Abstract B114: Humanized anti-Sialyl-Tn monoclonal antibody-drug conjugates inhibit tumor growth in vitro and in vivo (2018)

Abstract Targeted therapeutics that can differentiate between normal and malignant tumor cells represent the ideal standard for the development of a successful anticancer strategy. The Sialyl-Thomsen-nouveau antigen (STn or Sialyl-Tn, also known as CD175s) is rarely observed in normal adult tissues, but it is abundantly expressed in many types of human epithelial cancers. Interestingly, we have observed that the level of this carbohydrate is elevated following chemotherapy treatment in both in vitro and in vivo model systems, suggesting a potential role of STn in chemoresistance. 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. We have demonstrated that these Abs are highly selective in binding assays demonstrating robust nanomolar EC50s, possess specificity on cancer 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 using MMAE as the cytotoxic agent. Cell cytotoxicity was demonstrated in a panel of STn-expressing cell lines with low nanomolar IC50s. In vivo, single-dose mouse PK studies were performed with humanized anti-STn ADCs and we determined half-life of approximately 3 days for both SIA01-ADC and SIA02-ADC. 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-derived and patient-derived (PDX) ovarian cancer and pancreatic cancer xenograft models. Inhibition of tumor progression was observed in all models with complete regressions observed in some treatment arms. No significant weight loss occurred in 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 to these preclinical pharmacology studies, we demonstrated that the administration of our anti-STn ADC has an excellent safety profile through the completion of a non-GLP pilot PK/toxicity study in cynomolgus monkeys. No weight loss or deaths occurred in this study and no gross pathology changes were observed in all organs examined. Histopathologic changes were limited to the bone marrow with minimal to mild decreased cellularity and mild decrease in the myeloid to erythroid ratio observed. All clinical chemistry results (liver, kidney function, etc.) were normal throughout study. Changes in hematology parameters–modest neutropenia–were consistent with other MMAE ADCs and therefore, we conclude, are not related to the STn target, which is consistent with our tissue cross-reactivity studies demonstrating that overall normal tissue expression of the STn target is insignificant. Our data demonstrate that high-affinity, STn-selective humanized mAbs show promise as therapies for solid tumors. Citation Format: Daniel Dransfield, Jillian M. Prendergast, David A. Eavarone, Rawan Nazer, Linah Al-Alem, Bo Rueda, Jenna Stein, Jeff Behrens. Humanized anti-Sialyl-Tn monoclonal antibody-drug conjugates inhibit tumor growth in vitro and in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B114.