AL002

Cambodia origin cynomolgus monkeys (24 to 50 months old, male/female); naive female cynomolgus monkeys (2-3 kg)^[1]

20 mg/kg; 80 mg/kg; 250 mg/kg

i.v.; once weekly (5 doses for 4-week study; 3 doses for DRF study); once monthly (3 doses for interval study); 4-week recovery period for 250 mg/kg group

Dose-dependently decreased CSF sTREM2: 20 mg/kg caused a partial reduction, while 80 and 250 mg/kg caused >70% reduction compared with predose levels.\nDose-dependently reduced total TREM2 protein in brain tissues: 250 mg/kg significantly reduced TREM2 in frontal cortex (p < 0.001) and hippocampus (p < 0.0001); 80 mg/kg significantly reduced TREM2 in hippocampus (p < 0.001); 20 mg/kg showed a non-significant reduction trend.\nDose-dependently increased frontal cortex SPP1 mRNA expression: 80 and 250 mg/kg had significantly higher levels than controls (ps < 0.01).\nElevated CSF SPP1 protein levels: 80 and 250 mg/kg showed increases 48 hours after Day 1 dose; 250 mg/kg caused statistically significant increases 12 and 24 hours after each monthly dose; 80 mg/kg showed partial, non-significant increases after monthly doses.\nIncreased frontal cortex CSF1R mRNA and protein: 250 mg/kg had significantly elevated CSF1R mRNA and protein (p < 0.05) compared with controls; lower doses showed non-significant trends.\nElevated CSF IL1RN protein levels: 80 and 250 mg/kg had significantly higher levels 48 hours after Day 1 dose and 48 hours after Day 29 dose (ps < 0.0001).

BAC transgenic mice overexpressing human TREM2^[1]

50 mg/kg

single dose

Upregulated expression of Tyrobp (Dap12), Csf1r, and Gfap genes in frontal cortex.