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.
Highlights
RANK (TNFRSF11A), osteoprotegerin (OPG, TNFRSF11B), and their ligand (RANKL, TNFSF11) are key regulators of bone remodeling [1]
While this confirmed that multiple myeloma cells can express RANKL mRNA and protein, it shows that mRNA and protein expression, both with regard to membrane-bound RANKL (mRANKL) and soluble form of RANKL (sRANKL), do not necessarily correlate
While some investigators reported that primary multiple myeloma cells express RANKL themselves, others attributed RANKL expression to other cell types in bone marrow of patients with multiple myeloma [3, 8,9,10]
Summary
RANK (TNFRSF11A), osteoprotegerin (OPG, TNFRSF11B), and their ligand (RANKL, TNFSF11) are key regulators of bone remodeling [1]. RANKL may further influence progression of Bcell–derived malignancies such as chronic lymphocytic leukemia (CLL) or multiple myeloma [2, 3]. In CLL, RANKL mediates release of IL-8, which contributes to disease pathophysiology [2]. The balance of RANKL and OPG is disrupted causing activation of osteoclasts and bone destruction, and RANKL neutralization delayed multiple myeloma progression in mice [3,4,5,6]. Authors' Affiliations: Departments of 1Hematology and Oncology and 2Immunology, Eberhard Karls University, Tuebingen, Germany; 3Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan; and 4Department of Biochemistry, University of Lausanne, Epalinges, Switzerland. B.J. Schmiedel and C.A. Scheible contributed to this work
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