Summary: Researchers have developed a new antibody design that can increase the uptake of antibodies to the brain by almost a 100 fold.
Source: Uppsala University.
The green antibody is modified using two components that bind to the transferrin receptor and enable the antibody to pass through the blood-brain barrier. The components are placed in such a way that prevents them from being able to bind simultaneously. The placement is important, because otherwise the antibody would not detach on the far side of the blood-brain barrier. NeuroscienceNews.com image is credited to Greta Hultqvist.
Immunotherapy has proven to be effective against many serious diseases. But to treat diseases in the brain, the antibodies must first get past the obstacle of the blood-brain barrier. In a new study, a research group at Uppsala University describes their development of a new antibody design that increases brain uptake of antibodies almost 100-fold.
Immunotherapy entails treatment with antibodies; it is the fastest growing field in pharmaceutical development. In recent years, immunotherapy has successfully been used to treat cancer and rheumatoid arthritis, and the results of clinical studies look very promising for several other diseases. Antibodies are unique in that they can be modified to strongly bind to almost any disease-causing protein. In other words, major potential exists for new antibody-based medicines.
The problem with immunotherapy for diseases affecting the brain is that the brain is protected by a very tight layer of cells, called the blood-brain barrier. The blood-brain barrier effectively prevents large molecules, such as antibodies, from passing from the bloodstream into the brain. It has therefore been difficult to use immunotherapy to treat Alzheimer’s and Parkinson’s disease, which affect the brain, as well as cancerous tumours in the brain.
It has been known for a long time that some large proteins are actively transported across the blood-brain barrier. These include a protein called transferrin, whose primary task is to bind to iron in the blood and then transport it to the brain. The research group behind this new study has taken advantage of this process and modified the antibodies they want to transport into the brain using components that bind to the transferrin receptor. Then, like a Trojan horse, the receptor transports antibodies into the brain. The number of modifications to and placement of the antibodies have proven to be important factors for making this process as effective as possible.
“We’ve placed them so that each antibody only binds with one modification at a time, despite being modified in two places. Our design thus doubles the chances of the antibody binding to the transferrin receptor compared with only one modification. We’ve successfully increased the amount of antibodies in the brain almost 100-fold, which is the largest uptake improvement that has ever been shown,” says Greta Hultqvist, researcher at the Department of Public Health and Caring Sciences at Uppsala University.
To try out the new format, researchers have used it on an antibody that binds to a protein involved in the course of Alzheimer’s disease. Without the modification, they could only detect very small quantities of antibody in the brain in a mouse model of Alzheimer’s disease, while they could detect high levels of the modified antibody in the same mice.
“From a long-term perspective, it’s likely that the new format can be used to effectively treat not only Alzheimer’s disease, but also other diseases affecting the brain,” says Dag Sehlin, researcher at the Department of Public Health and Caring Sciences at Uppsala University.
Source: Uppsala University
Image Source: NeuroscienceNews.com image is credited to Greta Hultqvist.
Video Source: Gone With The Wind clip courtesy of MGM/Selznick International Pictures.
Original Research: Full open access research for “Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor” by Greta Hultqvist, Stina Syvänen, Xiaotian T Fang, Lars Lannfelt, and Dag Sehlin in Theranostics. Published online January 2017 doi:10.7150/thno.17155
Abstract
Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor
The blood-brain barrier (BBB) is an obstacle for antibody passage into the brain, impeding the development of immunotherapy and antibody-based diagnostics for brain disorders. In the present study, we have developed a brain shuttle for active transport of antibodies across the BBB by receptor-mediated transcytosis. We have thus recombinantly fused two single-chain variable fragments (scFv) of the transferrin receptor (TfR) antibody 8D3 to the light chains of mAb158, an antibody selectively binding to Aβ protofibrils, which are involved in the pathogenesis of Alzheimer’s disease (AD). Despite the two TfR binders, a monovalent interaction with TfR was achieved due to the short linkers that sterically hinder bivalent binding to the TfR dimer. The design enabled efficient receptor-mediated brain uptake of the fusion protein. Two hours after administration, brain concentrations were 2-3% of the injected dose per gram brain, comparable to small molecular drugs and 80-fold higher than unmodified mAb158. After three days, fusion protein concentrations in AD transgenic mouse brains were 9-fold higher than in wild type mice, demonstrating high in vivo specificity. Thus, our innovative recombinant design markedly increases mAb158 brain uptake, which makes it a strong candidate for improved Aβ immunotherapy and as a PET radioligand for early diagnosis and evaluation of treatment effect in AD. Moreover, this approach could be applied to any target within the brain.
“Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor” by Greta Hultqvist, Stina Syvänen, Xiaotian T Fang, Lars Lannfelt, and Dag Sehlin in Theranostics. Published online January 2017 doi:10.7150/thno.17155
http://neurosciencenews.com/immunotherapy-brain-diseases-5947/
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