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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Monoclonal, Humanized
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Antigen-Antibody Complex
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Cell Line, Tumor
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Cell Survival / drug effects
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Cells, Cultured
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Cytotoxicity, Immunologic / drug effects
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Drug Evaluation, Preclinical
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Humans
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Immunomodulation / drug effects
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Killer Cells, Natural / drug effects*
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Lenalidomide
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism
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Ligands
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Mice
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Mice, Inbred C57BL
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Multiple Myeloma / blood
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / immunology
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Multiple Myeloma / metabolism
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Receptors, KIR / antagonists & inhibitors*
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Thalidomide / analogs & derivatives*
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Thalidomide / pharmacology
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Thalidomide / therapeutic use
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Up-Regulation / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antigen-Antibody Complex
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Antineoplastic Agents
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Ligands
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Receptors, KIR
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Thalidomide
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IPH-2101
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Lenalidomide