title: RANKL expression, function, and therapeutic targeting in multiple myeloma and chronic lymphocytic leukemia.
abstract: Bone destruction is a prominent feature of multiple myeloma, but conflicting data exist on the expression and pathophysiologic involvement of the bone remodeling ligand RANKL in this disease and the potential therapeutic benefits of its targeted inhibition. Here, we show that RANKL is expressed by primary multiple myeloma and chronic lymphocytic leukemia (CLL) cells, whereas release of soluble RANKL was observed exclusively with multiple myeloma cells and was strongly influenced by posttranscriptional/posttranslational regulation. Signaling via RANKL into multiple myeloma and CLL cells induced release of cytokines involved in disease pathophysiology. Both the effects of RANKL on osteoclastogenesis and cytokine production by malignant cells could be blocked by disruption of RANK-RANKL interaction with denosumab. As we aimed to combine neutralization of RANKL with induction of antibody-dependent cellular cytotoxicity of natural killer (NK) cells against RANKL-expressing malignant cells and as denosumab does not stimulate NK reactivity, we generated RANK-Fc fusion proteins with modified Fc moieties. The latter displayed similar capacity compared with denosumab to neutralize the effects of RANKL on osteoclastogenesis in vitro, but also potently stimulated NK cell reactivity against primary RANKL-expressing malignant B cells, which was dependent on their engineered affinity to CD16. Our findings introduce Fc-optimized RANK-Ig fusion proteins as attractive tools to neutralize the detrimental function of RANKL while at the same time potently stimulating NK cell antitumor immunity.
authors.affiliation: Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Benjamin Joachim
authors.initials: BJ
authors.lastname: Schmiedel
authors.forename: Carolin Andrea
authors.initials: CA
authors.lastname: Scheible
authors.forename: Tina
authors.initials: T
authors.lastname: Nuebling
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kopp
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirths
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Gundram
authors.initials: G
authors.lastname: Jung
authors.forename: Ludger
authors.initials: L
authors.lastname: Grosse-Hovest
authors.forename: Helmut Rainer
authors.initials: HR
authors.lastname: Salih
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D045744:Cell Line, Tumor; D000069448:Denosumab; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism*; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011961:Receptors, Fc / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014162:Transfection
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053245:RANK Ligand; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D000069448:Denosumab