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Brain delivery of b...
Brain delivery of biologics using a cross-species reactive transferrin receptor 1 VNAR shuttle.
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- Sehlin, Dag, 1976- (författare)
- Uppsala universitet,Geriatrik
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Stocki, Pawel (författare)
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- Gustavsson, Tobias (författare)
- Uppsala universitet,Geriatrik
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- Hultqvist, Greta, 1980- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,protein drug design
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Walsh, Frank S (författare)
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Rutkowski, J Lynn (författare)
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- Syvänen, Stina (författare)
- Uppsala universitet,Geriatrik
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(creator_code:org_t)
- 2020
- 2020
- Engelska.
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Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 34:10, s. 13272-13283
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Transferrin receptor 1 (TfR1) mediated transcytosis is an attractive strategy to enhance brain uptake of protein drugs, but translation remains a challenge. Here, a single domain shark antibody VNAR fragment (TXB2) with similar affinity to murine and human TfR1 was used to shuttle protein cargo into the brain. TXB2 was fused to a human IgG1 Fc domain (hFc) or to the amyloid-β (Aβ) antibody bapineuzumab (Bapi). TXB2-hFc displayed 20-fold higher brain concentrations compared with a control VNAR-hFc at 18 hours post-injection in wt mice. At the same time point, brain concentrations of Bapi-TXB2 was threefold higher than Bapi. In transgenic mice overexpressing human Aβ, the brain-to-blood concentration ratio increased with time due to interaction with intracerebral Aβ deposits. The relatively stable threefold difference between Bapi-TXB2 and Bapi was observed for up to 6 days after injection. PET imaging and ex vivo autoradiography revealed more parenchymal distribution of Bapi-TXB2 compared with Bapi. In conclusion, the TXB2 VNAR shuttle markedly increased brain uptake of protein cargo and increased brain concentrations of the Aβ binding antibody Bapi.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- Alzheimer's disease (AD)
- amyloid-β (Aβ)
- antibody
- blood-brain barrier (BBB)
- positron emission tomography (PET)
- receptor mediated transcytosis
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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