Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β

Abstract

Aducanumab, a human-derived antibody targeting amyloid-β (Aβ), is in Phase 3 clinical trials for the treatment of Alzheimer’s disease. Biochemical and structural analyses show that aducanumab binds a linear epitope formed by amino acids 3–7 of the Aβ peptide. Aducanumab discriminates between monomers and oligomeric or fibrillar aggregates based on weak monovalent affinity, fast binding kinetics and strong avidity for epitope-rich aggregates. Direct comparative studies with analogs of gantenerumab, bapineuzumab and solanezumab demonstrate clear differentiation in the binding properties of these antibodies. The crystal structure of the Fab fragment of aducanumab bound to its epitope peptide reveals that aducanumab binds to the N terminus of Aβ in an extended conformation, distinct from those seen in structures with other antibodies that target this immunodominant epitope. Aducanumab recognizes a compact epitope that sits in a shallow pocket on the antibody surface. In silico analyses suggest that aducanumab interacts weakly with the Aβ monomer and may accommodate a variety of peptide conformations, further supporting its selectivity for Aβ aggregates. Our studies provide a structural rationale for the low affinity of aducanumab for non-pathogenic monomers and its greater selectivity for aggregated forms than is seen for other Aβ-targeting antibodies.

Discovery of conformation-sensitive anti-amyloid protofibril monoclonal antibodies using an engineered chaperone-like amyloid-binding protein

“…Our results indicate that, despite binding to the N-terminal Aβ peptide, both mAbs preferentially bind to protofibrils over monomers. The solution competition ELISA displays comparable results to that reported for aducanumab [48]. When conformation reactivity is measured by SPR, the mAbs-monomer binding is followed by an almost complete dissociation curve (Fig 3E, F), but the mAbsprotofibril association seems to be extremely strong and resistant to spontaneous dissociation ( Fig 3G, H).…”

“…Based on the knowledge that aducanumab is a high-affinity, conformation-selective anti-Aβ protofibril mAb that has reactivity against residues 3-6 on Aβ [47,48], we selected from the secondary screen five antibodies that showed N-terminus binding: two antibodies with the lowest and highest binding signal, 1A8 and 7C8, respectively, and three antibodies with an intermediate binding signal (1D9, 1E7, and 6G2). These five antibodies were sequenced, subcloned and re-tested for their conformation-selectivity by sandwich ELISA.…”

Antibodies to watch in 2020

“…Aducanumab binds a linear epitope formed by amino acids 3-7 of the Aβ peptide and discriminates between monomers and oligomeric or fibrillar aggregates based on weak monovalent affinity, fast binding kinetics and strong avidity for epitope-rich aggregates. 75 In August 2016 aducanumab was accepted into EMA's PRIME program. In September 2016 the FDA granted aducanumab Fast Track designation, and in April 2017 aducanumab was accepted into MHLW's Sakigake Designation System.…”

Nature-inspired design and evolution of anti-amyloid antibodies

“…All three of these mAbs display high affinity for A␤ fibrils. However, aducanumab displays unusually low affinity for disaggregated A␤ (EC 50 Ͼ1 M) (50, 51), whereas bapineuzumab displays high affinity for disaggregated A␤ (EC 50 of 4.4 nM; gantenerumab displays intermediate behavior) (50,52,53).…”