Anti-PD-1-IL-15 Prodrug Fusion Molecule ASKG915

**Semantic type:** Pharmacologic Substance

**Definition:** A fusion protein composed of a recombinant human monoclonal antibody targeting the negative immunoregulatory human cell receptor programmed cell death protein 1 (PD-1; PDCD1; CD279) fused to a prodrug for the immunostimulatory cytokine interleukin-15 (IL-15), composed of a potency reduced, mutein form of interleukin (IL)-15 complexed with the high-affinity IL-15 receptor alpha (IL-15Ra) binding sushi domain, that is masked by a protease-cleavable masking protein, with potential immune checkpoint inhibitory, immunomodulating and antineoplastic activities. Upon administration of anti-PD-1-IL-15 prodrug fusion molecule ASKG915, 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 a T-cell-mediated immune response against tumor cells. Upon cleavage of the protease-cleavable linker by proteases overexpressed in the tumor environment (TME), the IL-15 mutein moiety binds to the IL-15 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 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. The IL-15 mutein form lowers systemic toxicity of IL-15. Protease-dependent activation of IL-15 increases its efficacy and decreases systemic toxicity. IL-15Ra complexed with IL-15 domain improves stability and increases the half-life of IL-15.

**Synonyms:** - ASK G915 - ASK-G915 - ASKG915 - Anti PD-1 Antibody-IL-15 Prodrug Fusion Molecule ASKG915