Nasal administration of Protollin enhances monocyte phagocytosis and decreases CD8+ T cell cytotoxicity in subjects with early Alzheimer’s disease: a Phase 1 clinical trial

ABSTRACT Protollin, a nasal adjuvant, was evaluated in a randomized double-blind phase 1 study of 16 early Alzheimer’s disease (AD) patients to determine safety and to assess its immunomodulatory effects. In a double-blind dose escalation study, subjects received nasal Protollin at doses of 0.1mg, 0.5mg, 1.0mg, and 1.5mg or placebo twice over a two-week period. Treatment was well-tolerated with minimal side effects. Transcriptomic and single-cell analyses demonstrated that prior to treatment, AD blood monocytes had downregulation of phagocytosis-related genes and an increased pro-inflammatory signature. These AD monocyte abnormalities were reversed by nasal Protollin beginning at a dose of 1.0mg. Protollin induced a robust phagocytic gene signature, including upregulation of CD36 , ITGAL , LYST , and FCGR1A . A similar phagocytic signature was observed in brain- infiltrating amyloid-clearing monocytes in an APP Tg mouse model treated with nasal Protollin. Protollin treatment decreased the expression of costimulatory molecules on monocytes and decreased CD8+ T cell activation and cytotoxicity. Our results provide the basis for a phase 2 study of nasal Protollin in subjects with AD in which nasal Protollin at a dose of 1.0 mg will be administered weekly over 6 months to modulate peripheral immunity and clear amyloid from the brain. ClinicalTrials.gov registration no NCT07187141 .