TREM2 agonist therapy represents a breakthrough immunomodulatory approach targeting the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) pathway to enhance microglial function across multiple neurodegenerative diseases. TREM2 is a cell surface receptor primarily expressed on microglia in the central nervous system and plays a critical role in modulating the brain's innate immune response. [1]
Loss-of-function variants in the TREM2 gene (such as R47H, R62H, R47H) significantly increase risk for Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, making TREM2 activation a promising therapeutic strategy across these conditions. [2]
TREM2 is a cell surface receptor on microglia that recognizes multiple ligands including amyloid-beta plaques, lipid particles, apolipoprotein E (apoE), and cellular debris. Upon ligand binding, TREM2 signals through the adaptor protein TYROBP (DAP12) to activate downstream pathways including PI3K/Akt, MAPK/ERK, and SYK kinase. This signaling drives critical microglial functions: [3]
The TREM2 agonist approach aims to bypass the need for functional TREM2 variants by delivering exogenous activation signals that restore or enhance microglial function. This is particularly important for patients with TREM2 risk variants who have reduced endogenous TREM2 signaling.
AL002 is a monoclonal antibody designed to activate TREM2 by binding to a distinct epitope that promotes receptor clustering and signaling. It represents the most advanced TREM2-targeting antibody in clinical development.
| Trial | Phase | Status | Population | Primary Endpoints |
|---|---|---|---|---|
| INVOKE-2 | Phase 2 | Recruiting | Mild-to-moderate AD | Amyloid PET, cognition |
| Phase 1 | Phase 1 | Completed | Healthy volunteers, AD | Safety, PK/PD |
The Phase 1 study demonstrated:
HL-85 (also known as H3B-10252) is a TREM2-targeting monoclonal antibody being developed by H3 Biomedicine (a subsidiary of Eisai) for neurodegenerative diseases.
HL-85 represents Eisai's entry into the TREM2 agonist space, leveraging their experience with lecanemab and other Alzheimer's therapeutics. The program aims to develop a TREM2 agonist with optimal brain penetration and dosing. [5]
| Agent | Company | Mechanism | Stage | Focus |
|---|---|---|---|---|
| AL002 | Alector/AbbVie | TREM2 agonist mAb | Phase 2 | AD |
| AL003 | Alector | TREM2 agonist mAb | Phase 1 | AD |
| HL-85 | H3 Biomedicine/Eisai | TREM2 agonist mAb | Preclinical | AD, PD |
| H3B-10252 | H3 Biomedicine | TREM2 mAb | Preclinical | AD |
TREM2 agonists have the strongest clinical evidence in Alzheimer's disease, where microglial dysfunction plays a central role in disease progression.
TREM2 is implicated in Parkinson's disease through its role in clearing alpha-synuclein aggregates and regulating neuroinflammation.
Corticobasal syndrome involves tau pathology and benefits from microglial modulation.
Progressive supranuclear palsy is a tauopathy that may benefit from TREM2 agonism.
Amyotrophic lateral sclerosis involves motor neuron degeneration with microglial involvement.
Frontotemporal dementia involves protein aggregates and neuroinflammation.
Huntington's disease involves mutant huntingtin protein aggregation and microglial activation.
Soluble TREM2 (sTREM2) in cerebrospinal fluid reflects TREM2 shedding and microglial activation.
Patients with TREM2 risk variants may particularly benefit from TREM2 agonism:
TREM2 agonists require the presence of pathological protein aggregates as ligands:
Similar to other antibody therapies targeting immune pathways:
TREM2 agonists may be combined with:
TREM2: A Microglial Receptor for Amyloid Clearance (Cell, 2020). 2020. ↩︎
TREM2 Variants and Neurodegeneration Risk (Nature Reviews Neurology, 2022). 2022. ↩︎
TREM2 Signaling in Microglial Function (Nature Neuroscience, 2021). 2021. ↩︎
AL002 Phase 1 Results (Alector Corporate Presentation, 2024). 2024. ↩︎