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Evaluation of valen...
Evaluation of valency effects on TfR-mediated brain delivery in vivo
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- Bonvicini, Gillian (författare)
- Uppsala universitet,Geriatrik
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- Singh, Sunitha (författare)
- BioArctic AB
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- Sandersjöö, Lisa (författare)
- BioArctic AB
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visa fler...
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- Sehlin, Dag, 1976- (författare)
- Uppsala universitet,Geriatrik
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- Syvänen, Stina (författare)
- Uppsala universitet,Geriatrik
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- Andersson, Ken G. (författare)
- BioArctic AB
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visa färre...
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(creator_code:org_t)
- Engelska.
- Relaterad länk:
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https://urn.kb.se/re...
Abstract
Ämnesord
Stäng
- Monovalent binding to the transferrin receptor (TfR) is assumed to be the most efficient binding mode for avoiding lysosomal degradation of the protein constructs that utilise TfR-mediated transcytosis to cross the blood-brain barrier. However, past studies evaluating the effects of valency to TfR on brain uptake generally had shortcomings in the protein design. This led to protein constructs that differed in valency but also in affinity and/or protein size. Therefore, the aim here was to evaluate the effect of valency on TfR-mediated brain delivery.Affinity variants of antibody 8D3 were produced by introducing alanine point mutations into the complementarity-determining regions. Eleven Fab fragments and 29 IgGs were screened for affinity against murine TfR. Six of each were chosen to be produced with a knob-in-hole design to have monovalent and bivalent TfR binders in full-length antibody format. These 12 antibodies were tested in a cell assay and 2 pairs of monovalent and bivalent antibodies were determined based on the apparent affinity. The stronger apparent affinity pair was radiolabelled with iodine-125 and injected into WT mice at a tracer dose. The biodistribution was measured in brain, blood and peripheral organs at 4 h post-injection.The antibodies from the stronger apparent affinity pair had similar blood pharmacokinetics and peripheral distribution suggesting that the apparent affinities were indeed similar. The monovalent antibody had significantly higher brain uptake than the bivalent antibody; supporting that monovalent binding yields better brain delivery than bivalent binding to TfR. It further suggests that the effect of valency on brain delivery is apparent affinity independent.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- Transferrin receptor-mediated transcytosis
- valency
- affinity
- size
Publikations- och innehållstyp
- vet (ämneskategori)
- ovr (ämneskategori)