Abstract 5660: IGM-7354, an immunocytokine with IL-15 fused to an anti-PD-L1 IgM, induces NK and CD8+ T cell mediated cytotoxicity of PD-L1-positive tumor cells

Immunostimulatory cytokines are a promising immunotherapy for the treatment of advanced malignancies, but generally have been associated with severe toxicities when administered systemically. The recent development of antibody-cytokine fusion proteins, or immunocytokines, aims to localize cytokine activity to the tumor microenvironment and thus improve their therapeutic index. We have developed IGM-7354, a high affinity, high avidity anti-PD-L1 pentameric IgM antibody with an IL-15Rα chain and IL-15 fused to the joining (J) chain. The IGM-7354 immunocytokine was designed to deliver IL-15-mediated stimulation of NK and CD8+ T cells to PD-L1-expressing tumors and antigen-presenting cells, to enhance anti-tumor immune responses. The multivalent binding of IGM-7354 to PD-L1 provided a stronger binding avidity for human PD-L1 than the monovalent binding of IL-15 to IL-15Rb as confirmed in kinetic binding assays. In vitro IGM-7354 induced the proliferation of a cytotoxic T cell line responsive to IL-15 stimulation and enhanced the proliferation of NK and CD8+ T cells from healthy donor human PBMCs. In cytotoxicity assays with human PBMC and PD-L1+ cancer cell lines, IGM-7354 enhanced cancer cell killing through NK and CD8+ T cell expansion and cytotoxic activity, evidenced by Ki67 and Granzyme B upregulation in these cell populations. Next, in vivo pharmacodynamic studies were performed in two humanized mouse models: non-tumor-bearing BRGSF-HIS mice engrafted with human CD34+ cells, and PD-L1+ MDA-MB-231 tumor-bearing MHC-/- NSG mice engrafted with human PBMCs. In the BRGSF model, IGM-7354 increased NK cell activation and Granzyme B expression as well as NK and CD8+ T cell proliferation. In the tumor-bearing mouse model, IGM-7354 dose-dependently increased NK and CD8+ T cell proliferation in blood and infiltration of lymphocytes into the tumor. This pharmacodynamic activity correlated with IGM-7354 anti-tumor activity in the MDA-MB-231 model. Lastly, IGM-7354 increased the proliferation of NK and CD8+ T cells in cynomolgus monkeys and particularly induced the expansion of effector memory CD8+ T cells in the periphery. In summary, IGM-7354 induces NK and CD8+ T cell proliferation in both in vitro and in vivo preclinical models, resulting in the killing of PD-L1+ tumor cells. The strong avidity of IGM-7354 for PD-L1 may enhance IL-15 delivery to tumors and antigen-presenting cells and thus provide a more favorable safety profile. A Phase 1 clinical trial is planne