Premium
Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle
Author(s) -
Sehlin Dag,
Stocki Pawel,
Gustavsson Tobias,
Hultqvist Greta,
Walsh Frank S.,
Rutkowski J. Lynn,
Syvänen Stina
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000610rr
Subject(s) - transferrin receptor , transcytosis , transferrin , antibody , ex vivo , chemistry , human brain , cerebral amyloid angiopathy , in vivo , blood–brain barrier , receptor , biochemistry , biology , central nervous system , pathology , immunology , endocrinology , medicine , in vitro , dementia , endocytosis , disease , microbiology and biotechnology , neuroscience
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.