Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3 Positive Tumor Cells and Tumor Vasculature

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.

Graphical abstract

Seaman et al. show that CD276 is broadly overexpressed in cancer cells and tumor vascular cells and demonstrate anti-CD276-drug conjugates as promising anti-cancer reagents. The selection of conjugated drugs is important because tumor vascular cells can be resistant to a drug to which tumor cells are sensitive.