期刊
FASEB JOURNAL
卷 34, 期 10, 页码 13272-13283出版社
WILEY
DOI: 10.1096/fj.202000610RR
关键词
Alzheimer's disease (AD); amyloid-beta (A beta); antibody; blood-brain barrier (BBB); positron emission tomography (PET); receptor mediated transcytosis
资金
- Vetenskapsradet (VR) [2018-02715, 2017-02413]
- Alzheimerfonden
- Hjarnfonden (Swedish Brain Foundation)
- Torsten Soderbergs Stiftelse (Torsten Soderberg Foundation)
- Petrus och Augusta Hedlunds Stiftelse (Hedlund Foundation)
- Ake Wiberg Stiftelse (Ake Wiberg Foundation)
- Ahlenstiftelsen (Ahlen Foundation)
- Magnus Bergvalls Stiftelse (Magnus Bergvall Foundation)
- Gun och Bertil Stohnes Stiftelse (Stohnes Stiftelse)
- Stiftelsen for Gamla Tjanarinnor (Foundation for Old Servants)
- Stiftelsen Sigurd and Elsa Goljes Minne
- Swedish Research Council [2017-02413, 2018-02715] Funding Source: Swedish Research Council
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-beta (A beta) 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 A beta, the brain-to-blood concentration ratio increased with time due to interaction with intracerebral A beta 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 A beta binding antibody Bapi.
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