A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair

Monica Florio (), Kannan Gunasekaran, Marina Stolina, Xiaodong Li, Ling Liu, Barbara Tipton, Hossein Salimi-Moosavi, Franklin J. Asuncion, Chaoyang Li, Banghua Sun, Hong Lin Tan, Li Zhang, Chun-Ya Han, Ryan Case, Amy N. Duguay, Mario Grisanti, Jennitte Stevens, James K. Pretorius, Efrain Pacheco, Heidi Jones, Qing Chen, Brian D. Soriano, Jie Wen, Brenda Heron, Frederick W. Jacobsen, Emil Brisan, William G. Richards, Hua Zhu Ke and Michael S. Ominsky
Additional contact information
Monica Florio: Cardiometabolic Disorders, Amgen Inc.
Kannan Gunasekaran: Therapeutic Discovery, Amgen Inc.
Marina Stolina: Cardiometabolic Disorders, Amgen Inc.
Xiaodong Li: Cardiometabolic Disorders, Amgen Inc.
Ling Liu: Therapeutic Discovery, Amgen Inc.
Barbara Tipton: Therapeutic Discovery, Amgen Inc.
Hossein Salimi-Moosavi: Pharmacokinetics & Drug Metabolism, Amgen Inc.
Franklin J. Asuncion: Cardiometabolic Disorders, Amgen Inc.
Chaoyang Li: Cardiometabolic Disorders, Amgen Inc.
Banghua Sun: Cardiometabolic Disorders, Amgen Inc.
Hong Lin Tan: Cardiometabolic Disorders, Amgen Inc.
Li Zhang: Cardiometabolic Disorders, Amgen Inc.
Chun-Ya Han: Cardiometabolic Disorders, Amgen Inc.
Ryan Case: Therapeutic Discovery, Amgen Inc.
Amy N. Duguay: Therapeutic Discovery, Amgen Inc.
Mario Grisanti: Cardiometabolic Disorders, Amgen Inc.
Jennitte Stevens: Therapeutic Discovery, Amgen Inc.
James K. Pretorius: Comparative Biology & Safety Sciences, Amgen Inc.
Efrain Pacheco: Comparative Biology & Safety Sciences, Amgen Inc.
Heidi Jones: Therapeutic Discovery, Amgen Inc.
Qing Chen: Therapeutic Discovery, Amgen Inc.
Brian D. Soriano: Therapeutic Discovery, Amgen Inc.
Jie Wen: Process Development, Amgen Inc.
Brenda Heron: Comparative Biology & Safety Sciences, Amgen Inc.
Frederick W. Jacobsen: Therapeutic Discovery, Amgen Inc.
Emil Brisan: Therapeutic Discovery, Amgen Inc.
William G. Richards: Cardiometabolic Disorders, Amgen Inc.
Hua Zhu Ke: Cardiometabolic Disorders, Amgen Inc.
Michael S. Ominsky: Cardiometabolic Disorders, Amgen Inc.

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11505

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