title: Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide.
abstract: Despite recent treatment improvements, multiple myeloma remains an incurable disease. Since antibody-dependent cell-mediated cytotoxicity is an important effector mechanism of daratumumab, we explored the possibility of improving daratumumab-mediated cell-mediated cytotoxicity by blocking natural killer cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of natural killer cells with the immune modulatory drug lenalidomide. In 4-hour antibody-dependent cell-mediated cytotoxicity assays, IPH2102 did not induce lysis of multiple myeloma cell lines, but it did significantly augment daratumumab-induced myeloma cell lysis. Also in an ex vivo setting, IPH2102 synergistically improved daratumumab-dependent lysis of primary myeloma cells in bone marrow mononuclear cells (n=21), especially in patients carrying the FcγRIIIa-158F allele or the FcγRIIa-131R allele, who bind IgG1 with lower affinity than patients carrying the FcγRIIIa-158V allele or the FcγRIIa-131H allele. Finally, a further synergistically improved myeloma cell lysis with the daratumumab-IPH2102 combination was observed by adding lenalidomide, which suggests that more effective treatment strategies can be designed for multiple myeloma by combining daratumumab with agents that independently modulate natural killer cell function.
authors.affiliation: Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, The Netherlands Department of Hematology, University Medical Center Utrecht, The Netherlands Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Inger S
authors.initials: IS
authors.lastname: Nijhof
authors.affiliation: Genmab, Utrecht, The Netherlands.
authors.forename: Jeroen J
authors.initials: JJ
authors.lastname: Lammerts van Bueren
authors.affiliation: Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, The Netherlands Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Berris
authors.initials: B
authors.lastname: van Kessel
authors.affiliation: Research & Development, Innate Pharma, Marseille, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Andre
authors.affiliation: Research & Development, Innate Pharma, Marseille, France.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Morel
authors.affiliation: Department of Hematology, University Medical Center Utrecht, The Netherlands Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Lokhorst
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Niels W C J
authors.initials: NW
authors.lastname: van de Donk
authors.affiliation: Genmab, Utrecht, The Netherlands Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
authors.affiliation: Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, The Netherlands Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands t.mutis@vumc.nl.
authors.forename: Tuna
authors.initials: T
authors.lastname: Mutis
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D011110:Polymorphism, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017452:Receptors, IgG / Q000235:genetics; D054340:Receptors, KIR / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000911:Antibodies, Monoclonal; C445323:FCGR2A protein, human; D007074:Immunoglobulin G; D012333:RNA, Messenger; D017452:Receptors, IgG; D054340:Receptors, KIR; C556306:daratumumab; D013792:Thalidomide; D000077269:Lenalidomide