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    Generation and selection of novel fully human monoclonal antibodies that neutralize Dickkopf-1 (DKK1) inhibitory function in vitro and increase bone mass in vivo

    J Biol Chem. 2010 Oct 7. [Epub ahead of print]

    These authors have generated antibodies that neutralize the activity of Dickkopf-1 (DKK1), which like sclerostin is an inhibitor of Wnt signaling pathways. They find that this antibody is effective in mouse models to increase trabecular bone volume and structure, and trabecular and cortical bone mineral densities in a dose-related fashion.
    Authors: Glantschnig H, Hampton RA, Lu P, et. al

    Wnt/LRP5 signaling is a central regulatory component of bone formative and resorptive activities and the pathway inhibitor DKK1 is a suppressor of bone formation and bone mass accrual in mice. In addition, augmented DKK1 levels are associated with high bone turnover in diverse low-bone-mass states in rodent models and disease etiologies in human. However, examination of the precise role of DKK1 in the normal skeleton and in higher species requires the development of refined DKK1-specific pharmacological tools. Here, we report the strategy resulting in isolation of a panel of fully-human anti-DKK1 antibodies applicable to studies interrogating the roles of mouse, rhesus and human DKK1. Selected anti-DKK1 antibodies bind primate and human DKK-1 with picomolar-affinities, yet do not appreciably bind to DKK2 or DKK4. Epitopes mapped within the DKK1 COOH-terminal domain necessary for interaction with LRP5/6 and consequently effectively neutralized DKK1 function in vitro. When introduced into naive normal growing female mice IgGs significantly improved trabecular bone volume and structure, and increased both trabecular and cortical bone mineral densities in a dose-related fashion. Further, fully-human DKK1-IgG displayed favorable pharmacokinetic parameters in non-human primates. In summary, we demonstrate here a rate-limiting function of physiologic DKK1 levels in the regulation of bone mass in intact female mice, amendable to specific pharmacologic neutralization by newly identified DKK1-IgGs. Importantly the fully-human IgGs display a profile of attributes that recommends their testing in higher species and their use in evaluating DKK1 function in relevant disease models.

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