Structural Chemistry & Crystallography Communication

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.