The enzyme β-secretase (BACE1) remains an important potential disease-modifying target for developing drugs to treat Alzheimer's disease. However, finding selective BACE1 inhibitors that can penetrate the brain has proved challenging. In this issue of Science Translational Medicine, a pair of studies describes a new approach to inhibiting BACE1 using a human monoclonal antibody that uses receptor-mediated transcytosis to cross the blood brain barrier (Atwal et al. and Yu et al.). The authors engineer a low-affinity bispecific monoclonal antibody targeting both BACE1 and the transferrin receptor and show that this antibody enters the brain more readily and inhibits BACE1 activity more efficiently than does a monospecific antibody against BACE1 alone. These findings should stimulate attempts to use receptor-mediated transcytosis to increase brain uptake of therapeutic antibodies for a variety of brain disorders.
[Show abstract][Hide abstract] ABSTRACT: After decades of halting progress, recent large genome-wide association studies (GWAS) are finally shining light on the genetic architecture of schizophrenia. The picture emerging is one of sobering complexity, involving large numbers of risk alleles across the entire allelic spectrum. The aims of this article are to summarize the key genetic findings to date and to compare and contrast methods for identifying additional risk alleles, including GWAS, targeted genotyping and sequencing. A further aim is to consider the challenges and opportunities involved in determining the functional basis of genetic associations, for instance using functional genomics, cellular models, animal models and imaging genetics. We conclude that diverse approaches will be required to identify and functionally characterize the full spectrum of risk variants for schizophrenia. These efforts should adhere to the stringent standards of statistical association developed for GWAS and are likely to entail very large sample sizes. Nonetheless, now more than any previous time, there are reasons for optimism and the ultimate goal of personalized interventions and therapeutics, although still distant, no longer seems unattainable.Molecular Psychiatry advance online publication, 1 May 2012; doi:10.1038/mp.2012.34.
[Show abstract][Hide abstract] ABSTRACT: 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.
Science translational medicine 05/2013; 5(183):183ra57. DOI:10.1126/scitranslmed.3005338 · 15.84 Impact Factor
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