STRUCTURAL BASIS OF UNIQUE SELECTIVITY OF ADUCANUMAB FOR OLIGOMERIC FORMS OF AMYLOID-β

Abstract

There has been a renewed interest in immunotherapy targeting Aβ peptide for treatment of Alzheimer’s disease (AD) with the intriguing Phase 1b findings showing aducanumab significantly reduces amyloid in patients’ brains. Hypotheses being investigated for positive clinical data are the preferred epitope and selectivity for toxic Aβ aggregates. Aducanumab (BIIB037) is a human monoclonal antibody derived from a healthy donor cohort of elderly subjects lacking signs of cognitive impairment, which is in advanced clinical testing for treatment of AD. Aducanumab is unique among amyloid-targeted antibodies for its exquisite selectivity for both soluble oligomeric and insoluble fibrillar aggregates of Aβ found in brain β-amyloid plaques. To gain further insight into the epitope conformation and selectivity for Aβ aggregates, we investigated the structural details of amino-terminal epitope in Aβ using X-ray crystallography of aducanumab Fab:Aβ complex. Biochemical validation of critical interface residues was confirmed using standard ELISA and PepSpot binding assays. Here we report the crystal structure of a recombinant Fab fragment of aducanumab in complex with Aβ1-11 peptide solved at 2.5Å resolution. The N-terminus of Aβ is bound to aducanumab in an extended conformation with the binding interface composed primarily of Phe 4 and His 6 of Aβ. Comparison with other N-terminal Aβ targeting antibodies reveals that aducanumab has an exceptionally compact epitope, which contributes to its selectivity and high avidity for Aβ oligomers and fibrils, including aggregates composed of N-truncated Aβ variants, without targeting physiologic Aβ monomers. In silico Rosetta-based interface and antibody–flexible Aβ docking analysis further highlight aducanumab’s distinct biophysical interaction with the Aβ monomer that further corroborates its selectivity for Aβ oligomers. Aducanumab selectively targets pathologic Aβ conformations displayed by oligomeric and fibrillary aggregates. Our results provide the structural basis for this unique binding profile that differentiates aducanumab from other N-terminal specific antibodies, both in the conformation and orientation of the bound Aβ peptide, as well as the molecular details that comprise the antibody-peptide interface.