ATV:4D9

ATV:4D9 is a mouse-specific TREM2-activating antibody developed by Denali Therapeutics using their proprietary Antibody Transport Vehicle (ATV) technology. It consists of the 4D9 antibody, which targets the TREM2 stalk region, engineered onto a human IgG1 backbone containing LALA (Leu234Ala, Leu235Ala) mutations to minimize Fc-gamma receptor effector function. The antibody is further modified with a monovalent transferrin receptor (TfR) binding site in the Fc domain, enabling active transport across the blood-brain barrier (BBB) via receptor-mediated transcytosis. In preclinical models of Alzheimer's disease, ATV:4D9 demonstrates significantly enhanced brain exposure and microglial engagement compared to standard anti-TREM2 antibodies. It promotes microglial proliferation, enhances phagocytosis of myelin and amyloid-beta, and improves mitochondrial metabolism by boosting fatty acid and glucose oxidation. ATV:4D9 serves as a proof-of-concept surrogate for the human-specific clinical candidate ATV:TREM2 (DNL919).