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

• Published in: Blood Vol. 114; no. 13; pp. 2667 - 2677
• Main Authors: Romagné, Francois, André, Pascale, Spee, Pieter, Zahn, Stefan, Anfossi, Nicolas, Gauthier, Laurent, Capanni, Marusca, Ruggeri, Loredana, Benson, Don M., Blaser, Bradley W., Della Chiesa, Mariella, Moretta, Alessandro, Vivier, Eric, Caligiuri, Michael A., Velardi, Andrea, Wagtmann, Nicolai
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 24.09.2009; Americain Society of Hematology; American Society of Hematology
• Series: Immunobiology
• Subjects: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cells, Cultured; Cytotoxicity, Immunologic; Cytotoxicity, Immunologic - drug effects; Hematologic and hematopoietic diseases; Humans; Immunobiology; Immunology; Immunotherapy; Immunotherapy - methods; Killer Cells, Natural; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Life Sciences; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Neoplasms; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Receptors, KIR; Receptors, KIR - antagonists & inhibitors; Receptors, KIR - immunology; Receptors, KIR2DL1; Receptors, KIR2DL1 - chemistry; Receptors, KIR2DL1 - genetics; Receptors, KIR2DL1 - immunology; Receptors, KIR2DL2; Receptors, KIR2DL2 - chemistry; Receptors, KIR2DL2 - genetics; Receptors, KIR2DL2 - immunology; Receptors, KIR2DL3; Receptors, KIR2DL3 - genetics; Receptors, KIR2DL3 - immunology; Up-Regulation; Up-Regulation - drug effects; Up-Regulation - immunology; Natural killer cell; Human; Natural antibody; Treatment; Hematology; Killer immunoglobulin like receptor; T-Lymphocyte; Killer cell; Tumor cell; Biological receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-02-206532

Inhibitory-cell killer immunoglobulin-like receptors (KIR) negatively regulate natural killer (NK) cell–mediated killing of HLA class I–expressing tumors. Lack of KIR-HLA class 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 with KIR2DL1, -2, and -3 receptors, and prevents their inhibitory signaling. The 1-7F9 monoclonal antibody augmented NK cell–mediated lysis of HLA-C–expressing tumor cells, including autologous AML blasts, but did not induce killing of normal peripheral blood mononuclear cells, suggesting a therapeutic window for preferential enhancement of NK-cell cytotoxicity against malignant target cells. Administration of 1-7F9 to KIR2DL3-transgenic mice resulted in dose-dependent rejection of HLA-Cw3–positive target cells. In an immunodeficient mouse model in which inoculation of human NK cells alone was unable to protect against lethal, autologous AML, preadministration of 1-7F9 resulted in long-term survival. These data show that 1-7F9 confers specific, stable blockade of KIR, boosting NK-mediated killing of HLA-matched AML blasts in vitro and in vivo, providing a preclinical basis for initiating phase 1 clinical trials with this candidate therapeutic antibody.