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

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

  • Cancer Cell. 2017 Apr 10;31(4):501-515.e8. doi: 10.1016/j.ccell.2017.03.005.
Steven Seaman 1 Zhongyu Zhu 2 Saurabh Saha 3 Xiaoyan M Zhang 3 Mi Young Yang 1 Mary Beth Hilton 4 Karen Morris 4 Christopher Szot 1 Holly Morris 5 Deborah A Swing 5 Lino Tessarollo 6 Sean W Smith 7 Sylvia Degrado 7 Dmitry Borkin 7 Nareshkumar Jain 7 Julia Scheiermann 8 Yang Feng 2 Yanping Wang 2 Jinyu Li 2 Dean Welsch 3 Gary DeCrescenzo 3 Amit Chaudhary 1 Enrique Zudaire 1 Kimberly D Klarmann 9 Jonathan R Keller 9 Dimiter S Dimitrov 2 Brad St Croix 10
Affiliations

Affiliations

  • 1 Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA.
  • 2 Protein Interactions Section, Cancer and Inflammation Program (CIP), NCI, NIH, Frederick, MD 21702, USA.
  • 3 BioMed Valley Discoveries, Inc, Kansas City, MO 64111, USA.
  • 4 Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA; Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA.
  • 5 Transgenic Core Facility, MCGP, NCI, NIH, Frederick, MD 21702, USA.
  • 6 Neural Development Section, MCGP, NCI, NIH, Frederick, MD 21702, USA.
  • 7 Abzena, Bristol, PA 19007, USA.
  • 8 Immune Modulation Section, CIP, NCI, NIH, Frederick, MD 21702, USA.
  • 9 Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA; Hematopoiesis and Stem Cell Biology Section, MCGP, NCI, NIH, Frederick, MD 21702, USA.
  • 10 Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA. Electronic address: [email protected].
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.

Keywords

ADC; Abcb1; B7H3; P-glycoprotein; P-gp; PBD; TEM; angiogenesis; cancer; endothelium.

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