. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014 Jan 8;81(1):49-60. PubMed.

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  1. Niewoehner and colleagues set out to further improve approaches around targeting the transferrin receptor (TfR) for brain uptake of antibodies. This study is similar to those published by others, however, it further advances the possibilities by engineering a Fab to a traditional antibody, as opposed to using a bivalent anti-TfR format, or the more recently described bispecific monovalent anti-TfR format. The group shows that monovalent binding to TfR, similar to reduced affinity for the receptor, improves uptake and biodistribution of the antibody/anti-TfR complex. As stated in the preview by Bell and Ehlers, the study does not carefully evaluate pharmacokinetics, safety, or the relative contribution of valency and affinity for TfR. The claim of 55-fold increased target engagement at eight hours is based on quantification of immunofluorescence, which is semi-quantitative at best. Indeed, careful evaluation of the supplemental data (Figure S4) shows ~10-fold increased uptake when measuring drug levels in the brain at eight hours, which is reduced to 1.9-fold in wild-type mice at 24 hours. These fold differences are similar to what has been published previously. It is also interesting to note the quick clearance and relatively low total concentrations in the brain achieved at these doses (~2 nM max concentration). Overall this study provides an interesting next step in the effort to develop brain-penetrating molecules for CNS diseases. The modulatory nature of the approach opens opportunities that will need further investigation.

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