Membrane associated cancer-oocyte neoantigen SAS1B/ovastacin is a candidate immunotherapeutic target for uterine tumors

• Published in: Oncotarget 2015-10, Vol.6 (30), p.30194-30211
• Main Authors: Pires, Eusebio S, D'Souza, Ryan S, Needham, Marisa A, Herr, Austin K, Jazaeri, Amir A, Li, Hui, Stoler, Mark H, Anderson-Knapp, Kiley L, Thomas, Theodore, Mandal, Arabinda, Gougeon, Alain, Flickinger, Charles J, Bruns, David E, Pollok, Brian A, Herr, John C
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antibodies - metabolism; Antibodies - pharmacology; Antibodies - toxicity; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Endocytosis; Female; Humans; Immunoconjugates - metabolism; Immunoconjugates - pharmacology; Immunoconjugates - toxicity; Immunotherapy - adverse effects; Immunotherapy - methods; Metalloproteases - antagonists & inhibitors; Metalloproteases - genetics; Metalloproteases - immunology; Metalloproteases - metabolism; Mixed Tumor, Mullerian - drug therapy; Mixed Tumor, Mullerian - enzymology; Mixed Tumor, Mullerian - genetics; Mixed Tumor, Mullerian - immunology; Mixed Tumor, Mullerian - pathology; Molecular Sequence Data; Molecular Targeted Therapy; Oocytes - drug effects; Oocytes - enzymology; Research Paper; Ribosome Inactivating Proteins, Type 1 - metabolism; Ribosome Inactivating Proteins, Type 1 - pharmacology; Ribosome Inactivating Proteins, Type 1 - toxicity; Saporins; Signal Transduction - drug effects; Time Factors; Uterine Neoplasms - drug therapy; Uterine Neoplasms - enzymology; Uterine Neoplasms - genetics; Uterine Neoplasms - immunology; Uterine Neoplasms - pathology
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.4734

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.