Enhancing protective microglia activities with a dual function TREM2 antibody to the stalk region

Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease associated microglia state. To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by ADAM (A Disintegrin And Metalloproteinase; i.e. alpha-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for alpha-secretase mediated shedding. Monoclonal antibody 4D9 which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho-SYK signaling. 4D9 stimulated survival of macrophages, and increased microglial uptake of myelin debris and amyloid beta-peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9 bound. Moreover, in a mouse model for Alzheimer's disease related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression and reduced a homeostatic marker, suggesting a protective function by driving microglia towards a disease-associated state.