Evaluation of SAS1B as an Immunotherapeutic Target for the Treatment of Cancer
Knapp, Kiley, Experimental Pathology - School of Medicine, University of Virginia
Bullock, Timothy, Department of Pathology, Research, University of Virginia
Immunotherapeutic options for the treatment of cancer, which remains a major global health challenge, offer the allure of greater tumor specificity and less associated toxicity than is typically achieved with traditional chemo- and radio-therapeutic strategies. The success of some immunotherapies, such as ADCs and CAR-Ts, rely on identification and selection of targets which are highly tumor-specific with limited or no expression in normal tissues. Cancer germline antigens represent potential ideal targets for targeted immunotherapy as CGAs are expressed in cancer cells but show limited or no expression among normal tissues. Although many cancer-testis antigens have been described, SAS1B is the first, and only, cancer-oocyte antigen identified to-date. Owing to the limited expression of SAS1B among normal tissue combined with expression in a number of cancer indications, we propose that SAS1B is an attractive immunotherapeutic target.
We have shown that, in addition to previous work published in female reproductive cancers, SAS1B is expressed in a majority of pancreatic and head and neck cancers. SAS1B localized to both the cytoplasm and the cell surface in PDAC and HNSCC cell lines by IIF and flow cytometry, suggesting potential utility of SAS1B targeted immunotherapeutic strategies. Furthermore, an ADC targeting SAS1B administered to pancreatic cancer cell lines was internalized and subsequently caused significant cell death in a manner correlated with SAS1B cell surface expression. Thus, SAS1B represents a novel therapeutic target for the treatment of PDAC and HNSCC. These data support further development of a SAS1B-ADC including in vivo assessment using mouse xenograft systems.
Although we have shown proof of concept that SAS1B-ADC induces cytotoxicity in pancreatic cancer cell lines, addressing multiple fundamental biological questions which remain regarding SAS1B expression will also inform production of SAS1B targeted therapies. For example, we have identified six ASTL splice variants in cancer, known as SV-A to SV-F, and have shown differential cellular localization of recombinant SV-A and SV-C proteins (cell surface vs. cytoplasm, respectively). Further studies characterizing major SAS1B protein isoform(s) expressed at the cell surface in cancers may lead to development of more effective immunotherapies utilizing mAbs generated against cell surface, cancer-associated form(s) of SAS1B. Our work suggests SAS1B expression in a broad range of cancer indications and demonstrates efficacy of a SAS1B-ADC in vitro, thus supporting further assessment of SAS1B as an immunotherapeutic target for the treatment of cancer.
PHD (Doctor of Philosophy)
ASTL/SAS1B/ovastacin, Antibody-drug conjugates, Immunotherapy