{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:11:28Z","timestamp":1790223088675,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T00:00:00Z","timestamp":1711324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"publisher","award":["K08-130430"],"award-info":[{"award-number":["K08-130430"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"NIAMS","doi-asserted-by":"publisher","award":["R01-AR077538"],"award-info":[{"award-number":["R01-AR077538"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U-M MiMHC\/NIAMS","award":["P30-AR069620"],"award-info":[{"award-number":["P30-AR069620"]}]},{"DOI":"10.13039\/100000072","name":"NIDCR","doi-asserted-by":"publisher","award":["F30 DE029359"],"award-info":[{"award-number":["F30 DE029359"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Currently available biotherapeutics for the treatment of osteoporosis lack explicit mechanisms for bone localization, potentially limiting efficacy and inducing off-target toxicities. While various strategies have been explored for targeting the bone surface, critical aspects remain poorly understood, including the optimal affinity ligand, the role of binding avidity and circulation time, and, most importantly, whether or not this strategy can enhance the functional activity of clinically relevant protein therapeutics. To investigate, we generated fluorescent proteins (eg, mCherry) with site-specifically attached small molecule (bisphosphonate) or peptide (deca-aspartate, D10) affinity ligands. While both affinity ligands successfully anchored fluorescent protein to the bone surface, quantitative radiotracing revealed only modest femoral and vertebral accumulation and suggested a need for enhanced circulation time. To achieve this, we fused mCherry to the Fc fragment of human IgG1 and attached D10 peptides to each C-terminus. The mCherry-Fc-D10 demonstrated an ~80-fold increase in plasma exposure and marked increases in femoral and vertebral accumulation (13.6%\u2009\u00b1\u20091.4% and 11.4%\u2009\u00b1\u20091.3% of the injected dose\/g [%ID\/g] at 24\u00a0h, respectively). To determine if bone surface targeting could enhance the efficacy of a clinically relevant therapeutic, we generated a bone-targeted sclerostin-neutralizing antibody, anti-sclerostin-D10. The targeted antibody demonstrated marked increases in bone accumulation and retention (20.9\u2009\u00b1\u20092.5% and 19.5\u2009\u00b1\u20092.5% ID\/g in femur and vertebrae at 7\u00a0days) and enhanced effects in a murine model of ovariectomy-induced bone loss (bone volume\/total volume, connectivity density, and structure model index all increased [P\u00a0&amp;lt;\u2009.001] vs untargeted anti-sclerostin). Collectively, our results indicate the importance of both bone affinity and circulation time in achieving robust targeting of therapeutic proteins to the bone surface and suggest that this approach may enable lower doses and\/or longer dosing intervals without reduction in biotherapeutic efficacy. Future studies will be needed to determine the translational potential of this strategy and its potential impact on off-site toxicities.<\/jats:p>","DOI":"10.1093\/jbmr\/zjae050","type":"journal-article","created":{"date-parts":[[2024,3,23]],"date-time":"2024-03-23T11:40:34Z","timestamp":1711194034000},"page":"717-728","source":"Crossref","is-referenced-by-count":4,"title":["Affinity targeting of therapeutic proteins to the bone surface\u2014local delivery of sclerostin\u2013neutralizing antibody enhances efficacy"],"prefix":"10.1093","volume":"39","author":[{"given":"Boya","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Biointerfaces Institute, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Benton","family":"Swanson","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Science, School of Dentistry, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Durdan","sequence":"additional","affiliation":[{"name":"Biointerfaces Institute, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Department of Hematology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather N","family":"Livingston","sequence":"additional","affiliation":[{"name":"Biointerfaces Institute, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Department of Emergency Medicine, Michigan Medicine, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Dodd","sequence":"additional","affiliation":[{"name":"Biointerfaces Institute, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Department of Emergency Medicine, Michigan Medicine, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachith M","family":"Vidanapathirana","sequence":"additional","affiliation":[{"name":"Biointerfaces Institute, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Department of Emergency Medicine, Michigan Medicine, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec","family":"Desai","sequence":"additional","affiliation":[{"name":"Biointerfaces Institute, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Douglas","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Science, School of Dentistry, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Mishina","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Science, School of Dentistry, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Weivoda","sequence":"additional","affiliation":[{"name":"Biointerfaces Institute, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Department of Hematology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]},{"name":"Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan , Ann Arbor, MI 48109 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