| Literature DB >> 28399408 |
Steven Seaman1, Zhongyu Zhu2, Saurabh Saha3, Xiaoyan M Zhang3, Mi Young Yang1, Mary Beth Hilton4, Karen Morris4, Christopher Szot1, Holly Morris5, Deborah A Swing5, Lino Tessarollo6, Sean W Smith7, Sylvia Degrado7, Dmitry Borkin7, Nareshkumar Jain7, Julia Scheiermann8, Yang Feng2, Yanping Wang2, Jinyu Li2, Dean Welsch3, Gary DeCrescenzo3, Amit Chaudhary1, Enrique Zudaire1, Kimberly D Klarmann9, Jonathan R Keller9, Dimiter S Dimitrov2, Brad St Croix10.
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. Published by Elsevier Inc.Entities:
Keywords: ADC; Abcb1; B7H3; P-glycoprotein; P-gp; PBD; TEM; angiogenesis; cancer; endothelium
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Year: 2017 PMID： 28399408 PMCID： PMC5458750 DOI： 10.1016/j.ccell.2017.03.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743