Denosumab, a Fully Human Monoclonal Antibody to RANKL, Inhibits Bone Resorption and Increases BMD in Knock‐In Mice That Express Chimeric (Murine/Human) RANKL

摘要: RANKL is a TNF family member that mediates osteoclast formation, activation, and survival by activating RANK. The proresorptive effects of are prevented binding to its soluble inhibitor osteoprotegerin (OPG). Recombinant human OPG-Fc recognizes from multiple species reduced bone resorption increased volume, density, strength in number rodent models disease. clinical development was discontinued favor denosumab, fully monoclonal antibody specifically inhibits primate RANKL. Direct assays showed denosumab bound but not murine RANKL, TRAIL, or other members. Denosumab did suppress normal mice rats prevent the resorptive response challenged with fragment encoded primarily fifth exon gene. To create were responsive knock-in technology used replace 5 ortholog. resulting "huRANKL" exclusively express chimeric (human/murine) measurable assay maintained at slightly levels versus wildtype controls. In young huRANKL mice, each trabecular surfaces 95% density volume. adult resorption, cortical cancellous mass, improved microarchitecture. These have potential utility for characterizing activity variety disease models.