Proteomic profiling in anti-VEGF-treated AMD patients reveals VEGF-independent immune pathway activation.

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medRxiv Published April 14, 2026 Medically reviewed April 25, 2026 Study authors: Toral, M. A.; Ng, B.; Velez, G.; Yang, J.; Tsang, S. H.; Bassuk, A. G.; Mahajan, V. B. DOI ↗ By Dr. Lars van Dijk, PhD · Surgical, Procedural & Diagnostic

Key Takeaway

Note that VEGF-independent immune mechanisms may contribute to incomplete response in AMD, suggesting potential for combination therapies.

This observational study utilized proteomic profiling to investigate molecular pathways in patients with neovascular age-related macular degeneration (AMD) receiving anti-VEGF therapy. The cohort included eight anti-VEGF-treated AMD patients and six comparative controls. The primary objective was to identify VEGF-independent signaling pathways active within the vitreous, alongside secondary analyses of differential protein expression and drug-target relationships.

Analysis revealed 107 differentially expressed proteins with a p-value less than 0.05. Furthermore, significant activation was observed in pathways related to T-cell activation, interleukin signaling, and leukocyte-mediated cytotoxicity. Multiple components of the cytotoxic lymphocyte pathway were also found to be dysregulated. These findings indicate that immune signaling remains active despite anti-VEGF treatment.

Safety and tolerability data, including adverse events or discontinuations, were not reported. Key limitations include the small sample size of eight treated patients and the poorly understood molecular pathways underlying incomplete therapeutic response. The study does not establish causality, and the evidence remains preliminary due to the lack of reported follow-up and potential confounding factors inherent in observational designs.

Despite these constraints, the data provide a rationale for combination therapeutic strategies targeting both angiogenic and immune pathways in AMD. Clinicians should interpret these results cautiously, recognizing that VEGF-independent immune mechanisms may contribute to ongoing retinal damage and incomplete response, warranting further investigation before altering current management practices.

Study Details

Sample sizen = 8

EvidenceLevel 5

PublishedApr 2026

View Original Abstract ↓

PurposeAnti-vascular endothelial growth factor (anti-VEGF) therapy is the standard of care for neovascular age-related macular degeneration (AMD), yet many patients exhibit persistent retinal degeneration, fibrosis, and incomplete therapeutic response. The molecular pathways underlying this incomplete response remain poorly understood. We sought to identify VEGF-independent signaling pathways active in the vitreous of anti-VEGF-treated AMD patients. MethodsWe performed multiplex antibody-based proteomic profiling of 1,000 human proteins in vitreous samples from patients with neovascular AMD receiving anti-VEGF therapy (n=8) and comparative controls (n=6). Differential protein expression was assessed using one-way ANOVA, followed by gene ontology and pathway enrichment analyses. Drug-target relationships were evaluated to identify potential opportunities for therapeutic repositioning. ResultsWe identified 107 differentially expressed proteins (p<0.05), including key regulators of immune signaling, angiogenesis, and metabolism. Notably, multiple components of cytotoxic lymphocyte pathways were dysregulated, including IL-21R, SIGLEC-7, CTLA4, and IL-2-associated signaling. Enrichment analyses revealed significant activation of pathways related to T-cell activation, interleukin signaling, and leukocyte-mediated cytotoxicity. These immune signatures persisted despite suppression of VEGF signaling. Several clinically available immunomodulatory agents--including abatacept, sirolimus, and dupilumab--targeted pathways identified in this dataset. ConclusionsAnti-VEGF-treated neovascular AMD exhibits persistent cytotoxic immune signaling in the vitreous, suggesting that VEGF-independent immune mechanisms may contribute to ongoing retinal damage and incomplete therapeutic response. These findings provide a rationale for combination therapeutic strategies targeting both angiogenic and immune pathways in AMD.