Definition

A cis-acting immunocytokine and human Fc fusion protein composed of a humanized, Fc-silenced monoclonal antibody against the human negative immunoregulatory checkpoint receptor programmed cell death protein 1 (PD-1; PDCD1; CD279) fused to a covalent receptor-linker interleukin-15 (RLI-15) complex containing a human attenuated IL-15 mutein linked to the high-affinity binding sushi domain site of the IL-15 receptor alpha (IL-15Ralpha; IL-15Ra), with potential immunomodulatory and antineoplastic activities. Upon administration, IL-15 superagonist SOT201 targets and binds, with its anti-PD-1 moiety, to PD-1-expressing tumor-infiltrating lymphocytes (TILs), thereby blocking PD-1-mediated T-cell signaling in these cells in the tumor microenvironment (TME). This brings the IL-15 moiety to PD-1-expressing TILs in the TME. The attenuated IL-15 mutein moiety targets and binds, via the IL-2/IL-15betagamma receptor (IL-2/IL-15 receptor beta-common gamma chain), to antigen-specific PD-1-positive CD8+ T cells and natural killer cells (NK cells) without stimulating regulatory T cells (Tregs). This activates and increases the levels of NKs and antigen-specific PD-1-positive CD8+ T cells. The cytotoxic T lymphocytes (CTLs) enhance the secretion of the cytokine interferon-gamma (IFN-g), which further potentiates the immune response against tumor cells. This may increase CTL-mediated tumor cell killing and decrease tumor cell proliferation. IL-15 regulates CD8+ T and NK cell development, activation, and proliferation. The Fc moiety allows for an extended half-life of SOT201 while cross linking IL-15 with IL-15Ra sushi domain improves stability. PD-1, a transmembrane protein in the immunoglobulin superfamily (IgSF) expressed on T cells, functions as an immune checkpoint that negatively regulates T-cell activation and effector function when activated by its ligands, programmed cell death-1 ligand 1 (PD-L1; B7-H1; CD274) and 2 (PD-L2); it plays an important role in tumor evasion from host immunity.