1区 · 医学
Article
作者: Seaman, Steven ; Zhu, Zhongyu ; Saha, Saurabh ; Zhang, Xiaoyan M. ; Yang, Mi Young ; Hilton, Mary Beth ; Morris, Karen ; Szot, Christopher ; Morris, Holly ; Swing, Deborah A. ; Tessarollo, Lino ; Smith, Sean W. ; Degrado, Sylvia ; Borkin, Dmitry ; Jain, Nareshkumar ; Scheiermann, Julia ; Feng, Yang ; Wang, Yanping ; Li, Jinyu ; Welsch, Dean ; De Crescenzo, Gary ; Chaudhary, Amit ; Zudaire, Enrique ; Klarmann, Kimberly D. ; Keller, Jonathan R. ; Dimitrov, Dimiter S. ; St. Croix, Brad
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 the development of highly selective broad-acting anti-cancer therapies.