BHQ880, a novel anti-DKK1 neutralizing antibody, inhibits tumor-induced osteolytic bone disease

3987 Several cancers have a pathology which includes lytic bone disease. In particular, Multiple Myeloma (MM) patients often develop debilitating bone pain and fractures from osteolytic lesions. Recent publications have demonstrated elevated levels of DKK1 in the serum of MM patients, and this is correlated with an increase in osteolytic lesions. DKK1 is also elevated in patients with other tumor types that give rise to osteolytic metastases, such as breast and prostate cancers. DKK1 is a negative regulator of the canonical Wnt signaling pathway, which is a critical mediator of osteoblast differentiation and survival. We have identified a fully human IgG1λ monoclonal antibody (BHQ880) that potently and selectively neutralizes DKK1 suppression of Wnt signaling. BHQ880 was selected based on its high affinity for human, mouse, rat, and monkey DKK1 using MorphoSyś HuCAL GOLD® phage display library. BHQ880 neutralizes DKK1 suppression of Wnt signaling in a TCF luciferase reporter assay. Furthermore, BHQ880 reactivates the production of Alkaline Phosphatase from DKK1-suppressed, osteoblast-like, mouse embryonic fibroblast cells (C3H10T1/2). BHQ880 binds within the Cys-2 domain of DKK1 and inhibits the interaction between DKK1 and both LRP5 and LRP6. BHQ880 has demonstrated potent efficacy in several models of tumor-induced osteolytic disease. These include two models of osteolytic metastasis that express high levels of DKK1, an intratibial prostate (PC3M-2AC6) tumor model in mice and an osteolytic breast tumor (MDA-MB-231) model using both intratibial and systemic delivery. Additionally, BHQ880 significantly inhibited bone loss in a systemic MM model (MMIS). In all three models, BHQ880 protected mice from tumor induced bone loss. These data highlight the potential for anti-DKK1 therapy in tumor induced osteolytic bone disease.