期刊
BLOOD
卷 114, 期 13, 页码 2667-2677出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-02-206532
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类别
资金
- National Cancer Institute (NCI)/National Institutes of Health (NIH
- Bethesda, MD) [PO1 CA95426-01, R01 CA68458-08]
- Leukemia & Lymphoma Society
- Italian Association for Cancer Research
- Italian Ministry of Further Education
- Italian Ministry of Health
- European Community [LSHB-CT2004-503319]
- NIH [1 PO1 CA100265]
- Associazione Italiana per la Ricerca sul Cancro
- Istituto Superiore di Sanita
- Ministero della Sanita
- Ministero dell'Istruzione
- dell 'Universita' e della Ricerca Scientifica e Tecnologica
- European Union [LSHB-CT-2004-503319]
- Ligue Nationale contre le Cancer
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. (Blood. 2009; 114: 2667-2677)
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