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SOT101 among other immune cells specifically stimulates natural killer (NK) cells and memory CD8<jats:sup>+<\/jats:sup>T cells with no significant expansion or activation of the regulatory T cell compartment. In this study, we showed that SOT101 induced expression of cytotoxic receptors NKp30, DNAM-1 and NKG2D on human NK cells. SOT101 stimulated dose-dependent proliferation and the relative expansion of both major subsets of human NK cells, CD56<jats:sup>bright<\/jats:sup>CD16<jats:sup>-<\/jats:sup>and CD56<jats:sup>dim<\/jats:sup>CD16<jats:sup>+<\/jats:sup>, and these displayed an enhanced cytotoxicity<jats:italic>in vitro<\/jats:italic>. Using human PBMCs and isolated NK cells, we showed that SOT101 added concomitantly or used for immune cell pre-stimulation potentiated clinically approved monoclonal antibodies Cetuximab, Daratumumab and Obinutuzumab in killing of tumor cells<jats:italic>in vitro<\/jats:italic>. The anti-tumor efficacy of SOT101 in combination with Daratumumab was assessed in a solid multiple myeloma xenograft in CB17 SCID mouse model testing several combination schedules of administration in the early and late therapeutic setting of established tumors<jats:italic>in vivo<\/jats:italic>. SOT101 and Daratumumab monotherapies decreased with various efficacy tumor growth<jats:italic>in vivo<\/jats:italic>in dependence on the advancement of the tumor development. The combination of both drugs showed the strongest anti-tumor efficacy. Specifically, the sequencing of both drugs did not matter in the early therapeutic setting where a complete tumor regression was observed in all animals. In the late therapeutic treatment of established tumors Daratumumab followed by SOT101 administration or a concomitant administration of both drugs showed a significant anti-tumor efficacy over the respective monotherapies. These results suggest that SOT101 might significantly augment the anti-tumor activity of therapeutic antibodies by increasing NK cell-mediated activity in patients. These results support the evaluation of SOT101 in combination with Daratumumab in clinical studies and present a rationale for an optimal clinical dosing schedule selection.<\/jats:p>","DOI":"10.3389\/fimmu.2022.989895","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T15:06:49Z","timestamp":1665414409000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor 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