#alzheimer #abeta #crenezumab #ADPD
Abstract: 044
CRENEZUMAB’S PREFERENTIAL BINDING OF OLIGOMERIC AMYLOID-BETA SPECIES UNDERLIES ITS UNIQUE MECHANISM OF ACTION
Aims
To better understand crenezumab’s mode of action by investigating the binding of crenezumab to various amyloid-beta (Abeta) species both in vitro and in vivo.
Method
We investigated the binding of crenezumab to: monomeric and soluble oligomeric Abeta using surface plasmon resonance (SPR), fibrillar Abeta by immunogold negative staining transmission electron microscopy, and amyloid plaques by immunohistochemistry. We used x-ray crystallography to determine the molecular structure of the crenezumab Fab:Abeta complex.
Results
Using SPR, we found that crenezumab binds with ~10-fold greater affinity to oligomeric Abeta compared with monomeric Abeta. Crenezumab also shows binding to Abeta fibrils by electron microscopy. Crenezumab is able to recognize amyloid plaques in brain tissue sections, and shows low levels of binding to plaques in vivo following dosing in human amyloid precursor protein (hAPP) transgenic mice. The crystal structure of crenezumab Fab with an Abeta peptide reveals a well-defined contiguous epitope His13Abeta - Val24Abeta in an extended conformation.
Conclusion
Our results suggest that the preferential species for crenezumab binding is Abeta oligomers, widely considered a highly neurotoxic species. The binding studies confirm crenezumab’s ability to bind multiple forms of Abeta (monomers, oligomers, fibrils, and plaques) and the crystal structure reveals antibody binding that is consistent with the ability to bind Abeta across different aggregation states. Crenezumab’s preferential binding to Abeta oligomers supports the clinical rationale for crenezumab as an antibody-targeting toxic, oligomeric Abeta species in Alzheimer’s disease.
