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

Romagné, François; Pèlegrin, André; Spee, Pieter; Zahn, Stefan; Anfossi, Nicolas; Gauthier, Laurent; Capanni, Marusca; Ruggeri, Loredana; Benson, Don M.; Blaser, Bradley W.; Chiesa, Mariella Della; Moretta, Alessandro; Vivier, Éric; Caligiuri, Michael A.; Velardi, Andrea; Wagtmann, Nicolai

doi:10.1182/blood-2009-02-206532

Cited by 356 publications

(340 citation statements)

References 46 publications

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“…Hence ''a therapeutic window'' for induction of selective tumor cell rejection appears to exist. Similar results have been obtained using KIR blocking Ab in vitro and in KIR/HLA-ligand double transgenic mice [36,37].…”

Section: Discussionsupporting

confidence: 85%

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

et al. 2010

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Missing-self-reactivity can be mimicked by blocking self-specific inhibitory receptors on NK cells, leading to increased rejection of syngeneic tumor cells. Using a mouse model, we investigated whether Ab-mediated blocking of inhibitory receptors, to a degree where NK cells rejected syngeneic tumor cells, would still allow self-tolerance toward normal syngeneic cells. Ly49C/I inhibitory receptors on C57BL/6 (H-2 b ) NK cells were blocked with F(ab') 2 fragments of the mAb 5E6. Inhibitory receptor blockade in vivo caused rejection of i.v. inoculated fluorescence-labeled syngeneic lymphoma line cells but not of syngeneic spleen cells, BM cells or lymphoblasts. The selective rejection of tumor cells was NK celldependent and specifically induced by Ly49C/I blockade. Moreover, selective tumor rejection was maintained after treatment with 5E6 F(ab') 2 for 9 wk, arguing against the induction of NK cell anergy or autoreactivity during this time. Combination therapy using 5E6 F(ab') 2 together with high dose IL-2 treatment further increased lymphoma cell rejection. In addition, combination therapy reduced growth of melanoma cell line tumors established by s.c. inoculation 3 days before start of treatment. Our results demonstrate that inhibitory receptor blockade does not result in attack on normal cells, despite potent reactivity against MHC class I-expressing tumors.

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Section: Discussionsupporting

confidence: 85%

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

et al. 2010

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“…A novel human anti-KIR receptor therapeutic antibody that blocks KIR2DL1-3 impressively augments NK-mediated tumor cell killing. 183 Study in a preclinical mouse model with all NK cells educated by a single transgenic inhibitory receptor, human KIR2DL3, by engaging its ligand, HLA-Cw3 indicated that anti-KIR mAb treatment induced HLA 1 target cell lysis without breaking self-tolerance in vivo, and long-term anti-KIR mAb infusion did not abolish NK cell education or tumor cell recognition. 184 Therefore, blocking inhibitory receptors like KIR may be an effective way to enhance NK cell-mediated cytotoxicity toward tumors.…”

Section: Clinical Trials Of Nk Cell-mediated Tumor Immunotherapymentioning

confidence: 99%

NK cell-based immunotherapy for malignant diseases

et al. 2013

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Natural killer (NK) cells play critical roles in host immunity against cancer. In response, cancers develop mechanisms to escape NK cell attack or induce defective NK cells. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells (iPSCs), and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice (GMP) facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators. A list of NK cell therapies to treat several types of cancer in clinical trials is reviewed here. Several different approaches to NK-based immunotherapy, such as tissue-specific NK cells, killer receptor-oriented NK cells and chemically treated NK cells, are discussed. A few new techniques or strategies to monitor NK cell therapy by non-invasive imaging, predetermine the efficiency of NK cell therapy by in vivo experiments and evaluate NK cell therapy approaches in clinical trials are also introduced.

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“…Studies are ongoing to harness the reactivity of endogenous NK cells in patients with hematological malignancies, including AML, by administration of anti-KIR antibodies that can block NK cell inhibitory recognition without breaking selftolerance. [94][95][96] Indirect NK cell targeting by conditioning of the tumor cell A comparable scenario in favor of promoting NK cell cytotoxicity may be achieved by modulation of the tumor cells, rendering them more susceptible to NK cell recognition, which would facilitate their rapid elimination. Improvement of tumor cell immunogenicity could also promote uptake by DC and crosspresentation of tumor antigens to T cells.…”

Section: Nk Cell Immune Escape In Aml E Lion Et Almentioning

confidence: 99%