SwePub - sökning: WFRF:(Rutkowski J Lynn)

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1.	Sehlin, Dag, 1976-, et al. (författare) Brain delivery of biologics using a cross-species reactive transferrin receptor 1 VNAR shuttle. 2020 Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 34:10, s. 13272-13283 Tidskriftsartikel (refereegranskat)abstract 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.

Sehlin, Dag, 1976-, et al. (författare)
Brain delivery of biologics using a cross-species reactive transferrin receptor 1 VNAR shuttle.
2020
Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 34:10, s. 13272-13283
Tidskriftsartikel (refereegranskat)abstract
- 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.

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