regulation of innate immune responses and expression of Type I interferons, and ex vivo treatment of human and mouse immune cells with TAK-981 results in transcrip- tional upregulation of IFN-beta and Type I IFN receptor

Type I interferons, 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.In vivo, TAK-981 induces IFNARdependent antitumor activity and synergizes with rituximab in xenograft-bearing mice. 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 OCILy10-bearing SCID mice treated with TAK-981 and the LALA-PG version of rituximab, in which mutations in the Fc region prevent FcgR 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. TAK981 showed synergistic activity in combination with daratumumab in two CD38+ xenograft models, Daudi and LP1. 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.