Targeting Beta-Amyloid Protein with Monoclonal Antibodies: A New Hope for Alzheimer’s Treatment

Introduction

Alzheimer’s is an illness that is a type of dementia that causes progressive damage to the brain, leading to memory loss, cognitive decline, and behavioral changes. It is divided into mild, moderate, and severe stages and has a poor prognosis once diagnosed. It is statistically the most rampant type of dementia, making up 60%–70% of all cases. Dementia affected 57.4% of the global population in 2020, with Alzheimer’s disease (AD) being the most common type. The study also predicted that by 2050, approximately 152.8 million individuals worldwide will have dementia, with the highest increases expected in low- and middle-income countries. ¹ AD is characterized by a range of pathological mechanisms, including inflammation, oxidative stress, mitochondrial dysfunction, and synaptic dysfunction. The defining pathological characteristics of AD are the formation of beta-amyloid plaques and neurofibrillary tangles. Beta-amyloid peptides are produced through the processing of the amyloid precursor protein (APP), and their aggregation leads to the growth of beta-amyloid plaques within the gray matter, especially in areas involving memory and cognition. This, in turn, triggers an inflammatory response, resulting in the activation of microglia and astrocytes, which release cytokines and other inflammatory agents. Large bodies of ongoing research related to the amyloid b-protein (Ab) hypothesis show that a disparity between the creation and removal of Ab42 and its related peptides serves as an early and often times instigating factor in the development of AD. The confirmation that presenilin represents the catalytic site of c-secretase provides us with some vial biochemistry: the dominant mutations responsible for AD of the early-onset type are either of the two: a mutation of the substrate APP or of the protease (presenilin) involved in the reaction that produces Ab. ² Neurofibrillary tangles, on the other hand, arise from the hyperphosphorylation and collection of tau protein, which stabilizes microtubules in neurons. The accumulation of hyperphosphorylated tau protein interferes with microtubule stability, ultimately leading to the death of neurons.

Main Text

Currently, there are only two categories of pharmacological interventions available for the treatment of AD. Inhibitors of cholinesterase, namely donepezil, rivastigmine, and galantamine, are the recommended therapy for patients with dementia associated with AD ranging from mild to moderate to severe, as well as for those with Parkinson’s disease dementia. Additionally, memantine has been shown to have dopaminergic activity, further highlighting its potential role in the treatment of AD. ³

Aducanumab is a monoclonal antibody designed to target beta-amyloid, a protein commonly present in the brains of individuals with AD. Various clinical trials have been conducted to evaluate the efficacy and side effects of aducanumab in treating AD. One of the pivotal studies was a phase III clinical trial that enrolled 1,656 participants in the initial-stage of Alzheimer’s disease. This trial, which utilized a randomized, double-blind, placebo-controlled design, found that aducanumab substantially diminished beta-amyloid levels in the brain and slowed cognitive decline in comparison to the placebo. ⁴ However, the trial was stopped early due to an interim analysis that suggested a lack of efficacy, and subsequent analyses of the data have been controversial. ⁵ Despite these positive results, there are multiple disadvantages to the therapy of aducanumab. One of the key worries is the cost of the drug, which is estimated to be around US$56,000 per year, ⁶ and amyloid-related imaging abnormalities (ARIAs), the side effects associated with the removal of Aβ, were dose-dependent in the aducanumab-treated group. ⁷ Additionally, the drug requires monthly infusions, which can be burdensome for patients and caregivers. There are also potential side effects of aducanumab, including brain swelling and bleeding, which occurred in some participants in the clinical trials. ⁴

On January 6, 2023, the Food and Drug Administration (FDA) granted approval to leqembi (lecanemab-irmb) through the accelerated approval process. This pathway is reserved for serious illnesses with no available medical treatments where the drug has shown efficacy in a surrogate endpoint that can predict a clinical benefit for patients. ⁸ Lecanemab-irmb, being a humanized IgG1 antibody derived from murine mab158, exhibits selective binding affinity towards the large, soluble Aβ protofibrils, which are widely recognized as the most neurotoxic species and are considered significant contributors to the underlying pathogenesis of AD. ⁹ Lecanemab-irmb’s effectiveness was tested in research on 856 people with Alzheimer’s disease utilizing a double-blind, placebo-controlled, parallel-group, dose-finding methodology. Its findings support lecanemab-irmb’s accelerated approval, which is based on a reduction in the levels of amyloid beta plaque, an indicator of Alzheimer’s syndrome. Beta-amyloid plaque levels were evaluated employing positron emission tomography (PET) imaging, which allowed the estimation of plaque levels in brain zones commonly influenced by AD disease pathology rather than parts of gray matter predicted to be unaffected. These outcomes validate lecanemab-irmb as a medication option for AD. ⁷ The first study’s trial revealed that a greater number of patients treated with Lecanemab-irmb stopped their treatment due to negative reactions, specifically infusion-related ones and ARIA, which occurs due to antibodies of this class and is usually symptoms-less but can rarely cause temporary brain swelling that settles on its own but could be associated with minute bleeding in the brain, compared to those who received the placebo.

Around 9.9% of subjects showed radiological evidence of edema or effusion related to amyloid at 10 mg/kg biweekly of lecanemab-irmb ¹⁰ as compared to aducanumab, which showed that high-dose aducanumab led to ARIA-related cerebral edema in 35% of the patients, and 18%–22.7% of the patients treated with aducanumab showed ARIA-related microhemorrhages. ⁷

The other adverse reactions that occurred in at least 5% of patients who received lecanemab-irmb and were at least 2% more frequent than in the placebo group included atrial fibrillation and lymphopenia. These reactions were more frequently observed in the lecanemab-irmb group than in the placebo group. ⁸

Donanemab, a monoclonal antibody in phase 3 showed improved cognition and daily living abilities in early AD patients compared to placebo after 76 weeks of treatment. ¹¹ Despite these positive results, the FDA rejected its accelerated approval in January 2023, but this drug is currently assessing safety and efficacy in its current phase 3 trial, Donanemab (LY3002813) Prevention Study in Participants with AD (TRAILBLAZER-ALZ 3) and can show positive results in the future. Gantenerumab is an investigational antibody in Phase III development for early AD, but it was stopped due to its futility. Although a dose-dependent effect was observed, further research is needed. ¹² Solanezumab reduced brain Aβ levels but did not decrease cognitive decline in its phase 3 trial, ⁷ while bapineuzumab did not outperform placebo in AD assessment. ¹³ Further investigation is needed to understand the effectiveness and safety of these antibodies.

Conclusion

Lecanemab-irmb shows more promising results in the management of Alzheimer’s disease, but its efficacy for the treatment of Alzheimer’s still remains unknown. The infusion-related side effects and ARIA are the major potential side effects. Although further research is required to completely understand the long-term impact and benefits of lecanemab-irmb, the results thus far are encouraging. It is essential to continue conducting ongoing research and development in this area, as this treatment alternative can significantly improve the lives of the millions who are affected by this debilitating disease globally. While aducanumab was the first approved monoclonal antibody for the treatment of Alzheimer’s and has shown good results, due to its high cost and adverse effects profile, it is not as effective as lecanemab-irmb.