Tetravalent TREM2 agonist antibody for Alzheimer's

An engineered tetravalent, brain-penetrant TREM2 agonist antibody could help treat Alzheimer's. Screening of a phage-displayed human single chain variable fragment (scFv) library for binding to the mouse TREM2 extracellular domain, followed by screening for TREM2 binding on cell surfaces, lack of competition with the receptor's endogenous ligands, and activation of signaling downstream of TREM2 identified an antibody that increased TREM2 signaling in a reporter assay and lipid phagocytosis in mouse microglial cell cultures with EC50s of 79.4 nM and 405.2 nM, respectively; this antibody was engineered into a tetra-variable domain Ig format, which increased TREM2 signaling with an IC50 of 0.42 nM, and the tetravalent construct was fused to an antibody targeting the transferrin receptor to facilitate blood-brain-barrier crossing.

In a genetic mouse model of Alzheimer's, the antibody decreased overall plaque intensity, number, and size in the brain; decreased neuronal loss, tau hyperphosphorylation, and axonal damage; and improved hippocampus-dependent contextual memory, compared with constructs that targeted either TREM2 or the transferrin receptor alone...