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Indium-111 radiolab...
Indium-111 radiolabeling of a brain-penetrant antibody for in vivo SPECT of brain Aβ
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- Tobias, Gustavsson, 1985- (författare)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap,Molecular Geriatrics
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- Sehlin, Dag (författare)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap
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- Syvänen, Stina (författare)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap
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(creator_code:org_t)
- Engelska.
- Relaterad länk:
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https://urn.kb.se/re...
Abstract
Ämnesord
Stäng
- Background: Development of bispecific antibodies that pass the blood-brain barrier has enabled brain-directed immunotherapy, and when radiolabelled, immunoPET. The aim of the present study was to explore how indium-111 (111In) radiolabeling with compatible chelators affects the biodistribution of the bispecific antibody RmAb158-scFv8D3, that binds to amyloid-beta (Aβ) and the transferrin receptor (TfR), in Aβ pathology expressing, tg-ArcSwe, and aged-matched wild-type (WT) control mice. Methods: RmAb158-scFv8D3 was radiolabelled with 111In using CHX-A"-DTPA, DOTA, or DOTA-tetrazine. Affinity towards TfR and Aβ, as well as stability was investigated in vitro. Mice were then i.v. administered with the three different RmAb158-scFv8D3 variants and blood samples were collected for monitoring of pharmacokinetics. Brain concentration was quantified after 2 h and 72 h, and organ-specific retention was measured at 72 h by gamma-counting. A subset of mice also underwent whole-body SPECT scanning at 72 h after injection. Following post-mortem isolation, brains of tg-ArcSwe and WT mice were sectioned, and the spatial distribution of RmAb158-scFv8D3 was further investigated with autoradiography.Results: RmAb158-scFv8D3 labeled with 111In using CHX-A"-DTPA, DOTA, or DOTA-tetrazine chelators displayed similar blood pharmacokinetics and brain uptake at 2 h. Radiolabeling did not compromise affinity, and all variants showed good stability, especially the DOTA-tet variant. Whole-body SPECT scanning indicated high liver, spleen, and bone accumulation of [111In]RmAb158-scFv8D3. Subsequent ex vivo measurement of organ retention confirmed SPECT data, with retention in spleen, liver, and bone – with very high bone marrow retention. Ex vivo gamma measurement of brain tissue isolated at 72 h post injection and ex vivo autoradiography showed similar retention of 111In labeled RmAb158-scFv8D3 in tg-ArcSwe and WT mice, despite the lack of Aβ in the WT brain. Conclusions: Successful 111In labeling of RmAb158-scFv8D3 with retained binding to TfR and Aβ, and retained ability to enter the brain demonstrated that radiometals can be used to generate immunoPET radioligands. However, high bone marrow retention and intracellular accumulation in brain tissue indicated off-target interactions, or potentially interaction with intrabrain TfR, of RmAb158-scFv8D3
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
Publikations- och innehållstyp
- vet (ämneskategori)
- ovr (ämneskategori)