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Monoclonal Antibodies for Alzheimer’s Disease – Are We Barking Up The Wrong Tree?

Monoclonal antibodies for Alzheimer’s disease or mAbs are proteins produced in a lab, engineered to target and neutralize certain proteins and pathogens in the body. The field of Alzheimer’s disease (AD) therapeutics is currently flooded with mAbs, each hoping to finally solve the problem of bad proteins accumulating in the brain.

As of February 2024, disease-modifying therapies (DMTs) make up 82.5% of the considered agents in the Alzheimer’s Disease drug development pipeline.

15.4% of these DMTs are monoclonal antibodies meant to clear out beta amyloid plaque. 10.6% of these DMTs are monoclonal antibodies created to eliminate phosphorylated tau.

Table of Contents

    Why Target Beta-Amyloid Plaques?

    The amyloid hypothesis posits that amyloid accumulation is the key initiating event of Alzheimer’s and is followed by downstream effects including: 

    • formation of neurofibrillary tangles (NFTs)
    • neuroinflammation, cell death and 
    • neurotransmitter deficits.

    How Do Monoclonal Antibodies Treat Alzheimer’s?

    Monoclonal antibodies are often administered intravenously to allow them to circulate in the bloodstream. From the bloodstream, they then cross the blood-brain barrier to start clearing out beta-amyloid plaques in the brain. 

    Monoclonal antibodies attach selectively to beta-amyloid plaques, marking them for destruction or elimination by the microglia (the brain’s immune cells).

    monoclonal antibodies for alzheimer's disease
    Source: Springer
    1. mABs are administered intravenously intravenous (IV)
    2. bind to soluble Aβ peptides in the periphery
    3. sequester them into an immune complex 
    4. Complex is removed by the microglia 
    5. Plasma Aβ levels is reduced.

    By promoting the clearance of beta-amyloid plaques, the monoclonal antibody aims to reduce the overall buildup of these plaques in the brain. This reduction in plaque buildup could potentially slow down the progress of Alzheimer’s disease, or does it really?

    Beyond Plaque Removal: mAbs Reduce Brain Inflammation Too!

    While the primary goal is to reduce plaque buildup, emerging research suggests that mAbs may offer additional benefits. One benefit of using mAbs is reduced brain inflammation, which protects neurons from future damage. 

    A study in the Journal of Neuroinflammation describes a new mAb that targets triggering receptors expressed in myeloid cells (TREM2). The antibody binds to both soluble and membrane-bound TREM2, which improves cognitive function and reduces chronic neuroinflammation.

    Failure Of Monoclonal Antibodies for Alzheimer's Disease

    monoclonal antibodies for alzheimer's disease

    The early phases of monoclonal antibodies for Alzheimer’s disease treatment were brimming with hope since this method offered a focused strategy that targeted one of the disease’s key pathological processes: the deposition of beta-amyloid plaques in the brain.

    Nevertheless, there were actually 2 main issues pertaining to the usage mAbs:

    1. Lack of evidence supporting the association between amyloid load and cognitive outcomes, with studies reporting only an indirect link between amyloid plaques and cognitive decline
    2. Higher risk of developing vasogenic cerebral edema and cerebral microhemorrhages was observed in participants treated with mAbs

    Lecanemab and Aducanumab are two mAbs that were approved by the FDA based primarily on their effect on imaging and biomarkers. They were approved despite not demostrating any meaningful improvement in clinical outcomes. 

    According to a November 2023 STAT article, clinical trials of lecanemab, aducanumab, and donanemab have shown that 12–35% of treated patients experience brain swelling and/or bleeding due to amyloid-related imaging abnormalities (ARIA). This is compared to 3–13% in patients receiving a placebo.

    This implies that mAbs may even cause more harm than benefit.

    Most Recent Monoclonal Antibody Failures

    Solanezumab did not clear or halt accumulation of amyloid plaque. Nor did it slow down cognitive decline in treatment participants.

    Gantenerumab was part of the pipeline of Swiss pharma company, Roche. However, the drug candidate failed to improve the rate of cognitive and functional decline in a pair of phase 3 clinical trials, delivering yet another blow to the field.

    In March 2024, the FDA delayed the approval of Donanemab, an experimental Alzheimer’s drug developed by Eli Lilly. Lilly had asked the FDA to expedite the approval, but was rejected in January 2024. FDA told Lilly that at minimum they needed data from 100 patients receiving the treatment for 12 months. 

    According to Lilly, “due to the speed of plaque reduction that we saw, many patients were able to stop dosing as early as six months into treatment, resulting in fewer patients receiving 12 months or more of Donanemab dosing.

    These disparities are prompting researchers to reconsider their understanding of the significance of beta-amyloid plaques in disease development. 

    Why Are mAbs Being Approved By The FDA?

    We identified 19 reports of 24 studies of monoclonal antibodies targeting amyloid depositions in patients who largely had mild cognitive impairment and mild Alzheimer disease,” investigators wrote.

    In no case did the results of any single study, of all combined studies for an individual drug, or of all combined studies overall find a change in cognition or function that exceeded the MCID for that scale.

    These mAbs were studied in large randomized controlled trials that found substantial reductions in amyloid deposition but only modest improvements in cognition and function

    Overall, it seems that mAbs only provided marginal benefits on cognitive and functional scales far below the minimal clinically important difference, with some accompanied by harm that was clinically-significant.

    Onlookers are now asking the question: What were these drugs approved by the FDA despite being unable to show significant improvement in cognition?

    FDA Should Approve A Drug Based On MCID

    monoclonal antibodies for alzheimer's disease

    The FDA broke its own protocols in approving Biogen’s Alzheimer drug in 2021. This was Aducanumab (Aduhelm), which was approved despite the objections of its panel of outside advisers.

    The FDA has previously argued that decisions about drug approvals should be based on the minimally clinically important difference (MCID).

    Aducanumab and Lecanemab were both approved based primarily on their effect on imaging and biomarkers, without any meaningful improvement in clinical outcomes.

    Some might argue that a longer study would find a minimum clinically important difference (MCID), but the changes we documented were so much lower than the MCIDs that this seems unlikely.

    This is inappropriate and sets a bad precedent for the FDA, not only in drug discovery for Alzheimer’s Disease but also for other conditions where intermediate markers are easily measured but may not reliably predict clinical outcomes.

    What We Have Learned So Far From These Failures

    From these failures, it does seem that:

    1. These mAbs need to be given earlier in the disease course before severe brain damage occurs.
    2. MAbs should be tackling more of the soluble amyloid beta oligomers, and not just insoluble AB plaques

    This is because not every beta-amyloid is similar. Beta-amyloid plaque can be insoluble or soluble. Soluble plaques are more neurotoxic and more easy to spread around.

    Take the drug by Biogen and Eisai, Lecanemab-irmb, as an example. It is an immunoglobulin that mainly targets insoluble forms of amyloid beta (Aβ). As we’ve seen from above, this drug did not show very significant improvement in AD patients. 

    According to some evidence, soluble beta-amyloid (sAβ) oligomers are an early trigger of cognitive impairment and synaptic damage in Alzheimer’s disease (AD). This evidence suggests that sAβ oligomers are an early biomarker, while plaques appear later in the disease.

    Thankfully, mAbs are becoming even more specific in targeting soluble ABOs.

    Soluble Aβ42 - A Conformation-specific Marker For Alzheimer’s

    Research shows soluble Aβ42 is detectable at 2 months, primarily in the cortex and hippocampus, possibly representing soluble oligomers that form prior to the deposition of amyloid. 

    Amyloid β-protein (Aβ42) oligomerization occurs very early in Alzheimer’s. Current diagnostic methods using sequence-specific antibodies against less toxic fibrillar and monomeric Aβ42 run the risk of overdiagnosis. 

    Conformation-specific antibodies against neurotoxic Aβ42 oligomers have garnered much attention for developing more accurate diagnostics. 

    Antibody 24B3 has a highly specific conformation for the toxic Aβ42 conformer that has a turn at Glu22 and Asp23, recognizes a putative Aβ42 dimer (which forms stable and neurotoxic oligomers more potently than the monomer). 

    This implies that 24B3 may significantly reduce Aβ42-induced neurotoxicity, in the very early stages of Alzheimer’s. 

    TLDR:Monoclonal antibodies should, instead of focusing solely on insoluble beta-amyloid plaques, target more soluble ABOs. 

    New Advances Point to More Options For Alzheimer’s Treatment

    monoclonal antibodies for alzheimer's disease

    Research into antibodies against tau protein, another crucial contributor to Alzheimer’s, represents a significant step forward in tackling the disease’s complications. 

    Lilly also has zagotenemab in its pipeline. It is a humanized IgG1 that is specific for neurofibrillary tangles. Zagotenemab targets tau protein in its neurofibrillary form at its N-terminus. 

    Monoclonal Antibody Treatment Cannot Work In Isolation

    Alzheimer’s disease is characterized by a variety of pathological processes other than beta-amyloid plaque formation, such as tau protein tangles, inflammation, as well as loss of neurons. Due to its complexity, treating a single aspect of the disorder might not be enough to arrest its progression.

    This is why the pharmaceutical universe is now suggesting that monoclonal antibodies be used in combination with other medications, so that multiple mechanisms are now targeted, instead of just one.

    In cancer, some drugs combine two monoclonal antibodies, one that attaches to a cancer cell and one that attaches to a specific immune system cell. This connection may promote immune system attacks on the cancer cells.

    If researchers take inspiration from the field of cancer, combining monoclonal antibodies allows for several pathways to be targeted simultaneously, potentially leading to synergistic effects.

    Interestingly, a study found that combining focused ultrasound to one side of the brain with infusions of aducanumab, is able to clear more amyloid-β plaque from those regions than the ones that were treated with the mAB alone. 

    Soluble ABOs Is Why Alzheimer’s Drugs Have Not Worked

    reverse brain age alzheimer drug binding of monoclonal antibodies to different types of amyloid beta

    From this image, it seems that almost none of these drugs target soluble ABOs. Their main focus has been on insoluble fibrils – and this seems to be the problem behind why most of the trials have failed. 

    Conclusion 1: MAbs May Have Failed Thus Far, But We Could Discover Something Very Good Very Soon.

    Looking back on failed trials, it seems the use of monoclonal antibodies in treating Alzheimer’s disease does not show much promise. This entire journey of drug discovery also demonstrated how FDA could approve a drug based on success in altering intermediate markers, despite it not demonstrating sufficient clinical outcome on humans.

    Based on our hypotheses, to involve mAbs in the treatment of Alzheimer’s:

    1. Future mAbs need to specifically target soluble ABO. Soluble oligomers will eventually turn into plaque so if we just target the plaques are not treating the root.
    2. Newer drugs should aim to reduce the side effect of brain swelling (aka amyloid-related imaging abnormalities (ARIAs).
    3. Monoclonal antibodies may not work as well in the late stages, so the studies should arrange for interventions in the earlier stages of the disease. 
    4. Monoclonal antibodies should not be used alone; they should be used as part of a cocktail of Alzheimer drugs.

    Conclusion 2: Monoclonal Antibodies Treat The Symptom And Not The root.

    Treating the root means targeting APP processing. 

    The main problem in AD is that APP processing goes down the amyloidogenic pathway, producing the neurotoxic AB plaques.

    monoclonal antibodies for alzheimer's disease
    Aggregation pathway: soluble ABOs will eventually turn into insoluble plaque

    However, monoclonal antibodies just seem to “delay” the progression of AD, by removing the insoluble plaques once they are formed. It seems like they do not solve the root of the problem. 

    So why are pharma companies still focusing on mAbs, when they could target other pathways, such as the pathway of AB biogenesis?

    Isn’t it more logical to target the enzymes involved cleavage of the amyloid precursor protein, to stop it from becoming the plaques in the first place?`

    Frequently Asked Questions (FAQ)

    What are the monoclonal antibodies for alzheimer's?

    Monoclonal antibodies are a type of therapeutic agent that targets specific proteins or molecules in the body. In the case of Alzheimer's disease, these antibodies are designed to target the amyloid-𝛽β protein, which is a hallmark of the disease. 

     

    These monoclonal antibodies work by binding to amyloid-𝛽β in the brain, which helps to reduce the accumulation of this protein and slow the progression of the disease. They are administered intravenously and are typically given every 4-6 weeks.

     

    While these monoclonal antibodies show promise in reducing amyloid-𝛽β levels and slowing cognitive decline, they are not a cure for Alzheimer's disease. Further research is needed to fully understand their long-term effects and to determine their potential as a treatment for the condition.

    Which antibody is FDA approved for alzheimer's?

    The FDA has approved two monoclonal antibodies for the treatment of Alzheimer's disease:

    1. Lecanemab: Lecanemab was approved by the FDA in January 2023 for the treatment of early-stage Alzheimer's disease.
    2. Aducanumab: Aducanumab was initially approved by the FDA in June 2021 for the treatment of early-stage Alzheimer's disease, but its approval was later withdrawn in November 2021 due to concerns over its efficacy and potential side effects.

    Both of these antibodies have received accelerated approval from the FDA for the treatment of early Alzheimer's disease patients who have proven β-amyloid pathology (Aβ).

    What are 3 treatments for alzheimer's?

    1. Lecanemab: Lecanemab is a monoclonal antibody that targets amyloid-𝛽β, a protein that accumulates in the brain and is believed to contribute to the progression of Alzheimer's disease. It is designed to reduce the accumulation of amyloid-𝛽β in the brain, which may help slow down the progression of the disease.
    2. Aducanumab: Aducanumab is another monoclonal antibody that targets amyloid-𝛽β. It is designed to reduce the accumulation of amyloid-𝛽β in the brain and slow down the progression of Alzheimer's disease.
    3. Donanemab: Donanemab is a monoclonal antibody that targets amyloid-𝛽β and is being developed by Eli Lilly and Company. It is designed to reduce the accumulation of amyloid-𝛽β in the brain and slow down the progression of Alzheimer's disease.

    Is gantenerumab a monclonal antibody?

    Yes, gantenerumab is a monoclonal antibody. It is a fully human anti-amyloid-β (Aβ) IgG1 monoclonal antibody designed to promote clearance of amyloid plaques in the brain, through peptide-mediated interactions