The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation
Akito Nakamura, Stephen Grossman, Keli Song, Kristina Xega, Yuhong Zhang, Donna Cvet, Allison Berger, Gary Shapiro, Dennis Huszar, Akito Nakamura, Stephen Grossman, Keli Song, Kristina Xega, Yuhong Zhang, Donna Cvet, Allison Berger, Gary Shapiro, Dennis Huszar
Abstract
Small ubiquitin-like modifier (SUMO) is a member of a ubiquitin-like protein superfamily. SUMOylation is a reversible posttranslational modification that has been implicated in the regulation of various cellular processes including inflammatory responses and expression of type 1 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 natural killer (NK) cell activation, promoting macrophage phagocytosis and NK cell cytotoxicity in ex vivo assays. Furthermore, pretreatment with TAK-981 enhanced macrophage phagocytosis or NK cell cytotoxicity against CD20+ target cells in combination with the anti-CD20 antibody rituximab. In vivo studies demonstrated enhanced antitumor activity of TAK-981 and rituximab in CD20+ 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; www.clinicaltrials.gov) for the treatment of patients with lymphomas and solid tumors.
© 2022 by The American Society of Hematology.
Source: PubMed