Activatable photoimmunotherapy enables spatiotemporal depletion of pathogenic cells in immune-driven disease and cancer.

Photoimmunotherapy (PIT) combines antibody specificity with light-activated cytotoxicity to enable precise, spatially, and temporally confined cell depletion. However, the leading clinical-stage PIT agent, cetuximab-IRDye700DX, can induce inflammation, swelling, and edema that may restrict its use to oncology, likely due to the activation of unbound conjugates in illuminated tissues and robust on-target tumor necrosis. To overcome these limitations, we introduce vertamax, a benzoporphyrin-based antibody-photosensitizer conjugate platform engineered to remain quenched until it is enzymatically activated within target cells, enabling more selective PIT. Vertamax-PIT demonstrates versatility across multiple antibody targets, including T cell (CD2 and CD5) and tumor (EGFR) antigens. We show that CD5-directed vertamax-PIT selectively depletes T cells from healthy human skin biopsies and pathogenic T cells from a single-patient biopsy of cutaneous T-cell lymphoma. EGFR-targeted vertamax-PIT inhibited tumor growth without detectable off-target toxicity in vivo, distinguishing it from IRDye700DX-PIT. These findings establish vertamax as an alternative and potentially safer PIT platform that may be applied in oncology, autoimmunity, and other settings where inflammation must be minimized.