AQP4 and MOG as definers of distinct autoantibody signatures in immune checkpoint inhibitor–induced optic neuritis.

12128 Background: Checkpoint blockade–induced optic neuritis (CBON) is a rare but vision-threatening immune-related adverse event with limited response to standard immunosuppression and no established diagnostic biomarkers. The humoral immune mechanisms underlying CBON remain poorly characterized, limiting early recognition and mechanistic understanding. Methods: We conducted a multicenter study integrating three independent CBON cohorts (n=25, 29, and 34) and 49 ICI-treated controls without neuro-ophthalmic complications, enrolled between January 2020 and June 2025. CBON cases were identified from a prospective biospecimen bank of >2,300 ICI-treated patients. Leveraging pre-ICI baseline, prodromal-phase, onset, and follow-up serum samples (>2,300 total samples), IgG autoantibodies against 25 neural surface antigens were assessed using cell-based assays. Longitudinal antibody dynamics and associations with clinical and oncologic features were evaluated. Results: Across 88 CBON patients, the autoantibody response was highly antigen-specific and dominated by aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG). AQP4-IgG or MOG-IgG was detected in 32–48% of CBON cases across cohorts, while paraneoplastic, synaptic, and other neural autoantibodies were rare (<12%). AQP4-IgG and MOG-IgG were largely mutually exclusive, suggesting distinct immunologic subtypes of CBON. These antibodies were virtually absent in ICI-treated controls (0–2%). Longitudinal analyses demonstrated consistent seronegativity prior to ICI exposure, followed by seroconversion at symptom onset with persistent antibody titers during follow-up despite corticosteroid therapy, consistent with a sustained humoral immune response. Autoantibody status showed limited and inconsistent associations with demographic, oncologic, or clinical characteristics. Conclusions: CBON is characterized by a distinct, antigen-specific humoral immune response targeting AQP4 or MOG that emerges following ICI exposure. These findings support an ICI-triggered breakdown of immune tolerance and establish a serologic framework for CBON diagnosis and classification. Incorporation of AQP4-IgG and MOG-IgG testing may aid early recognition and risk stratification of visual immune-related adverse events during immunotherapy.