Pharmacodynamic evaluation of the novel SUMOylation inhibitor TAK-981 in a mouse tumor model

TAK-981 is a small molecule inhibitor of the SUMOylation enzyme cascade which is currently in a Phase I clinical trial (NCT03648372). TAK-981 selectively inhibits the activity of the SUMO activating enzyme, forming a covalent adduct between TAK-981 and SUMO, thereby decreasing levels of SUMOylated proteins. A central feature of pharmacological inhibition of SUMOylation is production of type I IFNs in immune cells, promoting both innate and adaptive immune responses. TAK-981 demonstrates antitumor activity, including complete regression (CR) of some tumors, in immune-competent BALB/c mice bearing syngeneic A20 lymphoma tumors. This model was utilized to investigate 1) target engagement and pathway inhibition, 2) modulation of IFN-regulated genes in tumor and blood, 3) dependence of antitumor activity on Type I IFN signaling and adaptive immunity, and 4) changes in immune cell infiltrates in tumors. IHC analysis of tumors showed TAK-981-SUMO adduct formation and decrease of SUMOylated protein levels after a single IV dose of 7.5 mg/kg TAK-981, as measured by assays for TAK-981-SUMO adduct and SUMO2/3 conjugates, respectively. IFN-regulated genes including CXCL10, IFIT1, and ISG15 are coordinately upregulated 4-8 hrs post-dose in tumor and in blood, as demonstrated by Nanostring, and plasma levels of IP-10 (CXCL10) increase. Single cell RNAseq experiments on dissociated tumors demonstrated upregulation of IFN-regulated genes in T cells and monocytes in the tumor microenvironment. TAK-981-mediated antitumor activity is fully dependent on Type I IFN signaling; administration of a neutralizing antibody against the IFN alpha/beta receptor 1 (IFNAR) before dosing TAK-981 results in the loss of antitumor activity against A20. TAK-981-mediated antitumor activity is also dependent on the adaptive immune system, as demonstrated by two experiments in mice lacking T cells (BALB/c Rag2 KO mice, and mice treated with an anti-CD8 antibody to deplete T cells). Antitumor response was diminished in both settings, with no CRs achieved in either model. Flow cytometric analysis of immune infiltrates in A20 tumors grown in BALB/c mice indicated that TAK-981 response is accompanied by an increase in activated T cells in the tumor microenvironment as well as increased NK cells, potentially supporting a role for both innate and adaptive immunity in the MOA. Evaluation of pharmacodynamic biomarkers in Phase I clinical development will be informed by these preclinical studies. Citation Format: Allison J. Berger, Sharon Friedlander, Omid Ghasemi, Stephen Grossman, Erik Koenig, Eric Lightcap, Michael Milhollen, Pooja Shah, Gary Shapiro, Vaishali Shinde, Keli Song, Kristina Xega, Agatha Zawadzka, Dennis Huszar. Pharmacodynamic evaluation of the novel SUMOylation inhibitor TAK-981 in a mouse tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3079.