Preclinical characterization of 1-7F9, a novel human anti–KIR receptor therapeutic antibody that augments natural killer–mediated killing of tumor cells

摘要: Inhibitory-cell killer immunoglobulin-like receptors (KIR) negatively regulate natural (NK) cell-mediated killing of HLA class I-expressing tumors. Lack KIR-HLA I interactions has been associated with potent NK-mediated antitumor efficacy and increased survival in acute myeloid leukemia (AML) patients upon haploidentical stem cell transplantation from KIR-mismatched donors. To exploit this pathway pharmacologically, we generated a fully human monoclonal antibody, 1-7F9, which cross-reacts KIR2DL1, -2, -3 receptors, prevents their inhibitory signaling. The 1-7F9 antibody augmented NK lysis HLA-C-expressing tumor cells, including autologous AML blasts, but did not induce normal peripheral blood mononuclear suggesting therapeutic window for preferential enhancement NK-cell cytotoxicity against malignant target cells. Administration to KIR2DL3-transgenic mice resulted dose-dependent rejection HLA-Cw3-positive In an immunodeficient mouse model inoculation cells alone was unable protect lethal, AML, preadministration long-term survival. These data show that confers specific, stable blockade KIR, boosting HLA-matched blasts vitro vivo, providing preclinical basis initiating phase 1 clinical trials candidate antibody.