A comparative study of binding properties of gantenerumab and aducanumab analog to aggregated amyloid-beta (P6.087)

Objective: To evaluate the binding of gantenerumab and an aducanumab analog to synthetic amyloid-beta in vitro, and to parenchymal and vascular amyloid-beta deposits ex vivo and in vivo. Background: Different types of anti-amyloid-beta monoclonal antibodies are being developed as potential disease-modifying treatments for AD. Antibodies that recognize and clear aggregated forms of amyloid-beta plaques and oligomers are predicted to confer clinical benefit, as recently demonstrated in a proof-of-concept study of aducanumab. Gantenerumab is a fully human, dual-epitope-specific antibody with high affinity for aggregated amyloid-beta. Design/Methods: Gantenerumab and aducanumab analog were expressed in a human IgG1 format. Ex vivo binding to human parenchymal and vascular amyloid-beta deposits was assessed by immunofluorescence and quantitative image analysis on AD brain sections. Similarly, target engagement in vivo was investigated in PS2APP mice at single doses. In vitro binding to synthetic amyloid-beta monomers, oligomers and fibrils was measured by Biacore and immunoassays. Results: Both antibodies bound to human amyloid-beta deposits in an effective and comparable manner in vivo (PS2APP mice) and ex vivo (human AD brain). No obvious difference in binding to parenchymal plaques or vascular amyloid-beta deposits was observed. In vitro binding properties to synthetic amyloid-beta species will be presented. Conclusions: Gantenerumab and the aducanumab analog bind oligomeric and fibrillar forms of amyloid-beta. Preferential binding to parenchymal over vascular amyloid-beta is not observed for either antibody. These data suggest that both antibodies are equally effective at binding and clearing aggregated forms of amyloid-beta. Study Supported by: F. Hoffmann-La Roche Ltd Disclosure: Dr. Bohrmann has received personal compensation for activities with F. Hoffmann-La Roche Ltd as an employee. Dr. Oroszlan-Szovik has received personal compensation for activities with F. Hoffmann-La Roche Ltd as employee. Dr. Anquez has received personal compensation for activities with F. Hoffmann-La Roche Ltd. as an employee. Dr. Baumann has received personal compensation for activities with La Roche Ltd. as an employee. Dr. Kusznir has received personal compensation for activities with F. Hoffmann-La Roche Ltd. Full time employee of F. Hoffmann-La Roche Ltd,,,,,, Dr. Messer has received personal compensation for activities with F. Hoffmann-La Roche Ltd. as an employee. Dr. Huber has received personal compensation for activities with F. Hoffmann-La Roche Ltd as an employee. Dr. Niewoehner has received personal compensation for activities with Hoffmann-La Roche. Dr. Richter has received personal compensation for activities with F Hoffmann-LaRoche Ltd. as an employee. Dr. Tiefenthaler has received personal compensation for activities with F. Hoffmann-La Roche Ltd as an employee.