PMID- 30107179 OWN - NLM STAT- MEDLINE DCOM- 20190610 LR - 20210109 IS - 1878-3686 (Electronic) IS - 1535-6108 (Print) IS - 1535-6108 (Linking) VI - 34 IP - 2 DP - 2018 Aug 13 TI - A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer. PG - 331-345.e11 LID - S1535-6108(18)30310-6 [pii] LID - 10.1016/j.ccell.2018.07.005 [doi] AB - 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 FcgammaRIIB 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. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Shivange, Gururaj AU - Shivange G AD - 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. FAU - Urbanek, Karol AU - Urbanek K AD - 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. FAU - Przanowski, Piotr AU - Przanowski P AD - 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. FAU - Perry, Justin S A AU - Perry JSA AD - Center for Cell Clearance and Department of Microbiology, Immunology, Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. FAU - Jones, James AU - Jones J AD - 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. FAU - Haggart, Robert AU - Haggart R AD - 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. FAU - Kostka, Christina AU - Kostka C AD - 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. FAU - Patki, Tejal AU - Patki T AD - 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. FAU - Stelow, Edward AU - Stelow E AD - Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. FAU - Petrova, Yuliya AU - Petrova Y AD - 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. FAU - Llaneza, Danielle AU - Llaneza D AD - 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. FAU - Mayo, Marty AU - Mayo M AD - Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. FAU - Ravichandran, Kodi S AU - Ravichandran KS AD - Center for Cell Clearance and Department of Microbiology, Immunology, Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. FAU - Landen, Charles N AU - Landen CN AD - 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. FAU - Bhatnagar, Sanchita AU - Bhatnagar S AD - 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. FAU - Tushir-Singh, Jogender AU - Tushir-Singh J AD - 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. LA - eng GR - P30 CA044579/CA/NCI NIH HHS/United States GR - R01 CA192399/CA/NCI NIH HHS/United States GR - T32 CA009109/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - Cancer Cell JT - Cancer cell JID - 101130617 RN - 0 (Antibodies, Bispecific) RN - 0 (FCGR2B protein, human) RN - 0 (FOLR1 protein, human) RN - 0 (Folate Receptor 1) RN - 0 (Receptors, IgG) RN - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand) RN - 0 (TNFRSF10B protein, human) SB - IM MH - Animals MH - Antibodies, Bispecific/*therapeutic use MH - Cell Line, Tumor MH - Female MH - Folate Receptor 1/*antagonists & inhibitors MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Ovarian Neoplasms/*drug therapy/pathology MH - Receptors, IgG/physiology MH - Receptors, TNF-Related Apoptosis-Inducing Ligand/*antagonists & inhibitors PMC - PMC6404966 MID - NIHMS1015270 OTO - NOTNLM OT - TRAIL-R2 OT - antibody therapy OT - cancer OT - cancer signaling OT - caspases OT - cell signaling OT - dual-specificity targeting OT - folate receptor alpha-1 OT - ovarian cancer OT - targeted therapies COIS- Declaration of Interests The authors declare no competing interests. BaCa antibody mediated targeting of FOLR1 and DR5, and "Cis"-"Trans" mechanism of apoptotic activation is part of a provisional patent here at University of Virginia Licensing and Venture Group. EDAT- 2018/08/15 06:00 MHDA- 2019/06/14 06:00 PMCR- 2019/03/07 CRDT- 2018/08/15 06:00 PHST- 2017/09/19 00:00 [received] PHST- 2018/05/07 00:00 [revised] PHST- 2018/07/16 00:00 [accepted] PHST- 2018/08/15 06:00 [entrez] PHST- 2018/08/15 06:00 [pubmed] PHST- 2019/06/14 06:00 [medline] PHST- 2019/03/07 00:00 [pmc-release] AID - S1535-6108(18)30310-6 [pii] AID - 10.1016/j.ccell.2018.07.005 [doi] PST - ppublish SO - Cancer Cell. 2018 Aug 13;34(2):331-345.e11. doi: 10.1016/j.ccell.2018.07.005.