Membrane associated cancer-oocyte neoantigen SAS1B/ovastacin is a candidate immunotherapeutic target for uterine tumors.
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.
Department of Cell Biology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Eusebio S
ES
Pires
Department of Cell Biology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Ryan S
RS
D'Souza
Department of Cell Biology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Marisa A
MA
Needham
Department of Cell Biology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Austin K
AK
Herr
Department of Obstetrics and Gynecology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Amir A
AA
Jazaeri
Department of Pathology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Hui
H
Li
Department of Pathology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Mark H
MH
Stoler
Department of Pathology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Kiley L
KL
Anderson-Knapp
Department of Obstetrics and Gynecology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Theodore
T
Thomas
Department of Cell Biology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Arabinda
A
Mandal
CRCL, UMR Inserm-1052, CNRS-5286, Faculté de Médecine Laënnec, Lyon, France.
Alain
A
Gougeon
Department of Cell Biology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Charles J
CJ
Flickinger
Department of Pathology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
David E
DE
Bruns
Neoantigenics, Inc, Charlottesville, Virginia, USA.
Brian A
BA
Pollok
Department of Cell Biology at The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
John C
JC
Herr
D000595:Amino Acid Sequence; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004705:Endocytosis; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018200:Mixed Tumor, Mullerian / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009865:Oocytes / Q000187:drug effects / Q000201:enzymology; D054789:Ribosome Inactivating Proteins, Type 1 / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000076985:Saporins; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology
D000906:Antibodies; D000951:Antigens, Neoplasm; D018796:Immunoconjugates; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D045726:Metalloproteases; C487826:ASTL protein, human
ASTL/SAS1B/ovastacin; cancer surface neoantigen; immunotherapy target; oocyte-specific protein; uterine tumor biomarkers