Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier.


Bispecific antibodies using the transferrin receptor (TfR) have shown promise for boosting antibody uptake in brain. Nevertheless, there are limited data on the therapeutic properties including safety liabilities that will enable successful development of TfR-based therapeutics. We evaluate TfR/BACE1 bispecific antibody variants in mouse and show that reducing TfR binding affinity improves not only brain uptake but also peripheral exposure and the safety profile of these antibodies. We identify and seek to address liabilities of targeting TfR with antibodies, namely, acute clinical signs and decreased circulating reticulocytes observed after dosing. By eliminating Fc effector function, we ameliorated the acute clinical signs and partially rescued a reduction in reticulocytes. Furthermore, we show that complement mediates a residual decrease in reticulocytes observed after Fc effector function is eliminated. These data raise important safety concerns and potential mitigation strategies for the development of TfR-based therapies that are designed to cross the blood-brain barrier.

DOI: 10.1126/scitranslmed.3005338

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@article{Couch2013AddressingSL, title={Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier.}, author={Jessica A Couch and Y Joy Yu and Yin Zhang and Jacqueline M Tarrant and Reina N Fuji and William J Meilandt and Hilda Solanoy and Raymond K Tong and Kwame Hoyte and Wilman Luk and Yanmei Lu and Kapil Gadkar and Saileta Prabhu and Benjamin A Ordonia and Quyen Nguyen and Yuwen Lin and Zhonghua Lin and Mercedesz Balazs and Kimberly Scearce-Levie and James A Ernst and Mark S Dennis and Ryan J Watts}, journal={Science translational medicine}, year={2013}, volume={5 183}, pages={183ra57, 1-12} }