In contrast to larger amyloid plaques,
soluble, oligomeric forms of Abeta are considered to be the most neurotoxic species. Crenezumab binds multiple forms of Abeta (i.e.,
monomers, oligomers, fibrils and plaques) with a binding preference for this oligomeric Abeta.
Figure 9: Binding
profile of crenezumab
Ref: Ultsch, et. Al., Sci Rep, Supp Info
2016; Atwal et. Al. ADPD 2017
In the figure above, crenezumab binds with
~10x higher affinity to oligomeric Abeta over monomers. Crenezumab’s binding affinity to monomeric (A) and oligomeric (B)
Abeta was assessed using surface plasmon resonance (SPR). Representative sensorgrams are shown. The full-length crenezumab IgG4
exhibited a KD in the range of 3.0–5.0 nM to Abeta monomers and 0.4-0.6 nM to Abeta oligomers, demonstrating a strong preference
for oligomeric Abeta.
Oligomeric forms of Abeta are believed
to be principally responsible for neurotoxicity in AD. Amyloid plaques occurring in all AD cases are in equilibrium with soluble
oligomers of Abeta. These can activate microglia and injure neurons including by inducing Tau positive neurites and tangles.
10: Reduction of oligomers in CSF by crenezumab: crenezumab’s binding affinities and translation into clinical benefits (data
from Phase 2)
Ref: Yang et. al. presentation at AAIC