title: A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair.
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.
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Florio
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Kannan
authors.initials: K
authors.lastname: Gunasekaran
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tipton
authors.affiliation: Pharmacokinetics &Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Salimi-Moosavi
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Franklin J
authors.initials: FJ
authors.lastname: Asuncion
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Li
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Banghua
authors.initials: B
authors.lastname: Sun
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Hong Lin
authors.initials: HL
authors.lastname: Tan
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Chun-Ya
authors.initials: CY
authors.lastname: Han
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Case
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Amy N
authors.initials: AN
authors.lastname: Duguay
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Grisanti
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Jennitte
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Comparative Biology &Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: James K
authors.initials: JK
authors.lastname: Pretorius
authors.affiliation: Comparative Biology &Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Efrain
authors.initials: E
authors.lastname: Pacheco
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Jones
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Soriano
authors.affiliation: Process Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Wen
authors.affiliation: Comparative Biology &Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Heron
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Jacobsen
authors.affiliation: Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Emil
authors.initials: E
authors.lastname: Brisan
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.affiliation: Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage*; D015519:Bone Density; D004195:Disease Models, Animal; D005260:Female; D050723:Fractures, Bone / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D060449:Wnt Signaling Pathway / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018033:Antibodies, Bispecific; C501127:Dkk1 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse