{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T13:45:08Z","timestamp":1782222308817,"version":"3.54.5"},"reference-count":57,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The blood\u2013brain barrier (BBB) presents a major challenge for the development of monoclonal antibody (mAb)\u2010based therapies for brain disorders. To improve the likelihood of success of such therapies, Roche Brainshuttle technology utilizes a single anti\u2010transferrin receptor 1 (TfR1)\u2010antigen\u2010binding antibody fragment linked to a therapeutic antibody, allowing engagement with TfR1 to transport the therapeutic antibody into the brain via receptor\u2010mediated transcytosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We compared Fc\u2010silenced and Fc\u2010competent variants of the Brainshuttle and the parental (non\u2010shuttled) type II CD20 mAb, obinutuzumab in in vitro and in vivo (mouse and cynomolgus macaque) models. Endpoints assessed included B cell binding, B cell killing, tolerability, and ability to cross the BBB.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The Fc\u2010silenced Brainshuttle construct showed a superior safety profile compared with the Fc\u2010competent construct while maintaining the ability to cross the BBB and to deplete B\u00a0cells in head\u2010to\u2010head comparisons in human and mouse in vitro and in mouse and cynomolgus macaque in vivo models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Together, our data provide a path forward for the future development of safe and efficacious brain\u2010targeted B\u2010cell\u2010depleting therapies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The BBB hinders mAb\u2010based brain disorder therapies<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>A brain\u2010targeted B\u2010cell\u2010depleting mAb for MS that efficiently crosses the BBB via hTfR1 was developed using Brainshuttle<jats:sup>\u2122<\/jats:sup> technology (1a and 1b)<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The Brainshuttle<jats:sup>\u2122<\/jats:sup>\u2010CD20 mAb was well tolerated (2a and 2b) and displayed B\u2010cell\u2010killing properties (1c), paving the way for future development and clinical translation of TfR1\u2010targetingtherapies for increased brain penetration<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70178","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T14:28:18Z","timestamp":1742740098000},"source":"Crossref","is-referenced-by-count":2,"title":["Preclinical B cell depletion and safety profile of a brain\u2010shuttled crystallizable fragment\u2010silenced CD20 antibody"],"prefix":"10.1002","volume":"15","author":[{"given":"Vanessa 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