Bien-Ly N, Yu YJ, Bumbaca D, Elstrott J, Boswell CA, Zhang Y, Luk W, Lu Y, Dennis MS, Weimer RM, Chung I, Watts RJ. Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. J Exp Med. 2014 Feb 10;211(2):233-44. Epub 2014 Jan 27 PubMed.

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  1. A major limitation of antibodies and other therapeutic proteins is that when given peripherally, the amount that gets across the BBB is only a small fraction of the concentration in the blood. One receptor that is normally involved in transporting a molecule across the BBB, and that is located on the surface of brain endothelial cells, is the transferrin receptor (TrF). Over the years, investigators have tried to increase CNS exposure to therapeutics by linking them to antibodies that bind to the TfR or by making bispecific antibodies with one arm to TfR and another arm to another protein. This did not work very well previously. However, recent studies from the lab of Ryan Watts have shown that if one arm of a bispecific antibody against TfR is of lower as opposed to higher affinity, this strongly increases transport across the BBB.

    In the current manuscript, the Watts lab has gone on to investigate the mechanism underlying this phenomenon. In several elegant experiments, they demonstrate that higher as opposed to lower affinity anti-TfR antibodies result in much greater intracellular degradation of the receptor due to its enhanced trafficking to lysosomes.  This then makes less TfR available on the surface of endothelial cells for further transport. Lower-affinity anti-TfR antibodies appear to improve transport across the BBB by dissociating from TfR before reaching and being degraded in lysosomes. This allows endosomes to transcytose and fuse with the brain side of the endothelial membrane, where they release their cargo. From a translational perspective, understanding this mechanism should allow for further development of even better bispecific antibodies to facilitate even greater transport into the CNS of a variety of cargoes with therapeutic potential for diseases such as AD.

    View all comments by David Holtzman

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