The search for brain drug delivery vectors has not yielded much success. Therefore, the discovery a few years ago that decreasing the affinity of antibodies to the transferrin receptor (TfR) actually increased their access to the brain was a groundbreaking feat (Yu et al., 2011). Still, there were concerns that lowering affinity may result in nonspecific effects in the periphery. In this follow-up paper, Couch et al. first confirmed efficacy of low-affinity TfR/BACE1 bispecific antibody in reducing total brain and plasma Aβ load for hours after a single injection. From an AD perspective, it would have been helpful to determine the subtype(s) and form(s) of Aβ as well as APP metabolites affected by TfR/BACE1 antibodies. But for the most part, the authors explore safety-relevant issues in great detail. Owing to notable expression of TfR, a loss of circulating reticulocytes was observed after TfR antibody administration. Importantly, these adverse effects could be lessened by decreasing the affinity to TfR and by removing effector functions (Fc) from the antibody. While the authors...  Read more

The search for brain drug delivery vectors has not yielded much success. Therefore, the discovery a few years ago that decreasing the affinity of antibodies to the transferrin receptor (TfR) actually increased their access to the brain was a groundbreaking feat (Yu et al., 2011). Still, there were concerns that lowering affinity may result in nonspecific effects in the periphery. In this follow-up paper, Couch et al. first confirmed efficacy of low-affinity TfR/BACE1 bispecific antibody in reducing total brain and plasma Aβ load for hours after a single injection. From an AD perspective, it would have been helpful to determine the subtype(s) and form(s) of Aβ as well as APP metabolites affected by TfR/BACE1 antibodies. But for the most part, the authors explore safety-relevant issues in great detail. Owing to notable expression of TfR, a loss of circulating reticulocytes was observed after TfR antibody administration. Importantly, these adverse effects could be lessened by decreasing the affinity to TfR and by removing effector functions (Fc) from the antibody. While the authors acknowledge that further studies in primates will be essential, their paper provides an inescapable source of information for the clinical development of anti-TfR therapeutics. Since the safety profile of a drug is key to its clinical success, such data early in the drug development process are always welcome.

References:
Yu YJ, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y, et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med 2011; 3: 84ra44. Abstract

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