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

Abstract

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.

• Authors: 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
• Journal: Cancer cell (Cancer Cell) Vol. 31 Issue 4 Pg. 501-515.e8 (04 10 2017) ISSN: 1878-3686 [Electronic] United States
• PMID: 28399408 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• Antineoplastic Agents
• B7 Antigens
• CD276 protein, human
• Cd276 protein, mouse
• Immunoconjugates
• Oligopeptides
• Pyrroles
• pyrrolo(2,1-c)(1,4)benzodiazepine
• Benzodiazepines
• monomethyl auristatin E

Topics

• Animals
• Antineoplastic Agents (immunology, pharmacology)
• B7 Antigens (genetics, immunology, metabolism)
• Benzodiazepines (pharmacology)
• Blood Vessels (metabolism, pathology)
• Cell Line, Tumor
• Endothelium, Vascular (drug effects, pathology)
• Female
• Humans
• Immunoconjugates (immunology, pharmacology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Molecular Targeted Therapy (methods)
• Neoplasms (blood supply, pathology, therapy)
• Oligopeptides (pharmacology)
• Pyrroles (pharmacology)
• Rabbits