Natural killer cell p46-related protein ligands (NKp46L)

NKp46 ligands represent a heterogeneous class of molecules expressed on the surface of malignant or pathogen-infected cells that serve as the primary recognition signals for the NKp46 (NCR1/CD335) activating receptor on Natural Killer (NK) cells [Mandelboim O, et al., 2001]. These ligands include viral proteins such as hemagglutinins from influenza and Sendai viruses, bacterial components like the Fap2 protein of Fusobacterium nucleatum, and host-derived molecules such as specific heparan sulfate proteoglycans (HSPGs) and calreticulin [Bloushtain N, et al., 2004; Gur C, et al., 2015]. The interaction between NKp46 and its ligands is a critical step in the innate immune system's ability to identify and eliminate stressed or non-self cells without prior sensitization. In many cancers, the downregulation or shedding of these ligands serves as a mechanism of immune escape, allowing tumors to evade NK cell-mediated destruction. From a therapeutic perspective, the NKp46-ligand axis is being heavily exploited through the development of multispecific NK cell engagers (NKCEs). These drugs, such as those based on the ANKET (Antibody-based NK cell Engager Therapeutics) platform, are designed to bypass natural ligand requirements by physically linking the NKp46 receptor to a known tumor-associated antigen [Gauthier L, et al., 2019]. This approach triggers potent NK cell activation and targeted cytotoxicity against tumor cells. Clinical development of these agents, including SAR443579 and IPH6501, is currently focused on hematological malignancies and solid tumors, with safety profiles generally showing a lower risk of severe cytokine release syndrome compared to T-cell engaging therapies [Coiffier B, et al., 2021].

Other names

NCR1 ligandsCD335 ligandsNKp46-binding ligandsViral hemagglutininsHeparan sulfate proteoglycansNKp46L

NK cell activation via NKp46 receptor engagement leading to targeted cell lysis