Background TAK-981 is a first-in-class small molecule inhibitor of the SUMO activating enzyme in Phase 1 clinical trials. SUMOylation has previously been implicated in the regulation of innate immune responses and expression of Type I interferons,¹ and ex vivo treatment of human and mouse immune cells with TAK-981 results in transcriptional upregulation of IFN-beta and Type I IFN receptor (IFNAR) signaling. We previously showed that TAK-981 increases NK cell activation and M1 macrophage polarization, leading to enhanced ADCC and ADCP in the presence of rituximab.²In vivo, TAK-981 induces IFNAR-dependent antitumor activity and synergizes with rituximab in xenograft-bearing mice.^{2 3} Here we investigated the mechanism of synergistic activity with rituximab and evaluated the combination of TAK-981 with daratumumab, another therapeutic mAb.

Methods The role of effector function of rituximab in the mechanism of synergy with TAK-981 was evaluated in OCI-Ly10-bearing SCID mice treated with TAK-981 and the LALA-PG version of rituximab, in which mutations in the Fc region prevent FcγR binding. The combination of TAK-981 and rituximab was also evaluated in OCI-Ly10 tumor-bearing mice in which macrophages and/or NK cells were depleted with clodronate and anti-asialo GM1. TAK-981 in combination with daratumumab was evaluated in two CD38+ xenograft models, Daudi (Burkitt’s lymphoma) and LP-1 (multiple myeloma). To test ADCP activity, Daudi-KILR cells were incubated with human monocyte-derived macrophages (hMDM) treated with TAK-981 in the presence or absence of rituximab or daratumumab, with or without a neutralizing antibody to IFNAR2.

Results Unlike rituximab, LALA-PG mutated rituximab did not synergize with TAK-981 in OCI-Ly10 tumor-bearing mice, indicating a requirement for Fc effector function. Depletion of macrophages with clodronate or NK cells with anti-asialo GM1 lessened the anti-tumor effect of the TAK-981 and rituximab combination, while dual depletion of macrophages and NK cells had a greater impact. TAK-981 showed synergistic activity in combination with daratumumab in two CD38+ xenograft models, Daudi and LP-1. In vitro, TAK-981-treated hMDM showed increased phagocytic activity against Daudi cells, and this effect was further enhanced in the presence of rituximab or daratumumab but prevented by a neutralizing antibody to IFNAR2.

Conclusions In preclinical models, TAK-981 synergizes with rituximab through a mechanism involving Type I-IFN dependent enhancement of ADCC and ADCP, and the combination of TAK-981 with daratumumab is also synergistic.

References

1. Decque A, Joffre O, Magalhaes JG, Cossec J-C, Blecher-Gonen R, Lapaquette P, Silvin A, Manel N, Joubert P-E, Seeler J-S, Albert ML, Amit I, Amigorena S, Dejean A. Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing. Nat Immunol 2016;17:140–149.

2. Nakamura A, Grossman S, Song K, Idamakanti N, Shaprio G, Huszar D. Inhibition of SUMOylation by TAK-981 induces antitumor innate immune responses by modulating macrophage and NK cell function through Type I IFN pathway activation [abstract]. In: Proceedings of the American Association forCancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Cancer Res 2019;79(13 Suppl):Abstract nr 1523.

3. Huszar D. TAK-981: A first-in-class SUMOylation inhibitor in phase 1 clinical trials promotes a Type I interferon response and antitumor immunity in preclinical models. AACR Annual Meeting 2019, American Association for Cancer Research; Mar 29-Apr 03; Atlanta, GA, US. Session DDT01.