Abstract B28: Targeting the tumor-associated carbohydrate antigen STn with humanized anti-Sialyl-Tn monoclonal antibody-drug conjugates inhibits ovarian cancer tumor growth in vitro and in vivo

Abstract

Abstract Ovarian cancer is the leading cause of death from gynecologic malignancies in the U.S. The current standard of care is tumor debulking followed by chemotherapy. This treatment results in approximately 70% of patients achieving an initial complete clinical response. However, many of these patients will unfortunately relapse with chemoresistant disease developing in part to the presence of cancer stem cells (CSCs) within the tumor. Indeed, ovarian CSCs have been identified and shown to be resistant to chemo- and radiotherapy. Cancer cell surface glycans, called tumor-associated carbohydrate antigens (TACAs), are a class of attractive cancer-specific targets found on the cell surface of many solid tumors. Siamab is targeting a glycan structure (Sialyl-Tn, STn) that is cancer-specific and a major reported constituent of two well-known CSC biomarkers, CD44 and MUC1, residing on both CSCs and mature malignant cells in some cancer types. Although CD44 and MUC1 are also present on normal tissue and normal stem cell surfaces, tumor and CSC specificity is conferred the presence of STn-glycosylated variants of these CSC markers and other cell surface proteins that are essentially absent from normal human tissues. Importantly, STn can be a component of CA-125 (MUC16), conferring additional specificity to this diagnostic marker for ovarian carcinoma. The elevated presence of STn in tumors is associated with metastatic disease, poor prognosis, and reduced overall survival. In addition, elevations in STn expression are linked to chemotherapy resistance and enable tumors to evade the host immune system. We have observed that STn levels are elevated in cancer cells following chemotherapy treatment in both in vitro and in vivo model systems and STn is present on specific subtype of tumor-infiltrating myeloid-derived suppressor cells. Both observations support the role of STn in tumor chemoresistance and immunomodulation. While attempts have been made to target STn clinically with a cancer vaccine, efficacy has been limited. Siamab has developed a unique immunotherapeutic solution aimed at eradicating human neoplasias by targeting both CSCs and bulk tumor to enable whole tumor killing. We have identified and humanized a panel of mouse monoclonal novel antibodies (Abs) that specifically target with high affinity the STn glycan independent of its carrier protein. These Abs are highly selective in binding assays demonstrating robust nanomolar EC50s, possess specificity on tissues as determined with neuraminidase treatment, and exhibit STn-specific glycan binding on Siamab’s proprietary glycan array. Antitumor efficacy was evaluated in vitro and in vivo utilizing humanized anti-STn antibody drug conjugated (ADC) material. Cell cytotoxicity was demonstrated in a panel of STn-expressing cell lines with low nanomolar IC50s. We confirmed that the decrease in proliferation in vitro can be translated to a reduction in tumor size in vivo, through a series of cell line and patient-derived ovarian cancer xenograft models. Inhibition of tumor progression were observed in all models, with complete regressions observed in some treatment arms. No significant weight loss was observed for any treatment groups, indicating the therapy was well tolerated by all the groups. A decrease in STn expression was noted in the tumors following treatment, indicating that we were hitting the target against which these Abs were generated. In addition, we have begun the development of both tissue- and serum-based biomarker assays utilizing these selective anti-STn Abs. Our data demonstrate that high-affinity, STn-selective humanized mAbs show promise as therapies for ovarian tumors, as well as tools for patient stratification and pharmacodynamic biomarker assessments. Citation Format: Daniel T. Dransfield, Jillian M. Prendergast, David A. Eavarone, Rawan Nazer, Linah Al-Alem, Jenna Stein, Jeff Behrens, Bo Rueda. Targeting the tumor-associated carbohydrate antigen STn with humanized anti-Sialyl-Tn monoclonal antibody-drug conjugates inhibits ovarian cancer tumor growth in vitro and in vivo. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B28.