2. Academic Validation
  3. 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: stcroixb@mail.nih.gov.
PMID: 28399408 DOI: 10.1016/j.ccell.2017.03.005
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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