Objective:

To examine the impact of the anti-human TREM2 agonistic mAb VHB937 in vitro and in vivo in models for neurodegenerative diseases.

Background:

TREM2 is an activating receptor expressed in microglia. Activation of TREM2 is crucial for homeostatic microglia to adopt the disease associated microglia phenotype which is a physiological response to restore homeostasis. This process might be impaired in chronic neurodegenerative diseases which is also observed genetically with TREM2 hypomorphic variants. TREM2 activation has been shown to affect microglial responsiveness.

Design/Methods:

VHB937 was profiled in vitro in human primary cells with endogenous TREM2 expression and in vivo in mechanistic animal models for neurodegenerative diseases.

Results:

VHB937 is a fully human mAb that activates selectively TREM2 in human M2A macrophages and human iPS microglia cells with sub-nanomolar affinities and increases TREM2 cell surface expression by reduction of shedding. Intracellularly, the antibody increases Syk-phosphorylation and drives calcium signaling. VHB937 facilitates key functions of microglia cells like chemotaxis and phagocytosis in vitro. In vivo, VHB937 displayed efficacy in a broad range of animal models that recapitulate pathological features of neurodegenerative diseases (both in toxin induced or transgenic animal models). The neuroprotective phenotype that emerged in microglia in vivo after VHB937 treatment promoted neuronal health (reduction of dystrophic neurites) and ameliorated astrogliosis, indicating promising efficacy beyond microglia. In line with this neuroprotective activity, a treatment dependent reduction of pro-inflammatory markers was observed both in vitro and in vivo. Thus, this mechanism could delay progression in neurodegenerative conditions in humans.

Conclusions:

The current pre-clinical profile of VHB937 supports further development in different neurodegenerative conditions.