Discovering and Overcoming Roadblocks in Crossing the Blood-Brain Barrier

Bispecific TfR/BACE1 antibodies have shown promise for boosting antibody uptake in brain. The blood-brain barrier (BBB) continues to hinder the development of therapies for neurological disease.

Although efforts to engineer anti- bodies to cross the BBB have received significant attention, this approach has been met with the challenge of demonstrating sustained uptake and associated activity in brain after therapeutic dosing.

While evaluating TfR/BACE1 bispecific antibody variants in mouse models, Genentech identified never before described findings that antibodies to TfR can cause side effects.By engineering traditional TfR/BACE1 bispecific antibody variants, we discovered that reducing TfR binding affinity improved s not only brain uptake but also  peripheral exposure of these antibodies in mouse studies. 

Read the publication in Science Translational Medicine.