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IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect.

Abstract

Multiple myeloma (MM) patients who receive killer cell Ig-like receptor (KIR) ligand-mismatched, T cell-depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand-matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.

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  • Authors+Show Affiliations

    ,

    Division of Hematology, The Ohio State University, Columbus, OH, USA. don.benson@osumc.edu

    , , , , , , , , , , , , , ,

    Source

    Blood 118:24 2011 Dec 08 pg 6387-91

    MeSH

    Animals
    Antibodies, Monoclonal
    Antigen-Antibody Complex
    Antineoplastic Agents
    Cell Line, Tumor
    Cell Survival
    Cells, Cultured
    Cytotoxicity, Immunologic
    Drug Evaluation, Preclinical
    Humans
    Immunomodulation
    Killer Cells, Natural
    Lenalidomide
    Leukocytes, Mononuclear
    Ligands
    Mice
    Mice, Inbred C57BL
    Multiple Myeloma
    Receptors, KIR
    Thalidomide
    Up-Regulation
    Xenograft Model Antitumor Assays

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22031859

    Citation

    Benson, Don M., et al. "IPH2101, a Novel Anti-inhibitory KIR Antibody, and Lenalidomide Combine to Enhance the Natural Killer Cell Versus Multiple Myeloma Effect." Blood, vol. 118, no. 24, 2011, pp. 6387-91.
    Benson DM, Bakan CE, Zhang S, et al. IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect. Blood. 2011;118(24):6387-91.
    Benson, D. M., Bakan, C. E., Zhang, S., Collins, S. M., Liang, J., Srivastava, S., ... Farag, S. S. (2011). IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect. Blood, 118(24), pp. 6387-91. doi:10.1182/blood-2011-06-360255.
    Benson DM, et al. IPH2101, a Novel Anti-inhibitory KIR Antibody, and Lenalidomide Combine to Enhance the Natural Killer Cell Versus Multiple Myeloma Effect. Blood. 2011 Dec 8;118(24):6387-91. PubMed PMID: 22031859.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect. AU - Benson,Don M,Jr AU - Bakan,Courtney E, AU - Zhang,Shuhong, AU - Collins,Shauna M, AU - Liang,Jing, AU - Srivastava,Shivani, AU - Hofmeister,Craig C, AU - Efebera,Yvonne, AU - Andre,Pascale, AU - Romagne,Francois, AU - Bléry,Mathieu, AU - Bonnafous,Cécile, AU - Zhang,Jianying, AU - Clever,David, AU - Caligiuri,Michael A, AU - Farag,Sherif S, Y1 - 2011/10/26/ PY - 2011/10/28/entrez PY - 2011/10/28/pubmed PY - 2012/2/15/medline SP - 6387 EP - 91 JF - Blood JO - Blood VL - 118 IS - 24 N2 - Multiple myeloma (MM) patients who receive killer cell Ig-like receptor (KIR) ligand-mismatched, T cell-depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand-matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/22031859/IPH2101_a_novel_anti_inhibitory_KIR_antibody_and_lenalidomide_combine_to_enhance_the_natural_killer_cell_versus_multiple_myeloma_effect_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=22031859 DB - PRIME DP - Unbound Medicine ER -