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

Publication date: 10 April 2017
Source:Cancer Cell, Volume 31, Issue 4
Author(s): Steven Seaman, Zhongyu Zhu, Saurabh Saha, Xiaoyan M. Zhang, Mi Young Yang, Mary Beth Hilton, Karen Morris, Christopher Szot, Holly Morris, Deborah A. Swing, Lino Tessarollo, Sean W. Smith, Sylvia Degrado, Dmitry Borkin, Nareshkumar Jain, Julia Scheiermann, Yang Feng, Yanping Wang, Jinyu Li, Dean Welsch, Gary DeCrescenzo, Amit Chaudhary, Enrique Zudaire, Kimberly D. Klarmann, Jonathan R. Keller, Dimiter S. Dimitrov, Brad St. Croix
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.

Graphical abstract

Teaser

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 drug selected for conjugation is important because tumor vascular cells can be resistant to a drug to which tumor cells are sensitive.


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