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Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells.
Blood 2009; 114(13):2667-77Blood

Abstract

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.

Authors+Show Affiliations

Innate-Pharma SA, Marseille, France. Francois.romagne@innate-pharma.frNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Evaluation Studies
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19553639

Citation

Romagné, Francois, et al. "Preclinical Characterization of 1-7F9, a Novel Human anti-KIR Receptor Therapeutic Antibody That Augments Natural Killer-mediated Killing of Tumor Cells." Blood, vol. 114, no. 13, 2009, pp. 2667-77.
Romagné F, André P, Spee P, et al. Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood. 2009;114(13):2667-77.
Romagné, F., André, P., Spee, P., Zahn, S., Anfossi, N., Gauthier, L., ... Wagtmann, N. (2009). Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood, 114(13), pp. 2667-77. doi:10.1182/blood-2009-02-206532.
Romagné F, et al. Preclinical Characterization of 1-7F9, a Novel Human anti-KIR Receptor Therapeutic Antibody That Augments Natural Killer-mediated Killing of Tumor Cells. Blood. 2009 Sep 24;114(13):2667-77. PubMed PMID: 19553639.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. AU - Romagné,Francois, AU - André,Pascale, AU - Spee,Pieter, AU - Zahn,Stefan, AU - Anfossi,Nicolas, AU - Gauthier,Laurent, AU - Capanni,Marusca, AU - Ruggeri,Loredana, AU - Benson,Don M,Jr AU - Blaser,Bradley W, AU - Della Chiesa,Mariella, AU - Moretta,Alessandro, AU - Vivier,Eric, AU - Caligiuri,Michael A, AU - Velardi,Andrea, AU - Wagtmann,Nicolai, Y1 - 2009/06/24/ PY - 2009/6/26/entrez PY - 2009/6/26/pubmed PY - 2009/10/29/medline SP - 2667 EP - 77 JF - Blood JO - Blood VL - 114 IS - 13 N2 - 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. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/19553639/Preclinical_characterization_of_1_7F9_a_novel_human_anti_KIR_receptor_therapeutic_antibody_that_augments_natural_killer_mediated_killing_of_tumor_cells_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=19553639 DB - PRIME DP - Unbound Medicine ER -