Aflibercept Resistance in Neovascular Age-Related Macular Degeneration 9210

Abstract Description Neovascular age-related macular degeneration (nAMD) is a major cause of severe central vision loss among the elderly. Aflibercept, a recombinant fusion protein targeting the vascular endothelial growth factor family, is a key treatment of nAMD. However, 5-10% of the patients are poor responders with mechanisms remaining poorly understood. In this study, neutralizing anti-drug antibody (nADA) levels in plasma and aqueous humor (AH) were quantified by ELISA, and single-cell RNA sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) of 16 AMD patients treated with aflibercept. Among these patients, 8 were defined as good responders maintaining remission for over 2 years after treatment discontinuation under a PRN regimen. 8 were classified as poor responders showing relapse for more than 2 years on “treat and extend” therapy even with therapy intervals of or less than 10 weeks. ELISA results showed significantly elevated nADA levels in AH of poor responders, while plasma nADA levels showed no significant difference. ScRNA-seq analysis showed reduced naïve CD4+ T cell frequency in poor responders, suggesting that nADA production by B cells may result from preferential differentiation of naïve CD4+ T cells into effector cells. This study demonstrates an association between elevated nADA levels and poor aflibercept responses in nAMD patients. Furthermore, scRNA-seq analysis provides insight into potential causes of nADA generation in poor responders. Topic Categories Translational and Interventional Immunology (TI)