Sgn-2ff: A Novel Small Molecule Inhibitor Of Fucosylation With Preclinical Antitumor Activity Through Multiple Immune Mechanisms

Increased fucosylation is associated with tumor progression and metastasis, and targeting fucosylation is a novel strategy in cancer therapy. 2-Fluorofucose (SGN-2FF) has been shown to inhibit cellular fucosylation by depletion of the fucosylation substrate GDP-fucose, as well as by direct inhibition of fucosyltransferases, leading to the production of afucosylated glycoproteins including antibodies. SGN-2FF has antitumor activity in multiple mouse tumor models, showing substantial tumor growth delay. SGN-2FF also enhanced the protective effect of a lymphoma vaccine in a syngeneic mouse model (1). This protection was determined to be immune dependent since depletion of CD4 and CD8 T cells reduced the SGN-2FF/vaccine activity. In vitro, SGN-2FF has been shown to activate human T cells in an antigen-dependent manner. Therefore, by inhibiting fucosylation SGN-2FF can potentially work through multiple mechanisms, including but not limited to effects on immune cells, tumor cells, and the tumor microenvironment. A first-in-human, phase 1, multicenter dose-escalation study of SGN-2FF is ongoing to investigate the safety, pharmacokinetics, and antitumor activity of SGN-2FF given orally to patients with advanced solid tumors (NCT# 02952989). Pharmacodynamic effects, including markers of fucosylation status, will also be evaluated to help determine the optimal biologic dose. This presentation reviews the preclinical activity data of SGN-2FF and describes the design of the phase 1 study, showing how demonstrated preclinical pharmacodynamic effects on fucosylation status informed how activity and pharmacodynamics will be monitored and evaluated in the phase 1 study. Reference 1. Okeley NM, Alley SC, Anderson ME, Boursalian TE, Burke PJ, Emmerton KM, et al. Development of orally active inhibitors of protein and cellular fucosylation. Proc Natl Acad Sci U S A 2013;110:5404-9. Citation Format: Stephen C. Alley, Megan O9Meara, Shyra J. Gardai, Nicole M. Okeley. SGN-2FF: A novel small molecule inhibitor of fucosylation with preclinical antitumor activity through multiple immune mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT02-02. doi:10.1158/1538-7445.AM2017-DDT02-02