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Article from the Symposium
RANK-Fc: A therapeutic antagonist for RANK-L in myeloma
Version of Record online: 23 JAN 2003
Copyright © 2003 American Cancer Society
Supplement: Skeletal Complications of Malignancy
Volume 97, Issue Supplement 3, pages 802–812, 1 February 2003
How to Cite
Sordillo, E. M. and Pearse, R. N. (2003), RANK-Fc: A therapeutic antagonist for RANK-L in myeloma. Cancer, 97: 802–812. doi: 10.1002/cncr.11134
- Issue online: 23 JAN 2003
- Version of Record online: 23 JAN 2003
- Manuscript Accepted: 1 NOV 2002
- Manuscript Received: 15 JUL 2002
- International Myeloma Foundation
- Leukemia Society of America
- Dorothy Rodbell Cohen Foundation
- Charles A. Mastronardi Foundation
- receptor activator of NF-κB ligand;
- tumor necrosis factor-related activation-induced cytokine;
- multiple myeloma;
- monoclonal gammopathy of undetermined significance;
Severe bone destruction due to inappropriate osteoclastogenesis is a prominent feature of multiple myeloma (MM). MM increases bone loss by disrupting the checks that normally control signaling by receptor activator of nuclear factor κB ligand (RANK-L, also called TRANCE [tumor necrosis factor-related, activation-induced cytokine], osteoprotegerin ligand [OPG-L], osteoclast differentiation factor [ODF], and tumor necrosis factor superfamily member 11 [TNFSF11]), a TNF-family cytokine required for osteoclast differentiation and activation. RANK-L binds to its functional receptor RANK (TNF receptor superfamily member 11a [TNF RSF11a]) to stimulate osteoclastogenesis. Osteotropic cytokines regulate this process by controlling bone marrow stromal expression of RANK-L. Further control over osteoclastogenesis is maintained by regulated expression of osteoprotegerin (OPG, also called osteoclastogenesis inhibitory factor and TNFRSF11b), a soluble decoy receptor for RANK-L. In normal bone marrow, abundant stores of OPG in stroma, megakaryocytes, and myeloid cells provide a natural buffer against increased RANK-L. MM disrupts these controls by increasing expression of RANK-L and decreasing expression of OPG. Concurrent deregulation of RANK-L and OPG expression is found in bone marrow biopsies from patients with MM but not in specimens from patients with non-MM hematologic malignancies.
RANK-Fc is a recombinant RANK-L antagonist that is formed by fusing the extracellular domain of RANK to the Fc portion of human immunoglobulin G1 (hIgG1). In vitro, addition of RANK-Fc virtually eliminates the formation of osteoclasts in cocultures of MM with bone marrow and osteoblast/stromal cells. The severe combined immunodeficiency (SCID)/ARH77 mouse model and the SCID-hu-MM mouse model of human MM were used to assess the ability of RANK-Fc to block the development of MM-induced bone disease in vivo. Mice received either RANK-Fc or hIgG1 200 μg intravenously three times per week.
RANK-Fc limited bone destruction in both the SCID/ARH-77 model and the SCID-hu-MM model. Administration of RANK-Fc also caused a marked reduction in tumor burden and serum paraprotein in SCID-hu-MM mice that was associated with the restoration of OPG and a reduction in RANK-L expression in the xenograft.
MM-induced bone destruction requires increased RANK-L expression and is facilitated by a concurrent reduction in OPG, a natural decoy receptor for RANK-L. Administration of the RANK-L antagonist RANK-Fc limits MM-induced osteoclastogenesis, development of bone disease, and MM tumor progression. Cancer 2003;97(3 Suppl):802–12. © 2003 American Cancer Society.