The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation

SUMOylation is a reversible post-translational modification that has been implicated in the regulation of various cellular processes including inflammatory responses and expression of Type I interferons (IFN1). In this report, we have explored the activity of the selective small molecule SUMOylation inhibitor subasumstat (TAK-981) in promoting antitumor innate immune responses. We demonstrate that treatment with TAK-981 results in IFN1-dependent macrophage and NK cell activation, promoting macrophage phagocytosis and NK cell cytotoxicity in ex vivo assays. Furthermore, pre-treatment with TAK-981 enhanced macrophage phagocytosis or NK cell cytotoxicity against CD20-positive target cells in combination with the anti-CD20 antibody rituximab. In vivo studies demonstrated enhanced antitumor activity of TAK-981 and rituximab in CD20-positive lymphoma xenograft models. Combination of TAK-981 with anti-CD38 antibody daratumumab also resulted in enhanced antitumor activity. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with lymphomas and solid tumors.