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

• Published in: Cancer cell Vol. 31; no. 4; pp. 501 - 515.e8
• Main Authors: 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, DeCrescenzo, Gary, Chaudhary, Amit, Zudaire, Enrique, Klarmann, Kimberly D., Keller, Jonathan R., Dimitrov, Dimiter S., St. Croix, Brad
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.04.2017
• Subjects: Abcb1; ADC; angiogenesis; Animals; Antineoplastic Agents - immunology; Antineoplastic Agents - pharmacology; B7 Antigens - genetics; B7 Antigens - immunology; B7 Antigens - metabolism; B7H3; Benzodiazepines - pharmacology; Blood Vessels - metabolism; Blood Vessels - pathology; cancer; Cell Line, Tumor; endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - pathology; Female; Humans; Immunoconjugates - immunology; Immunoconjugates - pharmacology; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Molecular Targeted Therapy - methods; Neoplasms - blood supply; Neoplasms - pathology; Neoplasms - therapy; Oligopeptides - pharmacology; P-glycoprotein; P-gp; PBD; Pyrroles - pharmacology; Rabbits; TEM; ADC; P-glycoprotein; endothelium; P-gp; PBD; Abcb1; angiogenesis; cancer; TEM; B7H3
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.03.005

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. [Display omitted] •CD276/B7-H3 is broadly overexpressed in both cancer cells and tumor vasculature•Both angiogenic and non-angiogenic tumor vasculature express CD276•Anti-CD276-drug conjugates display potent anti-tumor and anti-metastatic activity•Pyrrolobenzodiazepine dimers are optimal warheads for targeting tumor vasculature 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.