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Monoclonal Antibody Treatment Delivery for Alzheimer’s Disease & BBBNayoung Kim1, Linh Huynh1, Priya1, Harpriya Khela, Moshe Shalom,

Authors:

Nayoung Kim1 , Linh Huynh1 , Priya1 , Harpriya Khela, Moshe Shalom,


Institution

Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv, Israel

Klatchkin Street 35, Tel Aviv, Israel 6997801


Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with neuron reduction and brain atrophy. It affects the aging population worldwide and is the most common form of age-related dementia. The disease is characterized by memory impairment and cognitive decline, which eventually leads to mood and behavioral changes. Currently, available treatments for AD provide symptomatic relief rather than alter the progression of the disease. The economic burden associated with AD is significant, with healthcare costs noted to increase as the population at risk grows. Therefore, there is a need to find effective treatments to slow disease progression and improve the quality of life for patients. The pathophysiology of AD involves the formation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. The plaques induce neurotoxicity and lead to cell death. NFTs consist of hyperphosphorylated tau proteins which accumulate in neurons and contribute to neurological dysfunction. Monoclonal antibodies (MA) have been shown to be effective in treating many neurological and non-neurological conditions, such as multiple sclerosis, Parkinson’s disease, and metastatic melanoma of the brain. MA treatments can target specific molecules involved in the pathologies of these conditions, providing symptomatic relief and disease-modifying effects. However, current research is exploring the use of MA treatments in targeting amyloid β aggregates in AD


Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that results in the reduction of neurons, gradually leading to brain atrophy1 . The disease has an estimated prevalence of 10-30% in the population over the age of 652 . Most Alzheimer’s patients (>95%) have the sporadic form and are characterized by the late onset (80-90 years of age)2 . It is the result of the failure to remove the amyloid plaques and neurofibrillary tangles (NFTs) from the interstices of the brain3 . AD is the most common form of age-related dementia in the world, and it is most often characterized by early memory impairment and cognitive decline3 . It can ultimately affect an individual’s mood and behavior, and can manifest as apathy, depression, psychosis, and aggression4 . Furthermore, functional decline in two or more cognitive domains, including memory, language, execution, and visuospatial function, can lead to the inability to perform basic activities of daily living and ultimately death5 .


The disease was named after the German psychiatrist Alois Alzheimer, who reported the first case of cerebral atrophy and “particular changes in cortical cell clusters” in his neuropathological evaluation in 19066 . He discovered the presence of amyloid plaques and massive loss of neurons while examining the patient’s brain, describing the condition as “a pellicular disease process of the cerebral cortex” 7 .

Despite the significant increase in our understanding of AD since then, there is no effective medical treatment options for the prevention and treatment of AD8 .


Current treatments for AD include cholinesterase inhibitors, which are commonly used in all stages of AD, and memantine, which is used in people with moderate to severe AD9 .

These medications have shown to improve the quality of life for both patients and caregivers when prescribed at the right time during illness; however, they do not alter the progression of disease or the rate of decline10 . Previous reports estimate that there are approximately 24 million AD cases worldwide, and the number of people with dementia is expected to quadruple by11 . As of 2021, it is estimated that 6.2 million Americans aged 65 and older are living with AD in the United States alone12 .


The estimated total cost of healthcare in the United States associated with AD for 2021 was $355 billion, and that number is projected to grow to over $1 trillion as the population at risk grows13 . Most of these costs can be attributed to skilled nursing, home health care, and hospice care, which are needed to best treat AD patients14 . The indirect care costs associated with maintaining a proper quality of life and informal caregiving are underestimated, and many people with AD suffer from significant social and personal burden14 .


Due to the current prevalence and economic burden of AD, finding an effective treatment that can provide symptomatic relief and slow the progression of AD is desperately needed. This review discusses our understanding of AD pathology and currently available treatments, and examines the potential for monoclonal antibodies to be used in the treatment of AD.


Pathophysiology - The Cause of Alzheimer’s Disease Aβ Plaques

A key feature of AD pathology is the presence of plaques consisting of aggregated amyloid-β (Aβ) peptides15 . Aβ was first identified in 1984 as a major component of amyloid deposits16 . The biological role of Aβ is suspected to involve homeostatic scaling of synapses, immunity, and lipid processing16 . Aβ oligomers can be produced in both extracellular an intracellular and can induce neurotoxicity in various ways16 .

First, Aβ can cause pore formation in the neuronal membrane, leading to leakage of ions, cellular calcium imbalance, loss of membrane potential, all of which can lead to accelerated apoptosis, loss of synaptic function, and destruction of the cytoskeleton17 . Neurogenic plaques in the brain are a major neuropathological feature of Alzheimer’s disease18 . They are formed by the deposition and aggregation of extracellular amyloid-β protein (Aβ)18 . Aβ is derived from the sequential cleavage of amyloid-β precursor protein (APP) by β-secretase and 𝛾-secretase18 . β-Site APP cleaving enzyme 1 (BACE1) functions as the primary, if not alone, β-secretase in vivo and is essential for Aβ production18 .


The extracellular secretion of Aβ is associated with several downstream effects such as hyperphosphorylation of tau protein leading to the NFTs generation, inflammation, oxidative stress, and excitotoxicity19 . Aβ plaques are responsible for many symptoms of AD, which can ultimately lead to cell death and deficiency of neurotransmitters20 .


Neurofibrillary Tangles (NFTs)

The presence of NFTs has been considered a pathological hallmark of AD21 . The number of NFTs is closely related to the severity of dementia, suggesting that the formation of NFTs is directly correlated with neurological dysfunction22 . NFTs consist of a highly phosphorylated form of the microtubule-associated protein22 . Tau is a microtubule-binding protein located predominantly in the axons of neurons under normal conditions23 . In pathological conditions, tau forms double paired helical filaments (PHFs) in both AD and a host of neurodegenerative diseases than as tauopathy24 . Phosphorylated tau proteins accumulate in neurons early in the disease even before NFTs are formed, suggesting that an imbalance between protein kinase and phosphatase activity in tau is an early phenomenon22 . The hyperphosphorylation of tau plays a pivotal role in tau’s pathogenicity because phosphorylation liberates tau from the microtubules, allowing them to aggregate and migrate to neuronal processes and cell body25 . An NFT is formed when PHF accumulates in the cell body of a neuron26 . In AD, different types of NFTs are present in neurons, including pre-tangles, intracellular tangles, or extra-neuronal tangles25 . Pre-tangles are defined as punctate tau staining, diffused within the cytoplasm of neurons with well-preserved processes27 . The pre-tangles can cause the formation of mature intraneuronal fibril tangles consisting of pathological tau aggregated in neuronal soma accompanied by dendrite28 . Extra-neuronal tangles are a result of death of neurons containing NFTs and are distinguished by the absence of a nucleus or cytoplasm29 .


Blood Brain Barrier (BBB) Breakdown

There are more than 400 miles of blood vessels in the human brain, 85% of which are capillary microvessels28 . Although it is only 2% of the body’s mass, the brain receives about 20% of the entire body’s glucose and oxygen28 . The blood flow required to satisfy the metabolic brain is largely dependent on the automatic regeneration of the brain microvascular bed29 . If this rich and delicate microvascular network is unhealthy, the brain network that supports cognitive, emotional, and behavioral processes cannot function normally30 .


Blood-brain barrier (BBB) is a highly selective semi-permeable structural and chemical barrier that ensures a stable internal environment of the brain and prevents foreign substances from attracting brain tissue31 .

Specialized endothelial cells align along the microvascular structure of the brain and help regulate the entry of plasma components, red blood cells, and white blood cells into the central nervous system32 . These cells also ensure the release of potentially neurotoxic molecules from the brain into the blood32 . Breakage of hard and adherent junctions, increase mass flow fluid transcytosis, and enzymatic degradation of the capillary basement membrane can all lead to the physical disruption of the BBB33 . BBB degradation has been shown to be associated with decreased cerebral blood flow and impaired hemodynamic responses34 .

A breakdown of the BBB can cause symptoms of AD, such as cognitive dysfunction and memory impairment35 . Levels of many tight junction proteins, adaptor molecules, and adhesion junction proteins are decreased in diseases that cause dementia, including AD36 . Recent imaging and biomarker studies have shown that early BBB breakdown and vascular dysregulation in AD may be detected prior to cognitive decline and/or other brain pathologies37 .


Monoclonal antibody treatment for neurological and non-neurological conditions
Monoclonal antibody (MA) treatment has been shown to be effective in treating neurological conditions such as multiple sclerosis, Parkinson's, metastatic melanoma of the brain, migraines, and more, and can potentially replace the standard therapy for those neurological conditions38 . In two identical 3 phases trials, patients who received ocrelizumab had a lower rate of multiple sclerosis progression and activity than those who received traditional treatments, such as interferon beta-1a39 .

MA treatment is also implemented for non-CNS diseases, including asthma and atopic diseases39 . Dupilumab is a MA that is utilized to treat patients with asthma by targeting the alpha subunit of the interleukin of the 4-receptor40 . Dupilumab then blocks the interleukin-4 and interleukin-13 signaling pathways, which are responsible for causing type 2 inflammation41 . Similar to MA therapy for neurological conditions, MA therapy for non-neurological conditions targets the specific molecules that cause the pathologies of those conditions40,41 .


Monoclonal antibody treatment for multiple sclerosis

MA treatment for multiple sclerosis (MS) has been shown to be a safe and effective treatment and works by depleting B cells and inhibiting inflammatory pathways such as blocking T lymphocytes from activating and expanding42,43 . MA treatment for MS can be used as monotherapy treatment or in combination with other treatments, especially for individuals who have experienced an incomplete response to standard therapies such as interferon beta-1a (IFN-B) treatment38 .


Rituximab, daclizumab and alemtuzumab have been shown to have better efficacy and tolerability in comparison to interferon beta-1a treatment39,40,43,44 . Rituximab, a B-cell-depleting monoclonal antibody, has been shown to have good efficacy and tolerability in treating various neurological diseases, including MS39 . In a 96-week multicentre randomized controlled trial, rituximab shows to be beneficial for young adults with multiple sclerosis and inflammatory lesions39 . A phase 2, double-blind, 48 week-trial also found that rituximab reduced inflammatory brain lesions in individuals with multiple sclerosis39 . In a 52-week phase 2 trial, MRI scans showed a reduction in lesions after patients received add-on rituximab therapy44 .

In terms of treatment satisfaction, individuals who undergo rituximab treatment also reported higher satisfaction than when they received injectable treatments43 , and increased patient satisfaction has been correlated with better treatment adherence43 . In a study on patient’s satisfaction for Rituximab, patients reported higher level of satisfaction when they switch from first line injection to Rituximab44 .


Daclizumab is a humanized monoclonal antibody that targets the interleukin 2 receptor alpha chain and can be used to treat multiple sclerosis in patients who have had an incomplete response to standard therapy38,45 . In comparison to IFN-B therapy, individuals who undergo treatment with Daclizumab have lower rates of relapse and new lesion formation42 . Daclizumab was found to stop the recurrence of multiple sclerosis in patients with relapsing-remitting multiple sclerosis, and in combination with other treatments, results in 78% reduction of new contrast-enhancing lesions40 . Alemtuzumab has been approved for treating multiple sclerosis in more than sixty-five countries43 .


Alemtuzumab targets CD52 resulting in B and T cell depletion48 . In three open trials, one Phase II trial and two-phase III trials, alemtuzumab has been shown to reduce the relapse rate, reduce the risk of and reverse disability, and improve radiological markers in individuals with multiple sclerosis43 . According to clinical and laboratory data from investigators-led studies in Cambridge, most patients who received alemtuzumab treatment only require two cycles of alemtuzumab46 . Therefore, the data show that the effectiveness of alemtuzumab is sustained over a long period of time46 . A Pathology-monitoring system has been developed to help patients who undergo monoclonal antibody treatment, Alemtuzumab, monitor the side effects of the treatment. The results from the system show high compliance of 96.7% and faster alerts of abnormalities than standard visits to neurologists43 .


Monoclonal antibody treatment for Parkinson

Monoclonal antibody treatment has been shown to also be effective in treating Parkinson's Disease41 . PRX002/RG7935 (PRX002), a humanized monoclonal antibody, is effective in slowing down the rate of progression of Parkinson's Disease by targeting the formation of alpha-synuclein by blocking the transmission of alpha-synuclein41 PRX002 has been tested in an in-human trial and is shown to be safe and well-tolerated44 . BIIB054 is another humanized monoclonal antibody that targets the alpha-synuclein47 . According to a study on dose selection of BIIBO54 in treating patients with Parkinson’s Disease, an effective dose of BIIBO54 can reduce the unbound alpha-synuclein in the brain48 .


Monoclonal antibody treatment for metastatic melanoma of the brain

Brain metastases can be treated with monoclonal antibodies such as nivolumab and ipilimumab43 . Pembrolizumab can be used to treat patients with lung and brain metastases49,50,51. Lambrolizumab is an anti-programmed death 1 receptor antibody that can be used to treat patients with brain melanoma52 . One study on the safety and tumor response of lambrolizumab treatment found that patients with melanoma have a high response rate of up to 52% 52 . Ipilimumab can also be used to treat patients with metastasis in the brain53 . Ipilimumab is a humanized monoclonal antibody that binds to Cytotoxic T lymphocyte Antigen 4 and inhibits the immune checkpoint during the process of cancer growth53 . In a study on the effectiveness of ipilimumab on pediatric patients with metastasis in the brain, pediatric patients were able to tolerate up to 3mg/kg of the antibody54 .


Monoclonal antibody treatment for Alzheimer

Monoclonal antibodies are under research and development to treat Alzheimer55 . Aducanumab is one of the monoclonal antibodies that have been under research to treat Alzheimer56 . Aducanumab can target the aggregated forms of amyloid B and reduce amyloid B plagues56 . Research on treatment of Aducanumab on patients with mild AD has found that aducanumab can reduce the amount of amyloid B when deliver on a monthly basis for a year56 . Therefore, more research should be done on MA with similar mechanism to Aducanumab to treat AD.


Single-chain fragment variable antibody treatment for chronic pain

Single-chain fragment variable antibody treatment, which has similar binding act

Single-chain fragment variable antibody treatment, which has similar binding activities as monoclonal antibody treatment, can be used to reduce pain in individuals with neurological conditions57 .

Single-chain fragment variable antibody treatment has been a focus of research as it has the potential to replace opioid and addictive treatments for individuals with chronic pain57 . Tanezumab is a humanized MA that can be also used to control chronic pain in patients with osteoarthritis58 . Tanezumab helps control pain by inhibiting nerve growth factors from binding to pain receptors59 . Because of its ability to improve pain, tanezumab can be used to treat conditions other than osteoarthritis, such as lower back pain59 . As a result, MA with similar mechanism to tanezumab can be used to treat pain that are caused by neurological disorders59 .


Blood-Brain Barrier:

The BBB is a selectively semipermeable membrane that plays a critical role in the protection of the CNS60 . The BBB is composed of endothelial cells that line the inside of the capillaries via tight junctions to form a physical barrier between the CNS and the systemic circulation60,61 . This allows the BBB to prevent the entrance of disease-causing pathogens, foreign particles, hydrophilic molecules, neurotoxins, and solutes from the systemic circulation into the cerebral spinal fluid (CSF) that fills the extracellular space of the brain parenchyma60,61,62 .


The BBB is composed of three layers of tissue each having a highly specified role in the protection of CNS61,63,64.The outermost layer is formed by the joining of endothelial cells through a tight junction in the walls of capillaries61,63 . This is where the largest control of exchange between the blood and the CNS occurs61,63 .The second layer is known as the blood-cerebrospinal fluid barrier (BCSFB)61,63 . This layer is formed by the epithelial cells located in the choroid plexus and it regulates the secretion of Cerebrospinal fluid (CSF) into the cerebral ventricular system61,63 .

Lastly, the innermost layer of the barrier is the arachnoid epithelial layer formed between the blood and the subarachnoid CSF61,63 . These three layers act as a physical, metabolic, and chemical barrier that control and protect the CNS from foreign particles and pathogens64 .


Disturbances to the BBB can occur due to various factors, such as aging and oxidative stress, and these factors have been shown to increase the prevalence of neurodegenerative diseases such as AD62,65 . This is because the breakdown of BBB weakens the regulation system and control checks, allowing neuro-toxic particles, blood debris, pathogens, etc. to enter the CNS leading to neurodegeneration65 .


Effect of aging on the blood-brain barrier:

Aging has shown to be a high-risk factor in the development of Alzheimer’s disease due to structural and functional changes of the BBB that comes upon during the aging process66,67 . The elderly population from various countries, and cultural and racial backgrounds, have shown a prevalence rate of 5-7% for developing AD68 . While aging does not directly lead to the development of AD, it is the loss and weakening of the BBB anatomy, its regulatory control, transport pathways, and functionality that increases one’s chances of being affected by this disease66,67 .


Thinning of the endothelial cytoplasm contributes to the thinning of white matter and this progresses as individual ages69 . This decline in the functionality of the white matter is seen at a higher rate in individuals that have been diagnosed with AD69 . Furthermore, the expression of low-density lipoprotein receptor-related protein (LRP-1), the receptor that is responsible for Amyloid B efflux, decreases with age, and decreased efflux is correlated with amyloid B peptide accumulation in the brain67 . The decreased clearance rate of toxins and amyloid-beta plaque buildup is further exacerbated due to age-dependent weakening of the blood-brain barrier66, 67, 69 .


Monoclonal antibodies:

The immune system produces highly specific antibodies that detect, bind, and attack pathogens that are toxic to the body to prevent the development of diseases or to cure existing ones70,71 . However, such highly specific antibodies can also be created in a lab and injected into an individual’s body to target and destroy disease-causing cells and proteins, called monoclonal antibodies (MAs)71 . Hence, MAs are used as therapeutic agents and have shown promise in treating and reducing symptoms of several diseases such as cancer, Parkinson’s’, and other neurodegenerative diseases such as Alzheimer’s 71 .


Monoclonal antibodies are highly specific for their respective and are created from cloning particles that are made by exposing the viral protein to human plasma cells72 . Upon binding to the targeted disease-causing cell, these then activate and use the individual’s own immune response to start a downward cascade of response72 . These have shown clinical and medical use for the treatment in cancer, Parkinson’s disease, and Alzheimer’s among many others.


Crossing the Blood-brain barrier:

Intracellular transport:

One of the trafficking methods between the outermost layer of BBB and the systemic circulation system is conducted via intracellular transport73,74 . Most substances that cross the BBB, such as neuropathic microorganisms, gain entry via two manners: receptor-mediated transcytosis (RMT) and adsorptive-mediated transcytosis (AMT)73,74,75 . During RMT, macromolecule ligands such as peptides and proteins bind to selective receptors on the cell surface and trigger a downstream cascade of events73,74,75 . In this manner, selective molecules can transport across the endothelial layer and make their way to the interstitial side of the CNS73,74,75 . During AMT, on the other hand, molecules such as peptides, microorganisms, and proteins can cross the BBB through charged interaction between the negatively charged outer membrane of BBB and the positively charged lipids, ligands, polymers, and nanoparticles75 .

RMT has been the mechanism of choice for many drugs and medications to enter the CNS through the BBB73,75 . Furthermore, RMT has been used to transport MAs that are used as therapeutic drug treatment for numerous diseases in a trojan-horse-type manner of transport73 . This has been seen for insulin treatment through insulin receptor, for transferrin through transferrin receptor, and for the entry of medication targeting low-density lipoprotein receptor-related protein 1 and 2 73,74,76.


Delivery of Monoclonal antibody via receptor-mediated transport:

MAs can cross the BBB via the trojan horse method via RMT77 . This increases the success of drug delivery to the targeted area since MAs are designed to target one specific disease-causing cell77 . Furthermore, one of the concerns with the use of MAs for targeting neurodegenerative disease-causing cells is crossing the BBB, and trojan horse via RMT allows these to cross over the BBB77 .

When MAs are created to cross the BBB via RMT, they are linked with a drug linker that binds to a cell receptor on the outermost layer of the BBB77 . Once the receptor recognizes the linker ligand, the entire receptor-ligand complex undergoes endocytosis and crosses the BBB77 . Once crossed, the drug linker and the MA complex are degraded, and the drug linker and the receptor are recycled back to the surface while the MA is able to travel to their targeted location77 . Through this method, MAs can pass through the highly selective BBB membrane and target disease-causing cells that contribute to the development of neurodegenerative diseases such as AD and Parkinson’s 77 .


Paracellular transport:

Through the paracellular transport pathway, microbes and mononuclear cells cross the endothelial layer of the BBB through the opening and closing of the tight junction complexes73,74 . This pathway is used at a significantly lower rate than the transcellular pathway for the active transport of foreign substances and drugs73,74 . It is mostly involved in the diffusion of polar solutes and proteins73 . Hence, serving a critical function in the integral regulation of the CNS through the BBB73 .



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