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      The sclerostin-neutralizing antibody AbD09097 recognizes an epitope adjacent to sclerostin's binding site for the Wnt co-receptor LRP6

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          Abstract

          The glycoprotein sclerostin has been identified as a negative regulator of bone growth. It exerts its function by interacting with the Wnt co-receptor LRP5/6, blocks the binding of Wnt factors and thereby inhibits Wnt signalling. Neutralizing anti-sclerostin antibodies are able to restore Wnt activity and enhance bone growth thereby presenting a new osteoanabolic therapy approach for diseases such as osteoporosis. We have generated various Fab antibodies against human and murine sclerostin using a phage display set-up. Biochemical analyses have identified one Fab developed against murine sclerostin, AbD09097 that efficiently neutralizes sclerostin's Wnt inhibitory activity. In vitro interaction analysis using sclerostin variants revealed that this neutralizing Fab binds to sclerostin's flexible second loop, which has been shown to harbour the LRP5/6 binding motif. Affinity maturation was then applied to AbD09097, providing a set of improved neutralizing Fab antibodies which particularly bind human sclerostin with enhanced affinity. Determining the crystal structure of AbD09097 provides first insights into how this antibody might recognize and neutralize sclerostin. Together with the structure–function relationship derived from affinity maturation these new data will foster the rational design of new and highly efficient anti-sclerostin antibodies for the therapy of bone loss diseases such as osteoporosis.

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          Most cited references 55

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          WNT signaling in bone homeostasis and disease: from human mutations to treatments.

          Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.
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            Proximal events in Wnt signal transduction.

            The Wnt family of secreted ligands act through many receptors to stimulate distinct intracellular signalling pathways in embryonic development, in adults and in disease processes. Binding of Wnt to the Frizzled family of receptors and to low density lipoprotein receptor-related protein 5 (LRP5) or LRP6 co-receptors stimulates the intracellular Wnt-beta-catenin signalling pathway, which regulates beta-cateninstability and context-dependent transcription. This signalling pathway controls many processes, such as cell fate determination, cell proliferation and self-renewal of stem and progenitor cells. Intriguingly, the transmembrane receptor Tyr kinases Ror2 and Ryk, as well as Frizzledreceptors that act independently of LRP5 or LRP6, function as receptors for Wnt and activate beta-catenin-independent pathways. This leads to changes in cell movement and polarity and to the antagonism of the beta-catenin pathway.
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              Function and biological roles of the Dickkopf family of Wnt modulators.

               C Niehrs (2006)
              Dickkopf (Dkk) genes comprise an evolutionary conserved small gene family of four members (Dkk1-4) and a unique Dkk3-related gene, Dkkl1 (soggy). They encode secreted proteins that typically antagonize Wnt/beta-catenin signaling, by inhibiting the Wnt coreceptors Lrp5 and 6. Additionally, Dkks are high affinity ligands for the transmembrane proteins Kremen1 and 2, which also modulate Wnt signaling. Dkks play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer's disease.
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                Author and article information

                Journal
                Open Biol
                Open Biol
                RSOB
                royopenbio
                Open Biology
                The Royal Society
                2046-2441
                August 2016
                24 August 2016
                24 August 2016
                : 6
                : 8
                Affiliations
                [1 ]Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs Institute of the University Wuerzburg , Julius-von-Sachs-Platz 2, 97082 Wuerzburg, Germany
                [2 ]Bio-Rad AbD Serotec , Zeppelinstr. 4, 82178 Puchheim, Germany
                [3 ]Pepscan Therapeutics , Zuidersluisweg 2, 8203RC, Lelystad, The Netherlands
                [4 ]Leibniz Institute for Molecular Pharmacology , Robert-Roessle Str. 10, 13125 Berlin, Germany
                Author notes
                Article
                rsob160120
                10.1098/rsob.160120
                5008011
                27558933
                27f4f0b6-7363-43c0-807d-b611a00b64c0
                © 2016 The Authors.

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

                Product
                Funding
                Funded by: European Commission FP7 HEALTH;
                Award ID: HEALTH-F2-2008-201099
                Funded by: Deutsche Forschungsgemeinschaft, http://dx.doi.org/10.13039/501100001659;
                Award ID: MU1095/5-1
                Categories
                1001
                15
                201
                129
                Research
                Research Article
                Custom metadata
                August 2016

                Life sciences

                sclerostin, neutralizing antibody, osteoporosis, phage display, wnt signalling

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