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A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo.

Abstract

The inability of the immune system to recognize and kill malignant plasma cells in patients with multiple myeloma (MM) has been attributed in part to the ineffective activation of natural killer (NK) cells. In order to activate and target NK cells to the malignant cells in MM we designed a novel recombinant bispecific protein (ULBP2-BB4). While ULBP2 binds the activating NK receptor NKG2D, the BB4 moiety binds to CD138, which is overexpressed on a variety of malignancies, including MM. ULBP2-BB4 strongly activated primary NK cells as demonstrated by a significant increase in interferon-gamma (IFN-gamma) secretion. In vitro, ULBP2-BB4 enhanced the NK-mediated lysis of 2 CD138+ human MM cell lines, U-266 and RPMI-8226, and of primary malignant plasma cells in the allogenic and autologous setting. Moreover, in a nude mouse model with subcutaneously growing RPMI-8226 cells, the cotherapy with ULBP-BB4 and human peripheral blood lymphocytes abrogated the tumor growth. These data suggest potential clinical use of this novel construct in patients with MM. The use of recombinant NK receptor ligands that target NK cells to tumor cells might offer new approaches for other malignancies provided a tumor antigen-specific antibody is available.

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  • Authors+Show Affiliations

    ,

    Laboratory of Immunotherapy, Department I for Internal Medicine, University Hospital of Cologne, Kerpener Str 62, D-50924 Köln, Germany. e.pogge@uni-koeln.de

    , , , , , , , , , ,

    Source

    Blood 107:5 2006 Mar 01 pg 1955-62

    MeSH

    Animals
    Antibodies, Monoclonal
    COS Cells
    Carrier Proteins
    Cell Line, Tumor
    Cercopithecus aethiops
    Drug Delivery Systems
    GPI-Linked Proteins
    Histocompatibility Antigens Class I
    Humans
    Immunoglobulin Variable Region
    Intercellular Signaling Peptides and Proteins
    Killer Cells, Natural
    Lymphocyte Activation
    Membrane Glycoproteins
    Mice
    Mice, Nude
    Multiple Myeloma
    NK Cell Lectin-Like Receptor Subfamily K
    Neoplasm Transplantation
    Proteoglycans
    Receptors, Immunologic
    Receptors, Natural Killer Cell
    Recombinant Fusion Proteins
    Syndecan-1
    Syndecans

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    16210338

    Citation

    von Strandmann, Elke Pogge, et al. "A Novel Bispecific Protein (ULBP2-BB4) Targeting the NKG2D Receptor On Natural Killer (NK) Cells and CD138 Activates NK Cells and Has Potent Antitumor Activity Against Human Multiple Myeloma in Vitro and in Vivo." Blood, vol. 107, no. 5, 2006, pp. 1955-62.
    von Strandmann EP, Hansen HP, Reiners KS, et al. A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo. Blood. 2006;107(5):1955-62.
    von Strandmann, E. P., Hansen, H. P., Reiners, K. S., Schnell, R., Borchmann, P., Merkert, S., ... Engert, A. (2006). A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo. Blood, 107(5), pp. 1955-62.
    von Strandmann EP, et al. A Novel Bispecific Protein (ULBP2-BB4) Targeting the NKG2D Receptor On Natural Killer (NK) Cells and CD138 Activates NK Cells and Has Potent Antitumor Activity Against Human Multiple Myeloma in Vitro and in Vivo. Blood. 2006 Mar 1;107(5):1955-62. PubMed PMID: 16210338.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo. AU - von Strandmann,Elke Pogge, AU - Hansen,Hinrich P, AU - Reiners,Katrin S, AU - Schnell,Roland, AU - Borchmann,Peter, AU - Merkert,Sabine, AU - Simhadri,Venkateswara R, AU - Draube,Andreas, AU - Reiser,Marcel, AU - Purr,Ingvill, AU - Hallek,Michael, AU - Engert,Andreas, Y1 - 2005/10/06/ PY - 2005/10/8/pubmed PY - 2006/4/4/medline PY - 2005/10/8/entrez SP - 1955 EP - 62 JF - Blood JO - Blood VL - 107 IS - 5 N2 - The inability of the immune system to recognize and kill malignant plasma cells in patients with multiple myeloma (MM) has been attributed in part to the ineffective activation of natural killer (NK) cells. In order to activate and target NK cells to the malignant cells in MM we designed a novel recombinant bispecific protein (ULBP2-BB4). While ULBP2 binds the activating NK receptor NKG2D, the BB4 moiety binds to CD138, which is overexpressed on a variety of malignancies, including MM. ULBP2-BB4 strongly activated primary NK cells as demonstrated by a significant increase in interferon-gamma (IFN-gamma) secretion. In vitro, ULBP2-BB4 enhanced the NK-mediated lysis of 2 CD138+ human MM cell lines, U-266 and RPMI-8226, and of primary malignant plasma cells in the allogenic and autologous setting. Moreover, in a nude mouse model with subcutaneously growing RPMI-8226 cells, the cotherapy with ULBP-BB4 and human peripheral blood lymphocytes abrogated the tumor growth. These data suggest potential clinical use of this novel construct in patients with MM. The use of recombinant NK receptor ligands that target NK cells to tumor cells might offer new approaches for other malignancies provided a tumor antigen-specific antibody is available. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/16210338/A_novel_bispecific_protein__ULBP2_BB4__targeting_the_NKG2D_receptor_on_natural_killer__NK__cells_and_CD138_activates_NK_cells_and_has_potent_antitumor_activity_against_human_multiple_myeloma_in_vitro_and_in_vivo_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=16210338 DB - PRIME DP - Unbound Medicine ER -