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Blood, 24 September 2009, Vol. 114, No. 13, pp. 2667-2677. Prepublished online as a Blood First Edition Paper on June 24, 2009; DOI 10.1182/blood-2009-02-206532. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-02-206532v1 114/13/2667    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Romagné, F. Articles by Wagtmann, N. PubMed PubMed Citation Articles by Romagné, F. Articles by Wagtmann, N. Related Collections Immunobiology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Preclinical characterization of 1-7F9, a novel human anti–KIR receptor therapeutic antibody that augments natural killer–mediated killing of tumor cells Francois Romagné1, Pascale André1, Pieter Spee2, Stefan Zahn2, Nicolas Anfossi1, Laurent Gauthier1, Marusca Capanni3, Loredana Ruggeri3, Don M. Benson, Jr4, Bradley W. Blaser4, Mariella Della Chiesa5, Alessandro Moretta5, Eric Vivier6, Michael A. Caligiuri4, Andrea Velardi3, and Nicolai Wagtmann2 1 Innate-Pharma, Marseille, France; 2 Biopharmaceuticals Research Unit, Novo Nordisk, Maaloev, Denmark; 3 Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; 4 Ohio State University Comprehensive Cancer Center, Columbus; 5 Dipartimento di Medicina Sperimentale e Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, V le Benedetto XV, Genova, Italy; and 6 Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Inserm, Centre National de la Recherche Scientifique (CNRS), Marseille, France 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: NK antibody therapy: KIR-ative intent Nina Shah and Elizabeth J. Shpall Blood 2009 114: 2567-2568. [Full Text] [PDF] This article has been cited by other articles: N. Shah and E. J. Shpall NK antibody therapy: KIR-ative intent Blood, September 24, 2009; 114(13): 2567 - 2568. [Full Text] [PDF]

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