Cancer Cell
Volume 31, Issue 4, 10 April 2017, Pages 501-515.e8
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Article
Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature

https://doi.org/10.1016/j.ccell.2017.03.005Get rights and content
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Highlights

  • CD276/B7-H3 is broadly overexpressed in both cancer cells and tumor vasculature

  • Both angiogenic and non-angiogenic tumor vasculature express CD276

  • Anti-CD276-drug conjugates display potent anti-tumor and anti-metastatic activity

  • Pyrrolobenzodiazepine dimers are optimal warheads for targeting tumor vasculature

Summary

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

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

Cited by (0)

10

Co-first author

11

Present address: Atlas Venture - Delinia, Cambridge, MA 02139, USA

12

Present address: Kyn Therapeutics, Cambridge, MA 02139, USA

13

Present address: Janssen Pharmaceutical Companies, J&J, Spring House, PA 19477, USA

14

Lead Contact