Alzheimer disease immunotherapeutics: Then and now

Abstract

Dementia is a public health priority and one of the major contributors to morbidity and global non-communicable disease burden, thus necessitating the need for significant health-care interventions. Alzheimer disease (AD) is the most common cause of dementia and may contribute to 60–70% of cases. The cause and progression of AD are not well understood but have been thought to be due at least in part to protein misfolding (proteopathy) manifest as plaque accumulation of abnormally folded β-amyloid and tau proteins in brain. There are about 8 million new cases per year. The total number of people with dementia is projected to almost double every 20 years, to 66 million in 2030 and 115 million in 2050. Immunotherapy in AD aimed at β-amyloid covers 2 types of vaccination: active vaccination against Aβ42 in which patients receive injections of the antigen itself, or passive vaccination in which patients receive injections of monoclonal antibodies (mAb) against Aβ42. Three of the peptide vaccines for active immunizations, CAD106, ACC001, and Affitope, are in phase 2 clinical trials. Three of the mAbs solanezumab, gantenerumab, and crenezumab, are or were in phase 2 and 3 clinical studies. While the phase 3 trials failed, one of these may have shown a benefit at least in mild forms of AD. There is a need for a greater initiative in the development of immunotherapeutics. Several avenues have been explored and still to come.

Introduction

Dementia is a public health priority and one of the major contributors to global morbidity and non-communicable disease burden, thus necessitating the need for health-care interventions. It is a syndrome that affects memory, thinking, behavior and ability to perform everyday activities. Not only it is overwhelming for those who have it, but also for their caregivers and families, and the lack of awareness and understanding in most countries results in social labeling, barriers to diagnosis and care which affects caregivers, families, and societies physically, psychologically, and economically.¹

AD is the most common cause of dementia and may contribute to 60–70% of cases of dementia.² AD was first described in 1906 by German psychiatrist and neuro-pathologist Alois Alzheimer.³ It affects all age groups with higher prevalence in >65-y-old people, and is predicted to affect 1 in 85 people globally by 2050.⁴

Although clinical manifestations of AD differ for every individual, there are many common symptoms. In the early stages, it affects short-term memory and thinking ability, and as the disease advances it includes confusion, irritability, aggression, mood swings, trouble with language, and long-term memory. Bodily functions are gradually lost, ultimately leading to death. The average life expectancy following diagnosis is ∼7 y.⁵ Fewer than 3% of individuals live >14 y after diagnosis.⁶

The causes and progression of AD are not well understood but have been thought to be due in part to protein misfolding (proteopathy) caused by the accumulation of abnormally folded β-amyloid in plaques and tau protein tangles in the brain. The disease, which has been found to be associated with plaques and tangles in the brain, has no cure and available treatments offer relatively small symptomatic benefit while remaining palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial, and caregiving. Five drugs are used to treat the symptoms of cognitive problems of AD: four are acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine, and donepezil) and the other (memantine) is an NMDA receptor antagonist. The benefit from their use is small.⁷ No medication has been shown to delay or halt the progression of the disease.

Global Burden of Disease

The current burden and future impact of the dementia epidemic has been underestimated, particularly for the East Asian and Sub-Saharan African regions. This is a global epidemic—although cases are disproportionately concentrated in the world's richest and most demographically aged countries, the majority (58%) of people with dementia live in low- and middle-income countries where access to social protection, services, support, and care are very limited.

Worldwide, 36 million people have dementia, with ∼8 million new cases annually. The number of people with dementia is projected to almost double to 66 million in 2030 and 115 million in 2050. Much of this increase is attributable to the rising numbers of people with dementia living in low- and middle-income countries.² It has been estimated that 5.2 million Americans have AD, of which 4% people are younger than 65 y. An addition 10 million additional people in the US are projected to develop AD in the baby-boom generation.⁸

The global economic cost of dementia in 2010 was estimated to be $604 billion = 1% of global GDP. Costs are expected to escalate proportionately with the numbers of affected individuals and with increased demand for care services, particularly in low- and middle-income countries.⁹

Immunotherapeutics

Research has investigated several avenues to attack AD, of which vaccination/immunotherapy is one of the most popular. Immunotherapy in AD covers 2 types of vaccination: active vaccination against Aβ42 in which patients receive injections of the antigen itself, or passive vaccination in which patients receive injections of anti-Aβ mAbs.

Active Immunotherapeutics

Beka Solomon's lab first suggested in the mid-1990s that anti-Aβ mAb could be used to prevent Aβ fibril formation and disaggregate pre-formed fibrils and plaque.¹⁰ Schenk and colleagues then published results on active Aβ1–42 peptide immunization in APP/PS1 double transgenic mice as an AD mouse model, which showed s reduction in Aβ levels in the brains of the treated mice as well as improvements in memory tasks.¹¹

The first active vaccine clinical trial for AD, AN1792, was halted early in 2002 due to the development of meningoencephalitis in ∼6% (18 of 300) of the enrolled moderate-to-severe AD patients.¹²

In the view of potentially dangerous autoimmune/inflammatory responses caused by newly activated Aβ-specific inflammatory T cells, new peptide vaccines were designed in which the sequences responsible for T-cell activation were deleted and only the parts needed for generation of Aβ-specific antibodies remained. Three such peptide vaccines for active immunizations, CAD106, ACC001, and Affitope. Phase 1 trials for each of these 3 vaccines showed specific antibody responses with no signs of adverse autoimmune inflammation, and these active immunization are continuing in phase 2 clinical trials.¹³

A randomized clinical trial in Sweden of CAD106 showed that the majority of subjects reported adverse events with nasopharyngitis and injection site erythema as the 2 most common adverse effects while 67–82% of subjects in the 2 cohorts developed anti-Aβ antibody responses, suggesting that CAD106 has a favorable safety profile and acceptable antibody response in subjects with AD.¹⁴ Further research is needed to confirm safety and to attempt to establish the efficacy of CAD106.

ACImmune-35 (ACI-35) vaccine is designed to stimulate the production of antibodies targeting the tau protein that forms fibers and tangles in the brain. ACI-35 is in a phase 1/2a clinical trial to clear such structures, another hallmark of the fatal brain-wasting disease.¹⁵

Passive Immunotherapeutics

Another approach employs humanized anti-Aβ mAbs that are injected as passive immunization therapy. Three such mAbs, solanezumab, gantenerumab, and crenezumab, have been in phase 2 and 3 clinical studies.¹³ Bapineuzemab was the first mAb to be used as passive immunotherapy in AD patients but was discontinued after phase 3 trials since it failed to achieve any efficacy. Solanezumab failed its primary outcome in a phase 3 trials but did show benefits in at least in mild forms of AD, and is in a new phase 3 trial in a defined cohort of early-stage disease subjects.

Challenges

Only a small percentage of antibodies cross the blood brain barrier in normal subjects (∼0.1%), with a somewhat higher percentage in AD subjects (0.5–1.0%); thus, it may be useful to find ways to improve antibody penetration into brain. Active vaccination requires particular attention to immune effects of immunotherapy, including immunosenescence in the elderly, the potential for autoimmune effects when vaccinating against self-proteins, and the use of strong, pro-inflammatory adjuvants. Removing amyloid after neurons have been lost has not been effective thus far, suggesting that treatment should be started earlier and perhaps tested over longer periods of time.¹⁶

Conclusion

Dementia is a public health priority, and AD is one of the most common causes. There is a need for a greater initiative in the development of immunotherapeutics. Several avenues have been explored and are still to come. Results to date have been mixed, and there still a long road ahead for an effective treatment of this debilitating disease.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.