Objective:

To characterize VGL101 as a high-affinity human TREM2 (hTREM2) agonistic monoclonal antibody and determine its capacity as a potential compensatory pharmacological approach to therapeutically circumvent colony-stimulating factor-1 receptor (CSF1R) dysfunction, which underlies the pathophysiology of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

Background:

Microglial dysregulation is broadly implicated in multiple neurodegenerative disorders and is directly causal for ALSP, a rare autosomal dominant CSF1R-related leukoencephalopathy associated with cardinal neuropathological features such as microglial loss, astrogliosis, and rapidly progressive neurodegeneration, leading to an average survival time of 6-8 years from diagnosis. Mechanistically, TREM2 and CSF1R share common microglial enrichment functions in CNS, converge on a shared intracellular signaling axis, play key roles in microglial survival, and are both established modifiers of neurodegenerative disease based on human genetic studies.

Design/Methods:

VGL101 effects on intracellular signaling were assessed in multiple cell-based systems to characterize TREM2-specific agonist pharmacology. To assess functional activity, human monocyte-derived macrophages (hMDMs) and stem cell‒derived microglia (iMGLs) were utilized to model ALSP via CSF1R ligand withdrawal, pharmacological inhibition of CSF1R activity, and heterozygous knock-in of CSF1R^I794T. VGL101 effects were also assessed via unbiased gene expression and multiplex chemokine arrays, comparing cortical responses in hTREM2 versus TREM2 knockout mice.

Results:

VGL101 demonstrated specific and potent activation of downstream hTREM2 signaling. Functionally, VGL101 protected hMDMs and iMGLs from CSF1R loss-of-function, preventing microglial degeneration and preserving microglial morphology. In iMGLs harboring the risk mutant CSF1R^I794T, VGL101 similarly improved key hallmarks otherwise associated with ALSP pathology. Furthermore, transcriptomic profiling and pathway analysis in mice confirmed VGL101-induced, TREM2-dependent pharmacological activity, supporting the promising in vivo pharmacological profile for VGL101.

Conclusions:

These findings demonstrate VGL101 is a potent and selective TREM2 agonistic antibody, align with the hypothesis that TREM2 activation can compensate for CSF1R dysfunction, and support continued clinical development of VGL101 for the treatment of patients with ALSP.