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Cancer Cell. 2018 Aug 13;34(2):331-345.e11. doi: 10.1016/j.ccell.2018.07.005.

A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer.

Author information

1
Laboratory of Novel Biologics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
2
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
3
Center for Cell Clearance and Department of Microbiology, Immunology, Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
4
Laboratory of Novel Biologics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Undergraduate Research Program, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
5
Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
6
Department of Obstetrics and Gynecology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
7
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
8
Laboratory of Novel Biologics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Electronic address: jogi@virginia.edu.

Abstract

Therapeutic antibodies targeting ovarian cancer (OvCa)-enriched receptors have largely been disappointing due to limited tumor-specific antibody-dependent cellular cytotoxicity. Here we report a symbiotic approach that is highly selective and superior compared with investigational clinical antibodies. This bispecific-anchored cytotoxicity activator antibody is rationally designed to instigate "cis" and "trans" cytotoxicity by combining specificities against folate receptor alpha-1 (FOLR1) and death receptor 5 (DR5). Whereas the in vivo agonist DR5 signaling requires FcγRIIB interaction, the FOLR1 anchor functions as a primary clustering point to retain and maintain a high level of tumor-specific apoptosis. The presented proof of concept study strategically makes use of a tumor cell-enriched anchor receptor for agonist death receptor targeting to potentially generate a clinically viable strategy for OvCa.

KEYWORDS:

TRAIL-R2; antibody therapy; cancer; cancer signaling; caspases; cell signaling; dual-specificity targeting; folate receptor alpha-1; ovarian cancer; targeted therapies

PMID:
30107179
PMCID:
PMC6404966
DOI:
10.1016/j.ccell.2018.07.005
[Indexed for MEDLINE]
Free PMC Article

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