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
  • 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].
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.
Products