Abstract
Effective delivery of protein therapeutics into the brain remains challenging because of difficulties associated with crossing the blood-brain barrier (BBB). 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). 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. As a result, anti-TfR antibodies are only maintained at high concentrations in the brain for a short time. 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. 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. 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. 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.
Highlights
There are many protein therapeutics, including antibodies and enzymes, undergoing clinical trials for central nerve system (CNS) diseases
This cross-reactivity is required for use in clinical, primary safety testing, and experimental animal models
The reason for this is that the blood-brain barrier (BBB) blocks the penetration of therapeutic antibodies from plasma into the brain
Summary
There are many protein therapeutics, including antibodies and enzymes, undergoing clinical trials for central nerve system (CNS) diseases. 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). 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 [1,2,3,4,5]. 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 [6,7].
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