Membrane associated cancer-oocyte neoantigen SAS1B/ovastacin is a candidate immunotherapeutic target for uterine tumors
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Eusebio S. Pires1, Ryan S. D’Souza1, Marisa A. Needham1, Austin K. Herr1, Amir A. Jazaeri3, Hui Li2, Mark H. Stoler2, Kiley L. Anderson-Knapp2, Theodore Thomas3, Arabinda Mandal1, Alain Gougeon5, Charles J. Flickinger1, David E. Bruns2, Brian A. Pollok4, John C. Herr1
1Department of Cell Biology at the School of Medicine, University of Virginia, Charlottesville, Virginia, USA
2Department of Pathology at the School of Medicine, University of Virginia, Charlottesville, Virginia, USA
3Department of Obstetrics and Gynecology at the School of Medicine, University of Virginia, Charlottesville, Virginia, USA
4Neoantigenics, Inc, Charlottesville, Virginia, USA
5CRCL, UMR Inserm-1052, CNRS-5286, Faculté de Médecine Laënnec, Lyon, France
John C. Herr, e-mail: firstname.lastname@example.org
Keywords: ASTL/SAS1B/ovastacin, cancer surface neoantigen, oocyte-specific protein, uterine tumor biomarkers, immunotherapy target
Received: May 18, 2015 Accepted: August 07, 2015 Published: August 18, 2015
The metalloproteinase SAS1B [ovastacin, ASTL, astacin-like] was immunolocalized on the oolemma of ovulated human oocytes and in normal ovaries within the pool of growing oocytes where SAS1B protein was restricted to follicular stages spanning the primary-secondary follicle transition through ovulation. Gene-specific PCR and immunohistochemical studies revealed ASTL messages and SAS1B protein in both endometrioid [74%] and malignant mixed Mullerian tumors (MMMT) [87%] of the uterus. A MMMT-derived cell line, SNU539, expressed cell surface SAS1B that, after binding polyclonal antibodies, internalized into EEA1/LAMP1-positive early and late endosomes. Treatment of SNU539 cells with anti-SAS1B polyclonal antibodies caused growth arrest in the presence of active complement. A saporin-immunotoxin directed to SAS1B induced growth arrest and cell death. The oocyte restricted expression pattern of SAS1B among adult organs, cell-surface accessibility, internalization into the endocytic pathway, and tumor cell growth arrest induced by antibody-toxin conjugates suggest therapeutic approaches that would selectively target tumors while limiting adverse drug effects in healthy cells. The SAS1B metalloproteinase is proposed as a prototype cancer-oocyte tumor surface neoantigen for development of targeted immunotherapeutics with limited on-target/off tumor effects predicted to be restricted to the population of growing oocytes.
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