A Bispecific Antibody Targeting Dickkopf-1 and Sclerostin Enhances Bone Formation in the Brtl/+ Mouse Model of Osteogenesis Imperfecta

Abstract

Osteogenesis imperfecta (OI) is a collagen-related disorder characterized by frequent fractures. Sclerostin neutralizing antibodies (Scl-Ab) have been shown to increase bone mass in mouse models and adults with OI. However, serum concentrations of the WNT antagonist dickkopf-1 (DKK1) are elevated in people with OI and expression of both Sost and Dkk-1 are elevated in mice after Scl-Ab treatment, potentially dampening the therapeutic response. We aimed to evaluate the effect of rodent bispecific antibody (rbsAb) against DKK1 and sclerostin in a mouse model of dominant OI with a Col1a1 structural defect. Ten-week-old male and female Brtl/+ and WT mice received twice weekly injections of rbsAb or vehicle for 8 weeks. Assessment of femoral bone microstructure and density using in vivo microCT showed rbsAb treatment led to greater percent change from baseline in all cortical and trabecular bone mass and microstructural parameters compared to vehicle in all groups (eg. Ct.Th in Brtl/+ males rbsAB: 52%, vehicle: 2%; females rbsAB: 55%, vehicle: 10%). MicroCT-based timelapse morphometry revealed that rbsAb led to greater bone formation and lower bone resorption on endocortical, periosteal, and trabecular surfaces. Fluorochrome-based histomorphometry primarily showed greater mineralizing surfaces with rbsAb treatment. rbsAb treated mice had greater bone strength and stiffness and there was no treatment-related difference in post-yield displacement. MicroCT analysis of L4 vertebrae revealed greater bone mass in all groups with rbsAb treatment compared to vehicle. The percent change from baseline in serum bone formation marker P1NP was greater after 4 weeks of treatment compared to vehicle in all groups, but only in females at 8 weeks; no treatment-related difference was measured in resorption marker TRAcP5b. rbsAb treatment led to greater Dkk-1 and Sost gene expression compared to vehicle in all groups. This data demonstrates rbsAb treatment elicited a potent anabolic response in both WT and Brtl/+ mice.