Definition

A fusion protein composed of a pentameric immunoglobulin M (IgM) antibody directed against the immunosuppressive ligand programmed cell death-1 ligand 1 (PD-L1; cluster of differentiation 274; CD274) fused to interleukin (IL)-15/IL-15 receptor alpha (IL-15Ra) complex, with potential immunostimulatory and antineoplastic activities. Upon administration of the anti-PD-L1 antibody/IL-15 fusion protein IGM-7354, the anti-PD-L1 antibody moiety specifically targets and binds to PD-L1 expressing cancer cells and antigen presenting cells (APCs) in the tumor microenvironment (TME), thereby delivering IL-15 to PD-L1-expressing tumor cells. In turn, the IL-15 stimulates the proliferation of natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) and memory T cells locally, and reverses T-cell exhaustion. This induces an anti-tumor immune response in the TME against PD-L1-expressing tumor cells. PD-L1, a transmembrane protein, is expressed on APCs and on various cancer cell types. PD-L1 binding to PD-1, a negative regulator of the immune system on activated T-cells, limits the expansion and survival of CD8-positive T cells, suppresses the immune system and results in immune evasion. The immunostimulatory cytokine IL-15 regulates CD8+ T and NK cell development, activation, and proliferation. IL-15Ra complexed with IL-15 increases the half-life of IL-15. By binding to PD-L1-expressing cells in the TME, IGM-7354 enhances its IL-15-mediated activity on the immune system locally and increases its efficacy while reducing systemic toxicities.