while avoiding T cell inflammatory responses.
During the phase I trial, patients with mild to moderate AD developed Aβ antibody responses, and the vaccine was safe and tolerable.
Currently during a Phase 2 trial, the primary goal is to collect further data on safety and immunogenicity.
Aβ immunotherapies under investigation but discontinued include peptide vaccines V950, ACC-001 and LU AF20513 .
Peptide vaccine V950 consists of Aβ1-14 bound to ISCOMATORIX.
During the trial period, however, the study was terminated and no clinical data are available yet.
The vaccine ACC-001, which consists of Aβ1-7, was found to be safe and well tolerated by patients during a phase 2 trials.
However, no improvement was found in the patients, which led to the termination of the study.
The LU AF20513 vaccine, which consists of Aβ1-12 repeats, was terminated due to lack of efficacy during the Phase 1 trial.
Passive immunotherapy
In passive immunotherapy, antibodies are produced outside the body and injected directly into the patient.
Anti-Aβ-specific monoclonal antibody demonstrated for the first time the effect of passive immunotherapy against AD in the PDAPP mouse model.
Over the course of 6 months, mice were found to have decreased levels of Aβ and increased Fc receptor-mediated phagocytosis of Aβ.
Subsequently, various anti-Aβ antibodies were developed, including bapineuzumab, gantenerumab, crenezumab, solanezumab and aducanumab, and BAN 20401 .
Bapineuzumab is the first humanized antibody that targets Aβ plaques and induces Fc receptor-mediated phagocytosis.
In Phase 1 and Phase 2 trials, results demonstrated cognitive benefits in patients who did not carry the APOEε4 gene and established overall safety and tolerability.
This prompted bapineuzumab to enter a phase III trials.
However, no apparent treatment effect on signs of cognitive and amyloid-related imaging abnormalities ( ARIA ) was found, leading to the study being terminated.
Gantenerumab is a human antibody with sub-millimolar affinity to the N-terminus of Aβ.
This antibody has been shown to reduce Aβ levels through a mechanism that induces phagocytosis after binding to plaques.
During the Phase 1 trial, the antibody was shown to be safe and tolerable.
Further studies were subsequently conducted in Phases 2 and 3, but no overall clinical benefit was considered.
Crenezumab is a humanized anti-Aβ antibody that inhibits the aggregation of Aβ in monomeric, oligomeric and fibrillar forms, while also aiding in the depolymerization process.
In Phase 1 trials, the antibody demonstrated adequate safety with no side effects.
An increase in beta-amyloid in the cerebrospinal fluid was observed in a phase II clinical trial using higher concentrations of the antibody.
However, cognition did not change. Oligomeric Aβ hypersensitivity immunoassays performed on patient cerebrospinal fluid ( CSF ) samples found reduced levels of oligomeric Aβ in CSF in more than 85% of patients, suggesting that the treatment was hitting its intended target in the brain.
Solanezumab is another humanized monoclonal antibody against soluble Aβ.
In early clinical trials, cognition did not improve in patients with moderate AD.
However, the exacerbation rate was reduced in patients with mild AD.
However, a phase 3 trial that began in 2013 failed to provide any statistically significant results during treatment.
Aducanumab is a human monoclonal antibody that binds to aggregated Aβ.
In March 2019, the Phase 3 study of aducanumab was suspended due to missed primary targets. However, in October 2019, the FDA again began approving aducanumab.
In June 2021, the FDA approved aducanumab, but there has been controversy surrounding the decision due to conflicting assessments of the treatment’s effectiveness.
The standard normal route was not approved, but the FDA opted for accelerated approval.
The decision was widely criticized over whether aducanumab had any cognitive benefits, or whether it would only offer false hope that it would not actually stop the disease from progressing.
Currently, post-marketing trials are awaiting completion in 2030 to demonstrate the drug’s cognitive benefits.
BAN2401 targets large soluble Aβ fibrils. During the Phase 1 trial, where safety and tolerability were tested, no ARIA was reported in patients with mild to moderate AD.
Subsequently, cognitive improvement and safety were tested for 12 months in a Phase 2 trial. However, the results showed no cognitive benefit over the 12-month period.
Currently, a large 4-year BAN2401 study is underway to determine changes in beta amyloid and cognitive function, which will run until October 2027.
Summary
To ensure greater progress in AD immunotherapy, AD must be considered as a heterogeneous multifactorial disease with multiple pathobiological and clinical subtypes.
AD has major subtypes such as mild atrophy, classic, limbic predominant and hippocampal sparing in terms of brain atrophy and tau pathological spread, but also has many different variants such as mild dementia, cortical atrophy, cortical atrophy Basal syndrome, primary progressive aphasia, amyloid-positive and immunogenic variants.
In addition to the complexities of AD , there are also intersections with different pathologies and clinics.
Therefore, the development of a generic AD drug is unlikely. Therefore, AD immunotherapy should focus on precise and personalized medicine.
In recent years, significant advances have been made in the application of imaging and genomic tools to help identify potential genetic risks of precise molecular pathways.
In addition, significant advances have been made in detection techniques for pathophysiological processes.
This has led to the beginning of the inclusion of precision and personalized treatments in clinical trials of various ADs, including the Anti-Amyloid Study in Asymptomatic AD, the AD Prevention Program, and the Dominant Inherited AD Network Trial, which focus on patients with well-established AD risk factors in patients, as well as neuroimaging and biomarkers to help detect AD pathogenesis.
In the future, personalized and precision medicine in AD will likely generate new treatments that will bring good news to patients.
references:
1. The Immune System as a Therapeutic Target for Alzheimer’s Disease. Life (Basel). 2022 Sep; 12(9): 1440.
What is the research progress of immunotherapy for Alzheimer’s disease?
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