Targeting the transferrin receptor for brain drug delivery

Johnsen, Kjeld; Burkhart, Annette; Thomsen, Louiza Bohn; Andresen, Thomas Lars; Moos, Torben

doi:10.1016/j.pneurobio.2019.101665

Cited by 228 publications

(188 citation statements)

References 443 publications

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“…The TfR can also be used to deliver biological drugs across the BBB. The exact mechanism of TfR-mediated transcytosis is under debate, which has been further detailed in an extensive review by Johnsen et al [ 17 ]. Multiple bispecific antibody constructs have been created that utilize TfR to improve brain parenchymal exposure to mAbs [ 18 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer’s disease

Gustavsson

Syvänen

O’Callaghan

et al. 2020

Transl Neurodegener

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Background Alzheimer’s disease (AD) immunotherapy with antibodies targeting amyloid-β (Aβ) has been extensively explored in clinical trials. The aim of this study was to study the long-term brain distribution of two radiolabeled monoclonal Aβ antibody variants – RmAb158, the recombinant murine version of BAN2401, which has recently demonstrated amyloid removal and reduced cognitive decline in AD patients, and the bispecific RmAb158-scFv8D3, which has been engineered for enhanced brain uptake via transferrin receptor-mediated transcytosis. Methods A single intravenous injection of iodine-125 (125I)-labeled RmAb158-scFv8D3 or RmAb158 was administered to AD transgenic mice (tg-ArcSwe). In vivo single-photon emission computed tomography was used to investigate brain retention and intrabrain distribution of the antibodies over a period of 4 weeks. Activity in blood and brain tissue was measured ex vivo and autoradiography was performed in combination with Aβ and CD31 immunostaining to investigate the intrabrain distribution of the antibodies and their interactions with Aβ. Results Despite faster blood clearance, [125I]RmAb158-scFv8D3 displayed higher brain exposure than [125I]RmAb158 throughout the study. The brain distribution of [125I]RmAb158-scFv8D3 was more uniform and coincided with parenchymal Aβ pathology, while [125I]RmAb158 displayed a more scattered distribution pattern and accumulated in central parts of the brain at later times. Ex vivo autoradiography indicated greater vascular escape and parenchymal Aβ interactions for [125I]RmAb158-scFv8D3, whereas [125I]RmAb158 displayed retention and Aβ interactions in lateral ventricles. Conclusions The high brain uptake and uniform intrabrain distribution of RmAb158-scFv8D3 highlight the benefits of receptor-mediated transcytosis for antibody-based brain imaging. Moreover, it suggests that the alternative transport route of the bispecific antibody contributes to improved efficacy of brain-directed immunotherapy.

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Section: Introductionmentioning

confidence: 99%

SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer’s disease

Gustavsson

Syvänen

O’Callaghan

et al. 2020

Transl Neurodegener

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“…8D3, a murine IgG1, 28 , 30 was selected as the anti-TfR antibody. This high affinity antibody recognizing an extracellular epitope of the mouse TfR, non-competitive with the endogenous substrate transferrin, has been widely used in several brain enhancement approaches, 9 enabling a more direct comparison of the different formats. TBTI proteins were produced by transient transfection in HEK293 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Receptor-mediated transcytosis is a specific endogenous process allowing brain transport of selected proteins such as insulin, transferrin, or lipoproteins. At present, the most convincing data on brain enhancement of antibodies have been reported with transferrin receptor (TfR), 9 , 10 , 11 using several antibodies fusions 12 , 13 , 14 , 15 , 16 , 17 , 18 or bispecific constructs 19 , 20 , 21 , 22 ( Figures 1 A–1I). The nature of the interaction of these constructs with TfR seems to be key to the extent of brain exposure, with the bispecific formats bivalent for TfR ( Figures 1 A–1C) using both high 13 , 16 , 17 , 18 , 25 and medium 17 affinity or avidity 14 TfR antibodies and the monovalent for TfR formats ( Figures 1 D and 1G) using either a low affinity 20 , 22 or low avidity 15 TfR antibodies.…”

Section: Introductionmentioning

confidence: 92%

Tetravalent Bispecific Tandem Antibodies Improve Brain Exposure and Efficacy in an Amyloid Transgenic Mouse Model

Capdevila

Pradier

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Most antibodies display very low brain exposure due to the blood-brain barrier (BBB) preventing their entry into brain parenchyma. Transferrin receptor (TfR) has been used previously to ferry antibodies to the brain by using different formats of bispecific constructs. Tetravalent bispecific tandem immunoglobulin Gs (IgGs) (TBTIs) containing two paratopes for both TfR and protofibrillar forms of amyloid-beta (Aβ) peptide were constructed and shown to display higher brain penetration than the parent anti-Aβ antibody. Additional structure-based mutations on the TfR paratopes further increased brain exposure, with maximal enhancement up to 13-fold in wild-type mice and an additional 4–5-fold in transgenic (Tg) mice harboring amyloid plaques, the main target of our amyloid antibody. Parenchymal target engagement of extracellular amyloid plaques was demonstrated using in vivo and ex vivo fluorescence imaging as well as histological methods. The best candidates were selected for a chronic study in an amyloid precursor protein (APP) Tg mouse model showing efficacy at reducing brain amyloid load at a lower dose than the corresponding monospecific antibody. TBTIs represent a promising format for enhancing IgG brain penetration using a symmetrical construct and keeping bivalency of the payload antibody.

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“…Enhanced drug delivery across the BBB can be achieved by conjugating drugs to antibodies targeting receptors involved in transcytosis. Much of such work has focused on targeting the BBB transferrin receptor and Johnsen et al [161] provide a review of that work. There has also been a thrust for using antibody fragments rather than fulllength antibodies and Belanger et al [162] reviewed current work on the use of small single-domain antibodies.…”

Section: Drug Deliverymentioning

confidence: 99%

This was the year that was: brain barriers and brain fluid research in 2019

Keep

Jones²,

Drewes

2020

Fluids Barriers CNS

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This editorial highlights advances in brain barrier and brain fluid research published in 2019, as well as addressing current controversies and pressing needs. Topics include recent advances related to: the cerebral endothelium and the neurovascular unit; the choroid plexus, arachnoid membrane; cerebrospinal fluid and the glymphatic hypothesis; the impact of disease states on brain barriers and brain fluids; drug delivery to the brain; and translation of preclinical data to the clinic. This editorial also mourns the loss of two important figures in the field, Malcolm B. Segal and Edward G. Stopa.

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Targeting the transferrin receptor for brain drug delivery

Cited by 228 publications

References 443 publications

SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer’s disease

SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer’s disease

Tetravalent Bispecific Tandem Antibodies Improve Brain Exposure and Efficacy in an Amyloid Transgenic Mouse Model

This was the year that was: brain barriers and brain fluid research in 2019

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