A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair
Citations Over TimeTop 1% of 2016 papers
Abstract
Inhibition of the Wnt antagonist sclerostin increases bone mass in patients with osteoporosis and in preclinical animal models. Here we show increased levels of the Wnt antagonist Dickkopf-1 (DKK-1) in animals treated with sclerostin antibody, suggesting a negative feedback mechanism that limits Wnt-driven bone formation. To test our hypothesis that co-inhibition of both factors further increases bone mass, we engineer a first-in-class bispecific antibody with single residue pair mutations in the Fab region to promote efficient and stable cognate light-heavy chain pairing. We demonstrate that dual inhibition of sclerostin and DKK-1 leads to synergistic bone formation in rodents and non-human primates. Furthermore, by targeting distinct facets of fracture healing, the bispecific antibody shows superior bone repair activity compared with monotherapies. This work supports the potential of this agent both for treatment and prevention of fractures and offers a promising therapeutic approach to reduce the burden of low bone mass disorders.
Related Papers
- → Sclerostin measurement in human disease: Validity and current limitations(2016)24 cited
- → Sclerostin: a new biomarker of interest in nephrology(2015)1 cited
- → Sclerostin Loop3 Participates in Whole-body Lipid and Glucose Metabolism Impairment Effects of Sclerostin(2023)1 cited
- → Serum Sclerostin as Biomarker in Osteogenesis Imperfecta(2015)1 cited
- → Serum Sclerostin as Biomarker in Osteogenesis Imperfecta(2017)1 cited