Preclinical B cell depletion and safety profile of a brain‐shuttled crystallizable fragment‐silenced CD20 antibody
Year: 2025
Type: article
Abstract: BACKGROUND: The blood-brain barrier (BBB) presents a major challenge for the development of monoclonal antibody (mAb)-based therapies for brain disorders. To improve the likelihood of success of such therapies, Roche Brainshuttle technology utilizes a single anti-transferrin receptor 1 (TfR1)-antigen-binding antibody fragment linked to a therapeutic antibody, allowing engagement with TfR1 to transport the therapeutic antibody into the brain via receptor-mediated transcytosis. METHODS: We compared Fc-silenced and Fc-competent variants of the Brainshuttle and the parental (non-shuttled) 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. RESULTS: The Fc-silenced Brainshuttle construct showed a superior safety profile compared with the Fc-competent construct while maintaining the ability to cross the BBB and to deplete B cells in head-to-head comparisons in human and mouse in vitro and in mouse and cynomolgus macaque in vivo models. CONCLUSION: Together, our data provide a path forward for the future development of safe and efficacious brain-targeted B-cell-depleting therapies. KEY POINTS: -CD20 mAb was well tolerated (2a and 2b) and displayed B-cell-killing properties (1c), paving the way for future development and clinical translation of TfR1-targetingtherapies for increased brain penetration.
DOI: 10.1002/ctm2.70178
Authors: Vanessa L. Schumacher, Solen Pichereau, Juliana Bessa, Juergen Bachl, Sylvia Herter, Felix C. Weber, Johannes Auer, Anja Kipar, Michael Winter, Martina Stirn, Michael B. Otteneder, Kevin Brady, Anne Eichinger‐Chapelon, Adrian Roth, Nadine Stokar‐Regenscheit, Nicole Clemann, Shanon Seger, Claudia Senn, Juliane Hönig, Cordula Jany, Elisa Di Lenarda, Alain C. Tissot, Christian Klein, H.‐Christian von Büdingen, Robert Mader, Mohammed Ullah, Niels Janssen, Eduard Urich
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,470
OpenAlex ID: W4408745476