Therapeutic agents for disorders of bone and calcium metabolism--Denosumab, a fully human monoclocal antibody-targeting RANKL as a therapy for cancer-induced bone diseases

Abstract

Receptor activator of nuclear-kappaB ligand (RANKL) is a protein expressed by oseoblastic stromal cells, binds to receptor activator of nuclear factor-kappaB (RANK) and is the primary mediator of osteoclast differentiation, activation, and survival. RANKL is responsible for osteoclast-mediated bone resorption in a broad range of conditions and play a key role in establishment and propagation of skeletal disease in patients with advanced cancer. Denosumab is a fully human monoclonal antibody that binds RANKL with high affinity and specificity and inhibits RANKL-RANK interaction, mimicking the endogenous effects of osteoprotegerin, a soluble RANKL decoy receptor. In the phase 1 clinical trials in healthy post menopausal women and patients with multiple myeloma or breast cancer with bone metastasis including Japanese (except for multiple myeloma) showed that single and multiple subcutaneous injection of denosumab caused rapid and sustained suppression of markers of osteoclastic bone resorption with favorable safety profiles. Currently, the larger global clinical trials to investigate the effect of this agent for the treatment of cancer-induced bone disease as well as osteoporosis are underway.