ArticleJournal of immunotherapy (Hagerstown, Md. : 1997)2026
Internalization-Dependent EGFR-Targeted Photoactivation by Cetuximab-I21 Conjugates.
Article in Journal of immunotherapy (Hagerstown, Md. : 1997), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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7 authors.
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Abstract
Photosensitizer-based antibody conjugates can provide tumor-selective phototoxicity by combining receptor-mediated targeting with local light activation. IR700-based near-infrared photoimmunotherapy represents the clinical benchmark for this strategy; however, photosensitizers with alternative cellular trafficking and phototoxic mechanisms remain of interest. We developed and characterized 2 cetuximab-I21 conjugates, cetuximab-I21-2 and cetuximab-I21-3, targeting epidermal growth factor receptor (EGFR)-expressing tumors. The chemical structures and key photophysical properties of the I21 payload-linkers are disclosed in this revision. Both conjugates achieved a drug-to-antibody ratio of 8 and demonstrated strictly light-dependent cytotoxicity in EGFR-positive cells, with IC 50 values of 0.051-1.093 μg/mL in A431 cells and no detectable dark toxicity. EGFR-low cells showed >400-fold reduced sensitivity, supporting receptor-dependent selectivity. Mechanistic studies revealed receptor-mediated internalization and endolysosomal trafficking, with peak lysosomal colocalization at 3 hours (Pearson r =0.81), followed by mitochondrial membrane depolarization and dose-dependent apoptosis-associated cell death. In vivo fluorescence imaging demonstrated tumor-selective accumulation with sustained retention through 96 hours. In A431 xenografts, cetuximab-I21-3 with triple irradiation (200 J/cm 2 ×3) achieved 50.42% tumor growth inhibition ( P =0.0002). These findings establish cetuximab-I21 as a light-activated, EGFR-targeted antibody-photosensitizer conjugate with a mechanism distinct from that of canonical IR700-based NIR-PIT. Direct IR700 comparison, immune activation studies, photosafety evaluation, and light-dose optimization will be required to define its translational potential.
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