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 IL15/IL15Rα complex on the joining chain to IL15Rβγ-expressing cytotoxic NK and CD8+ T cells. We evaluated the pharmacologic and antitumor properties of IGM-7354 in preclinical models. IGM-7354 induced potent proliferation of NK and CD8+ T cells, both in vitro using healthy human peripheral blood mononuclear cells and in vivo in humanized mice, through the IL15/IL15Rα complex. In a mixed-lymphocyte reaction assay with exhausted human T cells, IGM-7354 restored the secretion of IFNγ compared with the IL15/IL15Rα 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. Antitumor responses were enhanced by adding IGM-7354 to the anti-CD38 daratumumab in RPMI-8226 multiple myeloma or anti-CD19 chimeric antigen receptor 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.