Passive and receptor mediated brain delivery of an anti-GFAP nanobody

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Meier, Silvio R.Uppsala universitet,Geriatrik (författare)

Passive and receptor mediated brain delivery of an anti-GFAP nanobody

Artikel/kapitelEngelska2022

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Elsevier,2022
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LIBRIS-ID:oai:DiVA.org:uu-437973
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-437973URI
https://doi.org/10.1016/j.nucmedbio.2022.04.002DOI

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Språk:engelska
Sammanfattning på:engelska

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Purpose: Antibody-based constructs, engineered to enter the brain using transferrin receptor (TfR) mediated transcytosis, have been successfully used as PET radioligands for imaging of amyloid-beta (Aβ) in preclinical studies. However, these radioligands have been large and associated with long circulation times, i.e. non-optimal properties for neuroPET radioligands. The aim of this study was to investigate the in vivo brain delivery of the radiolabeled nanobody VHH-E9 that binds to glial fibrillary acidic protein (GFAP) expressed by reactive astrocytes, without and with fusion to a TfR binding moiety, as potential tools to detect neuroinflammation.Methods: Three protein constructs were recombinantly expressed: 1) The GFAP specific nanobody VHH-E9, 2) VHH-E9 fused to a single chain variable fragment of the TfR binding antibody 8D3 (scFv8D3) and 3) scFv8D3 alone. Brain delivery of the constructs was investigated at 2 h post injection. Binding to GFAP was studied with autoradiography while in vivo brain retention of [125I]VHH-E9 and [125I]VHH-E9-scFv8D3 was further investigated at 8 h, 24 h and 48 h in wild-type (WT), and at the same time points in transgenic mice (ArcSwe) that in addition to Aβ pathology also display neuroinflammation.Results: At 2 h after administration, [125I]VHH-E9-scFv8D3 and [125I]scFv8D3 displayed 3-fold higher brain concentrations than [125I]VHH-E9. In vitro autoradiography showed distinct binding of both [125I]VHH-E9-scFv8D3 and [125I]VHH-E9 to regions with abundant GFAP in ArcSwe mice. However, in vivo, there was no difference in brain concentrations between WT and ArcSwe at any of the studied time points.Conclusions: Fused to scFv8D3, VHH-E9 displayed increased brain delivery. When radiolabeled and applied on brain sections, the bispecific construct was able to discriminate between WT and ArcSwe mice, but in vivo brain uptake and retention over time did not differ between WT and ArcSwe mice.

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Sehlin, Dag,1976-Uppsala universitet,Geriatrik(Swepub:uu)daseh499 (författare)
Syvänen, StinaUppsala universitet,Geriatrik(Swepub:uu)stsyv838 (författare)
Uppsala universitetGeriatrik (creator_code:org_t)

Sammanhörande titlar

Ingår i:Nuclear Medicine and Biology: Elsevier114-115, s. 128-1340969-80511872-9614

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Nuclear Medicine and Biology (Sök värdpublikationen i LIBRIS)

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Av författaren/redakt...: Meier, Silvio R.; Sehlin, Dag, 197 ...; Syvänen, Stina

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Neurovetenskaper

Artiklar i publikationen: Nuclear Medicine ...

Av lärosätet: Uppsala universitet

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