Aducanumab: An Amyloid-beta Targeted Antibody

Lauren Childs '24 and Isaac Johnson '24

Contents:

I. Introduction

Molecule:

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The current research for treating and mitigating Alzhiemer's disease focuses on immunotherapy, where the human body's natural defense system is utilized to fight against disease. Alzhiemer's is thought to be caused by an accumulation of the protein amyloid-beta (AB) in the brain. Therefore, the removal of this plaque could reduce the effects and slow the progression of Alzhiemer's, as well as even work to prevent its development.

The newest advancement in immunotherapeutic research against Alzhiemer's disease centers around the protein aducanumab. Aducanumab, an immunoglobulin G (IgG) antibody, is similar to previous antibodies studied for their targeting of amyloid-B (i.e. gantenerumab, bapineuzumab, solanezumab), but is also different in key ways. Namely, its weak monovalent affinity and strong aggregate avidity, which result in more plaque reduction than previous medications. 

II. General Structure

Aducanumab is classified as an immunoglobulin G (IgG) antibody, the most common subset of antibodies found in the blood, which aid in immune defense through a variety of mechanisms including triggering the complementary cascade and opsonization (when IgG-bound surfaces are recognized by phagocytic cells and digested).

Antibodies are visualized using a Y-shaped structure (Figure 1), where the two ends of the Y form the fragment-antigen binding (Fab) region containing the variable domain, and the stem comprises the constant domain. The variable domainsof antibodies are unique to each type and exhibit highly specific binding, while the constant domain is more conserved and serves a structural purpose rather than any binding sites.

Aducanumab contains four polypeptide chains, two and two , forming a molecule of 145912.34 g/mol. The two polypeptides are bound together through disulfide bonds. A is also present to neutralize charges from ions found in the blood. Without it, endogenous ions such as Na+ or Cl- would crowd around the protein and obstruct antigen binding. 

Ig fab

Figure 1. Anatomy of Ig fab protein. The fab region makes up the variable region and the constant region remains conserved across other amyloid-beta targeted antibodies. (UKessays, 2018)

III. AB Binding and Specificity

Aducanumab exhibits monovalent affinity, or affinity for only one epitope (antigen binding region) on amino acids 3-7 of the . This linear epitope is comprised of Glu3, Asp7, Phe4, His6, and Arg5, with Phe4 and His6 being the most crucial for binding. Residues further from the N terminus lack electron density, suggesting that these regions of AB lack an organized conformation. Twelve residues from aducanumab are within four angstroms of the AB peptide, forming 7 hydrogen bonds, one salt bridge, and several hydrophobic interactions.

These interfaces on aducanumab are defined as complementarity-determining regions (CDRs). The CDRs form a hydrophobic pocket in which Phe4 and His6 of AB are buried. This burying in the hydrophobic pocket accounts for most of the surface area shared between the antibody and the antigen, as well as contributing four out of the seven hydrogen bonds. AB binding does not induce any major conformational change; the change that does occur is constrained to CDR H3.

Other amyloid-beta antibodies have different, but overlapping, epitopes in amyloid-beta. A main distinction between antibodies is how deep AB binds in the binding cleft (in the case of aducanumab, the hydrophobic pocket is the binding cleft), and with what conformation it binds with. For example, aducanumab in fact contains a shallower binding cleft than past proteins, but this enables it to bind with a much greater diversity of AB conformations (Figure 2). This characteristic also leads to aducanumab depending on avidity more than affinity when binding to AB, resulting in greater efficiency when binding to AB aggregates, rather than monomers or oligomers. This proves to have fascinating implications when considering the nature of AB plaque degradation. 

AB conformations

Figure 2. Visual representation of Ig Fab proteins bound to possible AB conformations. (Arndt et al, 2018)

IV. AB Plaque and Mechanism of Degradation

Amyloid-beta accumulation in the brain develops from a variety of reasons brought on by aging. Interstitial fluid drainage pathways of the central nervous system can stiffen, similar to other vascular systems throughout the body. Another culprit is a transmembrane precursor protein (APP) which is highly expressed in the brain. The molecule has a complex degradation pathway and, when mutated, APP can turn into AB through proteolytic cleavage.

Amyloid-beta peptides bond together to form AB fibrils , which make up AB plaque. This causes inflammatory responses in the brain, as well as neurochemical responses including the phosphorylation and propagation of the tau protein. This leads to the formation of tau aggregates, which cause synaptic loss and the symptoms typically associated with Alzhiemer's disease.

Unlike previous antibodies, aducanumab exhibits much more binding with amyloid aggregates rather than monomers or oligomers, which tend to be more soluble. This allows aducanumab to target the macromolecules that are actually causing damage to the brain, rather than binding to the relatively harmless smaller AB peptides. After crossing the blood-brain barrier (BBB) and binding to AB plaque, FcY receptors recognize the plaque coated in aducanumab and signal to microglia cells to erode AB through phagocytosis. 

V. Current Applications and Controversy

Phase I of clinical trials for aducanumab began in 2012. Both phase I and phase II yielded promising results: the reduction of amyloid-beta plaque corresponded to an increase in aducanumab dosage. Phase III of clinical trials began in September 2015. In these two separate trials, aducanumab (or a placebo) was administered intravenously once a month in patients with mild cognitive impairment from Alzhiemer's.

Complications arose when one trial was trending positive (Figure 3) while the other showed no benefit between the placebo and aducanumab. Additionally, patients experienced adverse side effects including nausea (8% of patients), headache (47%), confusion (15%), cerebral hemorrhage (21%), and cerebral edema (31%). Cerebral edemas were discovered in patients on high dosages as well as patients carrying the apolipoprotein E (APOE) gene. Some sources reason that aducanumab was damaging the BBB during the receptor-mediated transcytosis, a process needed to go from the vascular system into the central nervous system.

This led to both trials being stopped prematurely by a review committee. However, Biogen, aducanumab's manufacturer, still applied for FDA approval in July of 2020, arguing that there was sufficient past evidence that showed the drug's efficacy in higher dosages. The application underwent accelerated review which included an evaluation by an outside advisory committee of 11 people. Ten of these individuals voted against approval, yet their guidance was overruled by FDA administrators and the drug was approved in June of 2021. Three members of the committee resigned in protest. Currently, aducanumab exists as an option for patients at an estimated $28,200 per year, with the cost varying depending on dosages. 

PET scan

Figure 3. Florbetapir positron emission tomography of reduced amyloid-beta plaque in Alzheimer's patients during phase III trials. Amyloid-beta plaque shown in red among patients treated with varying concentrations of aducanumab. (Sevigny et al, 2017)

VI. References

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