anti-PD-1 antibody-IL-15/IL-15Ra fusion protein IAP0971

A heterodimeric and bifunctional fusion protein composed of four chains: two heavy chains targeting the negative immunoregulatory human cell receptor programmed cell death protein 1 (PD-1; PDCD1; CD279), one of which is fused to the cytokine interleukin-15 (IL-15) while the other one is fused to IL-15 receptor alpha (IL15Ralpha; IL15Ra) sushi domain, which fuses the IL-15/IL-15Ra sushi domain complex, and two anti-PD1 antibody light chains, with potential immune checkpoint inhibitory, immunomodulating and antineoplastic activities. Upon administration of anti-PD-1 antibody-IL-15/IL-15Ra fusion protein IAP0971, the PD-1 targeting moiety specifically targets, binds to and inhibits PD-1 and its downstream signaling pathways. This may restore immune function through the activation of T cells and induces a T-cell-mediated immune response against tumor cells. The IL-15 moiety specifically binds to the IL-2/15Rbeta,gamma receptor and activates IL-15-mediated signaling. This stimulates the proliferation of natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) and memory T cells locally in the in the tumor microenvironment (TME), and further induces an anti-tumor immune response. This may increase tumor cell killing and decrease tumor cell proliferation. 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; cluster of differentiation 274; CD274) or 2 (PD-L2; CD273); it plays an important role in tumor evasion from host immunity. IL-15 regulates CD8+ T- and NK-cell development, activation and proliferation. IL-15Ra complexed with IL-15 domain improves stability. IAP0971 increases specific signaling of IL-15 in the TME due to the high expression of PD-1 in the TME, thereby preventing systematic non-specific IL-15-mediated signaling.