Furthermore, it is reported that IgG are rapidly discharged from the brain into circulating blood by neonatal Fc receptor (FcRn). To increase the concentration of therapeutic proteins in the brain, direct intrathecal and intracerebral injection has been tested, but the procedure is highly invasive. Therapeutic enzymes are effective against, and have been approved for, lysosomal storage diseases such as Fabry disease and Gaucher disease, but they are not effective against central nervous system conditions because their molecular weight is too high to allow for passage across the BBB. This is illustrated by the fact that the concentration ratio of IgG in CNS relative to plasma has been reported to be in the range of 1:500. It is well known that delivery of protein therapeutics into the brain remains challenging due to the difficulty of crossing the blood-brain barrier (BBB). There are many protein therapeutics, including antibodies and enzymes, undergoing clinical trials for central nerve system (CNS) diseases. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials. There are no further patents, products in development or marketed products to declare. The technology Accumubrain described in our manuscript was patented and published in June 2018 (Patent number WO2018123979).
The specific roles of these authors are articulated in the ‘author contributions’ section.Ĭompeting interests: We have the following interests Ryosuke Nakano, Sayaka Takagi-Maeda, Tomoko Osato, Kaori Noguchi, Kana Kurihara-Suda and Nobuaki Takahashi are employed by Kyowa Hakko Kirin Co., LTD. The funder Kyowa Hakko Kirin Co., LTD provided support in the form of salaries for authors Ryosuke Nakano, Sayaka Takagi-Maeda, Tomoko Osato Kaori Noguchi, Kana Kurihara-Suda, Nobuaki Takahashi, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the manuscript and its Supporting Information files.įunding: This research was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP18am0301006. Received: NovemAccepted: MaPublished: April 12, 2019Ĭopyright: © 2019 Nakano et al. PLoS ONE 14(4):Įditor: Joseph Najbauer, University of Pécs Medical School, HUNGARY (2019) A new technology for increasing therapeutic protein levels in the brain over extended periods. The mechanism of this technology is different from that of RMT technologies like TfR and would constitute a breakthrough for central nervous system disease therapeutics.Ĭitation: Nakano R, Takagi-Maeda S, Ito Y, Kishimoto S, Osato T, Noguchi K, et al. We report that, using our technology, anti-MOG antibody levels in the brains of mice ( Mus musculus) and rats ( Rattus norvegicus) were increased several tens of times for a period of one month. Here we report a new technology, named AccumuBrain, that achieves both high antibody concentration in the brain and a long half-life in blood by binding to myelin oligodendrocyte glycoprotein (MOG), which is specifically expressed in oligodendrocytes. To overcome this problem, we developed a different approach which slows down the export of therapeutic antibodies from the brain by binding them to a brain-specific antigen. As a result, anti-TfR antibodies are only maintained at high concentrations in the brain for a short time.
RMT and anti-TfR antibodies provide a useful means of delivering therapeutics into the brain, but the anti-TfR antibody has a short half-life in blood because of its broad expression throughout the body. To overcome this problem, many researchers have focused on antibodies binding the transferrin receptor (TfR), which is expressed in endothelial cells, including those of the BBB, and is involved in receptor-mediated transcytosis (RMT). Effective delivery of protein therapeutics into the brain remains challenging because of difficulties associated with crossing the blood-brain barrier (BBB).
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