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

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-03-21 DOI:10.1002/ctm2.70178

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

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引用次数: 0

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

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.