A rate-limiting role for DKK1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody


Helmut Glantschnig, Kevin Scott, Richard Hampton, Nan Wei, Paul McCracken, Pascale Nantermet, Jing Zhao, Salvatore Vitelli, Lingyi Huang, Peter Haytko, Ping Lu, John Fisher, Punam Sandhu, Jacquellynn Cook, Donald Williams, William Strohl, Osvaldo Flores, Donald Kimmel, Fubao Wang and An Zhiqiang


Genetic studies have linked both osteoporotic and high bone mass (HBM) phenotypes to LDL-receptor related proteins (LRP 4/5/6). LRP are receptors for inhibitory Dickkopf-1 (DKK1) protein and treatment modalities that modulate LRP/DKK1 binding may therefore act as stimulators of bone mass accrual. Here we report that RH2-18, a fully human monoclonal anti-DKK1 antibody elicits systemic pharmacologic bone efficacy and new bone formation at endosteal bone surfaces in vivo in a mouse model of estrogen deficiency induced osteopenia. This was paralleled by partial-to-complete resolution of osteopenia (bone mineral density, BMD) at all skeletal sites investigated in femur and lumbar-vertebral bodies and the restoration of trabecular bone micro-architecture. Importantly, testing of RH2-18 in adult, osteopenic rhesus macaques demonstrated a rate limiting role of DKK1 at multiple skeletal sites and responsiveness to treatment. In conclusion, this study provides pharmacologic evidence for modulation of DKK1 bioactivity in the adult osteopenic skeleton as a viable approach to resolve osteopenia in animal models. Thus, data described here suggest that targeting DKK1 through means such as a fully-human anti-DKK1-antibody provides a potential bone-anabolic treatment for postmenopausal osteoporosis.

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