ABSTRACT: IgM antibodies are preformed pentameric or hexameric molecules that can be engineered to generate high affinity and high avidity fully human antibody therapeutics. In this study, we report an immunocytokine, IGM-7354, which was designed to bind multiple PD-L1 receptors while trans-presenting a single IL-15/IL-15R_ complex on the joining chain to IL-15R__-expressing cytotoxic natural killer (NK) and CD8+ T-cells. We evaluated the pharmacological and anti-tumor properties of IGM-7354 in preclinical models. IGM-7354 induced potent proliferation of NK and CD8+ T-cells, both in vitro using healthy human PBMCs and in vivo in humanized mice, through the IL-15/IL-15R_ complex. In a mixed-lymphocyte reaction assay with exhausted human T-cells, IGM-7354 restored the secretion of IFN_ compared to the IL-15/IL-15R_ complex or anti-PD-L1 alone, suggesting a rescue of exhausted T-cells in vitro. Robust single agent activity was observed in the humanized PD-L1+ MDA-MB-231 breast cancer mouse model. Anti-tumor responses were enhanced by adding IGM-7354 to the anti-CD38 daratumumab in RPMI-8226 multiple myeloma or anti-CD19 CAR T-cell therapies in Raji lymphoma models. Finally, in cynomolgus monkeys, pharmacodynamic activity of increased NK and CD8+ T-cell proliferation was observed in multiple tissue compartments. Taken together, this study demonstrates the feasibility of developing a safe and effective IgM-based immunocytokine for the treatment of cancer, exploiting the multivalency of an IgM antibody to bind PD-L1 with high affinity and avidity and stimulate NK and CD8+ T-cell effectors.