Selection and structural characterisation of anti-TREM2 scFvs that reduce levels of shed ectodomain

Abstract

Single point mutations in TREM2, a receptor expressed by microglia in the brain, are associated with an increased risk of neurodegeneration including Alzheimer's disease. Numerous studies support a role for TREM2 in sensing damaging stimuli and triggering signalling cascades necessary for neuroprotection. Despite its significant role, ligands and regulators of TREM2 activation, and the mechanisms governing TREM2-dependent responses and its cleavage from the membrane, remain poorly characterised. Here, we present phage display generated scFv antibody binders to human TREM2 ectodomain. Co-crystal structures revealed the binding of two scFvs to an epitope on the globular TREM2 domain distal to the putative ligand-binding site. Enhanced functional activity was observed for oligomeric scFv species which inhibited the production of soluble TREM2 in a HEK293 cell model. We hope that detailed characterisation of their epitopes and properties will facilitate the use of these renewable binders as structural and functional biology tools for TREM2 research.

Decoding sTREM2: its impact on Alzheimer’s disease – a comprehensive review of mechanisms and implications

“…The precise mechanisms through which sTREM2 shedding influences TREM2 receptor signaling and the inherent functions of sTREM2 remain somewhat enigmatic. It has been observed that stabilizing TREM2 on the cellular membrane with antibodies to hinder its proteolytic shedding by sTREM2 enhances not only downstream TREM2 signaling but also critical functions of the receptor, such as the phagocytic activity of microglial cells (Schlepckow et al, 2020;Szykowska et al, 2021). This observation suggests that the detachment of TREM2 from the membrane, facilitated by ADAM metalloprotease activity leading to sTREM2 production, might play a regulatory role in attenuating TREM2 receptor signaling.…”