Study of the transcytosis of an anti-transferrin receptor antibody with a Fab′ cargo across the blood–brain barrier in mice

Manich, Gemma; Cabezón, Itsaso; Valle, Jaume del; Duran-Vilaregut, Joaquim; Camins, Antoni; Pallàs, Mercè; Pelegrí, Carme; Vilaplana, Jordi

doi:10.1016/j.ejps.2013.05.027

Cited by 38 publications

(33 citation statements)

References 32 publications

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“…After either iv injection or in situ brain perfusion of radiolabeled anti-TfR antibody in rats, immunofluorescence and capillary depletion experiments indicated antibody was predominantly localized to brain capillaries with limited amounts entering the parenchyma (114, 115). Similar results were observed after iv injection or brain perfusion of anti-TfR antibodies in mice (116–118). Collectively, these studies suggest that the mAbs become “trapped” in the brain endothelial cells upon endocytosis.…”

Section: Engineering Rmt Targeting Vectors For Improved Brain Penetrasupporting

confidence: 83%

“…For example, several studies investigating the details of transport of anti-TfR mAbs at the BBB have shown that despite substantial binding and endocytosis into BBB ECs, there was limited transcytosis into the brain parenchyma (114–118). After either iv injection or in situ brain perfusion of radiolabeled anti-TfR antibody in rats, immunofluorescence and capillary depletion experiments indicated antibody was predominantly localized to brain capillaries with limited amounts entering the parenchyma (114, 115).…”

Section: Engineering Rmt Targeting Vectors For Improved Brain Penetramentioning

confidence: 99%

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Targeting Receptor-Mediated Transport for Delivery of Biologics Across the Blood-Brain Barrier

Lajoie

Shusta

2015

Annu. Rev. Pharmacol. Toxicol.

320

229

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Biologics are an emerging class of medicines with substantial promise to treat neurological disorders such as Alzheimer’s disease, stroke and multiple sclerosis. However, the blood-brain barrier (BBB) presents a formidable obstacle that appreciably limits brain uptake and hence, therapeutic potential, of biologics following intravenous administration. One promising strategy for overcoming the BBB to deliver biologics is the targeting of endogenous receptor-mediated transport (RMT) systems that employ vesicular trafficking to transport ligands across the BBB endothelium. If a biologic is modified with an appropriate targeting ligand, it can gain improved access to the brain via RMT. Various RMT targeting strategies have been developed over the past 20 years, and this review will explore exciting recent advances, with a particular emphasis on those studies showing brain targeting in vivo.

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Section: Engineering Rmt Targeting Vectors For Improved Brain Penetrasupporting

confidence: 83%

Section: Engineering Rmt Targeting Vectors For Improved Brain Penetramentioning

confidence: 99%

Targeting Receptor-Mediated Transport for Delivery of Biologics Across the Blood-Brain Barrier

Lajoie

Shusta

2015

Annu. Rev. Pharmacol. Toxicol.

320

229

View full text Add to dashboard Cite

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“…Other targets that have been used for BBB-targeting of siRNA include the insulin receptor [104], and the LDL receptor [105]. Transferrin receptor targeted delivery has shown some success for protein and drug uptake into the brain [102,106] but in other cases, trapping in the brain microvasculature has been reported [107,108]. Recently, a more detailed insight into the mechanisms has revealed that the affinity (or avidity) of the peptide or protein ligand to the transferrin receptor is crucial in deciding the fate [103,106,109].…”

Section: Targets and Ligands For Bbb Transcytosismentioning

confidence: 98%

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Lorenzer

Dirin

Winkler

et al. 2015

Journal of Controlled Release

245

204

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Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in efficient uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.

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“…However, immunohistochemical staining along with 3D modeling clearly indicated that the 8D3 antibody infused into mouse brain failed to reach the cerebral parenchyma, i.e. neither did TfR [83]. Furthermore, recent data indicate that hBMVEC iron derived from TBI is exported from hBMVEC via a mechanism involving Fpn and an exocytoplasmic ferroxidase [36].…”

Section: Proteins Involved In Bmvec Iron Uptakementioning

confidence: 99%

Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy

McCarthy

Kosman

2014

Cell. Mol. Life Sci.

110

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There are two barriers for iron entry into the brain: 1) the brain-cerebrospinal fluid (CSF) barrier and 2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease.

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Study of the transcytosis of an anti-transferrin receptor antibody with a Fab′ cargo across the blood–brain barrier in mice

Cited by 38 publications

References 32 publications

Targeting Receptor-Mediated Transport for Delivery of Biologics Across the Blood-Brain Barrier

Targeting Receptor-Mediated Transport for Delivery of Biologics Across the Blood-Brain Barrier

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy

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