Structural insights into Crenezumab′s mechanism of action

International Conference on Applied Crystallography
October 16-17, 2017 | Chicago, USA

Weiru Wang

Genentech, USA

ScientificTracks Abstracts: Struct Chem Crystallogr Commun

DOI: 10.21767/2470-9905-C1-002

Abstract

Crenezumab is a fully humanized immunoglobulin isotype G4 (IgG4) monoclonal antibody that binds to monomeric as well as aggregated A�?² forms (oligomers, fibers and plaques). Notably, crenezumab binds with higher affinity to A�?² oligomers over monomers and in vitro studies have demonstrated crenezumabâ�?�?s ability to block A�?² aggregation and promote A�?² disaggregation. To understand the structural basis for this activity and crenezumabâ�?�?s broad binding profile, we determined the crystal structure of crenezumab in complex with A�?². The structure reveals a sequential epitope and the conformational requirements for epitope recognition, which include a subtle but critical element that is likely the basis for crenezumabâ�?�?s versatile binding profile. We find interactions consistent with high affinity for multiple forms of A�?², particularly oligomers. Crenezumab also sequesters the hydrophobic core of A�?² and breaks an essential salt-bridge characteristic of the �?²-hairpin conformation, eliminating features characteristic of the basic organization in A�?² oligomers and fibrils, and explains crenezumabâ�?�?s inhibition of aggregation and promotion of disaggregation. These insights highlight crenezumabâ�?�?s unique mechanism of action, particularly regarding A�?² oligomers and provide a strong rationale for the evaluation of crenezumab as a potential treatment for patients with Alzheimerâ�?�?s disease.

Biography

Weiru Wang has completed his PhD in Biophysics from Cornell University and Post-doctoral studies from University of California, Berkeley. He is currently a Senior Scientist and a Group Leader in the Structural Biology Department at Genentech, a member of the Roche Group. His research focuses on understanding of molecular basis of protein-drug interactions using biophysical methods, primarily macromolecular crystallography.

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