anti-PD-1/IL-2Ra/IL-2 fusion protein REGN10597

An antibody fusion protein composed of an antibody fragment targeting the negative immunoregulatory human cell receptor programmed cell death protein 1 (PD-1; PDCD1; CD279) and fused to the endogenous cytokine interleukin-2 (IL-2) and masked with an antibody fragment directed against the IL-2 receptor subunit alpha (IL2Ra; CD25) binding-site on IL-2, with potential immunostimulating and antineoplastic activities. Upon administration, anti-PD-1/IL-2Ra/IL-2 fusion protein REGN10597 targets and binds to PD-1 expressed on PD-1-expressing T cells in the tumor microenvironment (TME), thereby specifically bringing IL-2 to the PD-1-positive T cells in the TME. The PD-1 binding specifically induces a confirmational change in REGN10597 that allows its IL-2 moiety to bind to the IL-2Ra expressed on PD-1-positive CD8+ T effector cells and natural killer (NK) cells, thereby activating IL2Ra-mediated signaling within these immune cells. The activation of cytotoxic T-lymphocytes (CTLs) and NK cells mediate cytolytic immune responses against tumor cells causing tumor cell destruction and inhibition of tumor cell proliferation. By selectively activating PD-1 positive T cells with IL-2, but not PD-1 negative bystander or naïve T cells, the activity of tumor specific T cells is specifically enhanced while IL-2-induced systemic toxicity is decreased. 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); it plays an important role in tumor evasion from host immunity. The receptor-masked IL-2 allows for specific activation of IL-2 in the presence of PD-1-positive cells in the TME.