[Monoclonal antibody targeting RANKL as a therapy for cancer-induced bone diseases].
Receptor activator of NF-kappaB ligand (RANKL), its receptor RANK, and osteoprotegerin (OPG), the physiological inhibitor of RANKL, were discovered using a genomics-based approach. Bone loss is dependent on RANKL, the primary mediator of osteoclast formation, function, and survival. The study of the RANK/RANKL/OPG axis in animal models has firmly established the central importance of this pathway in bone mass regulation and provided the initial rationale for the design of a mechanism-based targeted approach to inhibit RANKL in pathologic bone loss settings, including cancer-induced bone disease. Denosumab (AMG 162), a fully human monoclonal antibody that can bind and inhibit human RANKL in a way that mimics the natural bone-protecting actions of OPG, is currently in development. A phase 1 clinical trial in patients with multiple myeloma or breast carcinoma with bone metastases showed that a single subcutaneous injection of denosumab caused rapid and sustained suppression of bone turnover markers and was well tolerated. Larger trials are underway to investigate the effect of denosumab for the treatment of cancer-induced bone disease and other bone loss disorders.
Amgen Inc. Washington, Department of Cancer Biology, Seattle, WA, USA.
William
W
Dougall
Michelle
M
Chaisson
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001847:Bone Diseases / Q000188:drug therapy* / Q000209:etiology*; D002352:Carrier Proteins / Q000276:immunology*; D017321:Clinical Trials, Phase I as Topic; D000069448:Denosumab; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology*; D009369:Neoplasms / Q000150:complications*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D000069448:Denosumab