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SUMMARY Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that, in order to be realized, must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276-ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276-ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276 targeted dual-compartment ablation could aid in development of highly selective broad-acting anti-cancer therapies.

To unravel the normal vasculature transcriptome and determine how it is altered by neighboring malignant cells, we compared gene expression patterns of endothelial cells derived from the blood vessels of eight normal resting tissues, five tumors, and regenerating liver. Organ-specific endothelial genes were readily identified, including 27 from brain. We also identified 25 transcripts overexpressed in tumor versus normal endothelium, including 13 that were not found in the angiogenic endothelium of regenerating liver. Most of the shared angiogenesis genes have expected roles in cell-cycle control, but those specific for tumor endothelium were primarily cell surface molecules of uncertain function. These studies reveal striking differences between physiological and pathological angiogenesis potentially important for the development of tumor-specific, vascular-targeted therapies.