Preclinical B cell depletion and safety profile of a brain‐shuttled crystallizable fragment‐silenced CD20 antibody

Abstract

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 The BBB hinders mAb‐based brain disorder therapies A brain‐targeted B‐cell‐depleting mAb for MS that efficiently crosses the BBB via hTfR1 was developed using Brainshuttle™ technology (1a and 1b) The Brainshuttle™‐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

Keywords

• antibodies
• antigens
• blood‐brain barrier
• CD20
• central nervous system
• monoclonal