Evaluation of SAS1B as a target for antibody-drug conjugate therapy in the treatment of pancreatic cancer

Kiley A Knapp; Eusebio S Pires; Sara J Adair; Arabinda Mandal; Anne M Mills; Walter C Olson; Craig L Slingluff Jr; J Thomas Parsons; Todd W Bauer; Timothy N Bullock; John C Herr

doi:10.18632/oncotarget.23944

Evaluation of SAS1B as a target for antibody-drug conjugate therapy in the treatment of pancreatic cancer

Oncotarget. 2018 Jan 4;9(10):8972-8984. doi: 10.18632/oncotarget.23944. eCollection 2018 Feb 6.

Authors

Kiley A Knapp¹, Eusebio S Pires^{2

3}, Sara J Adair⁴, Arabinda Mandal², Anne M Mills¹, Walter C Olson⁴, Craig L Slingluff Jr⁴, J Thomas Parsons⁵, Todd W Bauer⁴, Timothy N Bullock¹, John C Herr^{1

2}

Affiliations

¹ Department of Pathology, The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
² Department of Cell Biology, The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
³ Department of Obstetrics and Gynecology, The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
⁴ Department of Surgery, The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
⁵ Department of Microbiology, The School of Medicine, University of Virginia, Charlottesville, Virginia, USA.

Abstract

Successful therapeutic options remain elusive for pancreatic cancer. The exquisite sensitivity and specificity of humoral and cellular immunity may provide therapeutic approaches if antigens specific for pancreatic cancer cells can be identified. Here we characterize SAS1B (ovastacin, ASTL, astacin-like), a cancer-oocyte antigen, as an attractive immunotoxin target expressed at the surface of human pancreatic cancer cells, with limited expression among normal tissues. Immunohistochemistry shows that most pancreatic cancers are SAS1B^pos (68%), while normal pancreatic ductal epithelium is SAS1B^neg. Pancreatic cancer cell lines developed from patient-derived xenograft models display SAS1B cell surface localization, in addition to cytoplasmic expression, suggesting utility for SAS1B in multiple immunotherapeutic approaches. When pancreatic cancer cells were treated with an anti-SAS1B antibody-drug conjugate, significant cell death was observed at 0.01-0.1 μg/mL, while SAS1B^neg human keratinocytes were resistant. Cytotoxicity was correlated with SAS1B cell surface expression; substantial killing was observed for tumors with low steady state SAS1B expression, suggesting a substantial proportion of SAS1B^pos tumors can be targeted in this manner. These results demonstrate SAS1B is a surface target in pancreatic cancer cells capable of binding monoclonal antibodies, internalization, and delivering cytotoxic drug payloads, supporting further development of SAS1B as a novel target for pancreatic cancer.

Keywords: ASTL/SAS1B/ovastacin; antibody-drug conjugate; pancreatic cancer biomarker; surface cancer-oocyte antigen; targeted immunotherapy.

Abstract

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