Cargo Delivery into the Brain by in vivo identified Transport Peptides

Urich, Eduard; Ruderisch, Nadine; Kitas, Eric; Certa, Ulrich; Jacobsen, Helmut; Schweitzer, Christophe; Bergadano, Alessandra; Ebeling, Martin; Loetscher, Hansruedi; Freskgård, Per‐Ola

doi:10.1038/srep14104

Cited by 39 publications

(25 citation statements)

References 34 publications

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“…Whereas the molecular mechanisms of endocytosis and recycling triggered by specific receptor-ligand interactions, notably transferrin binding to TfR, have been studied extensively in various cell types, 42,46 the intracellular sorting of antibodies that leads to their polarized transport and transcytosis across brain endothelium is less well understood. 47 Some specific pathways favoring transcytosis have started to emerge from this study; in particular, it appears that a subset of MVBs bearing markers of exocytosing MVBs may be an important pathway leading to abluminal exocytosis of the BBB-crossing FC5 antibody.…”

Section: Discussionmentioning

confidence: 99%

Endosomal trafficking regulates receptor-mediated transcytosis of antibodies across the blood brain barrier

Haqqani

Delaney

Brunette

et al. 2017

J Cereb Blood Flow Metab

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Vous avez des questions? Nous pouvons vous aider. Pour communiquer directement avec un auteur, consultez la première page de la revue dans laquelle son article a été publié afin de trouver ses coordonnées. Si vous n'arrivez pas à les repérer, communiquez avec nous à PublicationsArchive-ArchivesPublications@nrc-cnrc.gc.ca. Questions? Contact the NRC Publications Archive team atPublicationsArchive-ArchivesPublications@nrc-cnrc.gc.ca. If you wish to email the authors directly, please see the first page of the publication for their contact information. NRC Publications Archive Archives des publications du CNRCThis publication could be one of several versions: author's original, accepted manuscript or the publisher's version. / La version de cette publication peut être l'une des suivantes : la version prépublication de l'auteur, la version acceptée du manuscrit ou la version de l'éditeur. NRC Publications Record / Notice d'Archives des publications de CNRC:http://nparc.cisti-icist.nrc-cnrc.gc.ca/eng/view/object/?id=33302487-9987-42d0-bb7f-3b59445d5f72 http://nparc.cisti-icist.nrc-cnrc.gc.ca/fra/voir/objet/?id=33302487-9987-42d0-bb7f-3b59445d5f72 AbstractCurrent methods for examining antibody trafficking are either non-quantitative such as immunocytochemistry or require antibody labeling with tracers. We have developed a multiplexed quantitative method for antibody 'tracking' in endosomal compartments of brain endothelial cells. Rat brain endothelial cells were co-incubated with blood-brain barrier (BBB)-crossing FC5, monovalent FC5Fc or bivalent FC5Fc fusion antibodies and control antibodies. Endosomes were separated using sucrose-density gradient ultracentrifugation and analyzed using multiplexed mass spectrometry to simultaneously quantify endosomal markers, receptor-mediated transcytosis (RMT) receptors and the co-incubated antibodies in each fraction. The quantitation showed that markers of early endosomes were enriched in high-density fractions (HDF), whereas markers of late endosomes and lysosomes were enriched in low-density fractions (LDF). RMT receptors, including transferrin receptor, showed a profile similar to that of early endosome markers. The in vitro BBB transcytosis rates of antibodies were directly proportional to their partition into early endosome fractions of brain endothelial cells. Addition of the Fc domain resulted in facilitated antibody 'redistribution' from LDF into HDF and additionally into multivesicular bodies (MVB). Sorting of various FC5 antibody formats away from late endosomes and lysosomes and into early endosomes and a subset of MVB results in increased antibody transcytosis at the abluminal side of the BBB.

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Section: Discussionmentioning

confidence: 99%

Endosomal trafficking regulates receptor-mediated transcytosis of antibodies across the blood brain barrier

Haqqani

Delaney

Brunette

et al. 2017

J Cereb Blood Flow Metab

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“…CSF and blood was collected from non-anesthetized rats at different time points as previously described [10]. Blood was collected in EDTA coated tubes (ThermoFisher) and plasma samples were obtained after spinning freshly collected blood at 2000 x g for 10 minutes.…”

Section: Serial Collection Of Csf and Bloodmentioning

confidence: 99%

“…Cisterna magna (CM) cannulated non-transgenic rats [10] with physiological levels of Aβ were used to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of the two singlearmed antibody NEP constructs in the plasma and CSF. Because NEP efficiently cleaves monomeric and oligomeric Aβ 40 [11] we used Aβ 40 levels as PD marker of NEP activity.…”

Section: Cns Delivery Of Nep and Aβ 40 Reduction In Plasma Csf And Bmentioning

confidence: 99%

Brain Shuttle Neprilysin reduces central Amyloid-β levels

et al. 2020

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Reducing Amyloid β (Aβ) in the brain is of fundamental importance for advancing the therapeutics for Alzheimer's disease. The endogenous metallopeptidase neprilysin (NEP) has been identified as one of the key Aβ-degrading enzymes. Delivery of NEP to the brain by utilizing the Brain Shuttle (BS) transport system offers a promising approach for clearing central Aβ. We fused the extracellular catalytic domain of NEP to an active or inactive BS module. The two BS-NEP constructs were used to investigate the pharmacokinetic/pharmacodynamics relationships in the blood and the cerebrospinal fluid (CSF) in dose-response and multiple dosing. As previously shown, NEP was highly effective at degrading Aβ in blood but not in the CSF compartment after systemic administration. In contrast, the NEP with an active BS module led to a significant CSF exposure of BS-NEP, followed by substantial Aβ reduction in CSF and brain parenchyma. Our data show that a BS module against the transferrin receptor facilitates the transport of an Aβ degrading enzyme across the blood-brain barriers to efficiently reduce Aβ levels in both CSF and brain.

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“…Some drugs and virus can be transported through the olfactory pathway after intranasal administration, but to the best of our knowledge, only Wan and co-workers have explored this route by phage display [89]. The CSF passage takes advantage of the influx of this fluid into the brain parenchyma, postulating that drugs could be transported by that influx once they reached the CSF, even though little is known on the specifics of this mechanism [103,107]. The RLSSVDSDLSGC peptide is thought to be transported this way, and even though only Wistar rats were used, this phage display study was especially thorough in terms of phage administration, isolation and sequencing.…”

Section: Brainmentioning

confidence: 99%

Phage-displayed peptides targeting specific tissues and organs

Andrieu

Russo

Nicotra

2018

Journal of Drug Targeting

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Phage display is a powerful and widely used technique to find novel peptide ligands. A massive amount of peptide sequences have been identified for all kinds of materials, and peptides that may have targeting capabilities towards specific cells and tissues have received special attention in biomedical sciences. As a result, it is increasingly harder to follow all the work that has been done, which sometimes leads to many promising ligands receiving little attention, together with the publication of false positives that have already been found. The aim of this review is to provide an updated and comprehensive list of phage-displayed peptides targeting different tissues and organs. The limitations of the technique are carefully analysed and the future perspectives envisaged. ARTICLE HISTORY

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Cargo Delivery into the Brain by in vivo identified Transport Peptides

Cited by 39 publications

References 34 publications

Endosomal trafficking regulates receptor-mediated transcytosis of antibodies across the blood brain barrier

Endosomal trafficking regulates receptor-mediated transcytosis of antibodies across the blood brain barrier

Brain Shuttle Neprilysin reduces central Amyloid-β levels

Phage-displayed peptides targeting specific tissues and organs

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