A ligand-mimetic anti-TREM2 agonist antibody elevates soluble TREM2 and ameliorates pathology in mouse models of Alzheimer's disease and multiple sclerosis - PubMed
4 hours ago
- #TREM2
- #neurodegenerative diseases
- #microglia
- A ligand-mimetic anti-TREM2 agonist antibody, 03O05, was developed to activate TREM2 while preserving physiological shedding.
- 03O05 binds a conformational epitope within the immunoglobulin-like domain, distal from the cleavage site, and enhances phagocytosis.
- Treatment with 03O05 increased soluble TREM2 (sTREM2) levels in serum and brain of wild-type and human TREM2 knock-in mice.
- In 5xFAD mice, chronic 03O05 treatment elevated sTREM2, promoted clearance of filamentous Aβ plaques, and reduced microgliosis while enhancing microglial phagocytosis.
- In the cuprizone model, 03O05 enhanced microglial phagocytosis and promoted remyelination by reducing degraded myelin basic protein (MBP).
- Unlike traditional anti-TREM2 agonist antibodies, 03O05 preserves ectodomain shedding, leading to transient receptor activation and increased sTREM2 levels.
- This approach promotes a neuroprotective microglial phenotype without inducing neuroinflammation, reduces amyloid pathology and neuronal dystrophy, and supports remyelination in multiple sclerosis (MS).
- The findings suggest the therapeutic potential of shedding-permissive TREM2 agonism in neurodegenerative diseases like Alzheimer's disease and multiple sclerosis.