Avidity-based Antibody Therapy for Alzheimer’s
In certain cases, an antibody, the principal effector of the immune system, can interact only weakly with the monomeric form of a molecule that is essential for normal physiological activities of the cell, but quite strongly with the pathogenic oligomeric form of the same molecule. This property has been successfully utilized in the development of some antibodies as biotherapeutic drugs for diseases such as Alzheimer’s.
Alzheimer’s disease (AD), a late-stage neurodegenerative disorder, is the fifth leading cause of death worldwide, affecting more that 50 million people. It is caused by both genetic and environmental factors. Although the pathogenesis of the disease is still not entirely clear, it is currently understood that the accumulation of toxic amyloid beta-protein, A(beta) in the central nervous system (CNS) is the main cause.
Molecular basis of Alzheimer’s
The A(beta) peptide is the proteolytic cleavage product of the transmembrane amyloid precursor protein (APP) – the two principal forms are A(beta)1-40 and A(beta)1-42. The peptide is mostly a helical but unstructured at the N-terminus between amino acid residues 1 and 14.
Normal physiological activities of the CNS, such as intracellular signaling, require Ab. Nevertheless, extracellular abnormalities lead to the accumulation of the peptide forming a structure rich in b sheet. Oligomerization of the monomers into fibrils results in the formation of pathogenic amyloid plaque.
Anti-A(beta) antibodies
AD has been subject to passive immunotherapy using anti- Ab antibodies (Ab’s). Two functions of an antibody molecule are responsible for immune response – the ability to bind specifically to its target antigen (Ag) and recruit other cells and molecules to encounter the bound Ag. Evidently, there must be sites on both the Ab and Ag to bind to each other. The binding site on the Ag is called the epitope while that on the Ab is called the paratope.
An Ab molecule consists of two identical heavy (H) chain and two identical light (L) chains. The four chains are held together by disulfide bonds to form a Y-shaped structure. The most commonly used antibody is IgG, which can be cleaved into three parts – two Fab’s and one Fc – by the proteolytic enzyme papain.
Aducanumab approved for Alzheimer’s treatment
In June 2021, the U. S. Food and Drug Administration approved aducanumab (marketed as Aduhelm) developed by the pharmaceutical biotech company Biogen for the treatment of Alzheimer’s. It is a recombinant human antibody derived from a blood lymphocyte library collected from a healthy donor population.
Aducanumab Fab (AduFab) binds a linear epitope in the Ab peptide; the primary epitope residues that are in contact with AduFab are Glu3, Phe4 and His6. Different amino acid residues of the antibody are involved in hydrogen boding, Coulombic and hydrophobic interactions with the epitope. Yet, the affinity of aducanumab for the non-pathogenic monomer is low and its selectivity is far greater for the oligomeric or fibrillar forms of the peptide. This selectivity for the pathogenic aggregated form is possibly avidity-driven.
Affinity vs avidity: In physical chemistry or chemical physics, affinity typically means the strength of a single bond or interaction. For example, we can talk about the affinity between an antigen’s epitope and the antibody’s paratope at a single “isolated” binding site.
Avidity, on the other hand, is defined as the accumulated binding strength of multiple affinities contributed by individual noncovalent interactions. Evidently, avidity is dependent on the valency (the number of binding sites) and the structural arrangement of the interacting molecules (in the present case, the antigen and antibody).
Antibodies contain between two and ten binding sites. The selectivity of aducanumab can be understood based on its bivalence and repeated binding to species (oligomeric or fibrillar aggregates) with high density of available epitopes.
References:
Arndt, J.W. et al. 2018. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-b. Sci Rep 8: 6412.
Ostindie, S. C. et al. 2022. Avidity in antibody effector functions and biotherapeutic drug design. Nat Rev Drug Discovery 21:715-735.
* The structural basis of immune response has been discussed in Fundamentals of Molecular Structural Biology (Section 16.2, Elsevier publication, 2019)