Indium-111 radiolabelling of a brain-penetrant Aβ antibody for SPECT imaging.
| Autor: | Gustavsson T; Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Herth MM; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Sehlin D; Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden., Syvänen S; Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden. |
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| Jazyk: | angličtina |
| Zdroj: | Upsala journal of medical sciences [Ups J Med Sci] 2024 May 20; Vol. 129. Date of Electronic Publication: 2024 May 20 (Print Publication: 2024). |
| DOI: | 10.48101/ujms.v129.10585 |
| Abstrakt: | Background: The development of bispecific antibodies that can traverse the blood-brain barrier has paved the way for brain-directed immunotherapy and when radiolabelled, immunoPET imaging. The objective of this study was to investigate how indium-111 ( 111 In) radiolabelling with compatible chelators affects the brain delivery and peripheral biodistribution of the bispecific antibody RmAb158-scFv8D3, which binds to amyloid-beta (Aβ) and the transferrin receptor (TfR), in Aβ pathology-expressing tg-ArcSwe mice and aged-matched wild-type control mice. Methods: Bispecific RmAb158-scFv8D3 (biAb) was radiolabelled with 111 In using CHX-A"-DTPA, DOTA, or DOTA-tetrazine (DOTA-Tz). Affinity toward TfR and Aβ, as well as stability, was investigated in vitro . Mice were then intravenously administered with the three different radiolabelled biAb variants, and blood samples were collected for monitoring pharmacokinetics. Brain concentration was quantified after 2 and 72 h, and organ-specific retention was measured at 72 h by gamma counting. A subset of mice also underwent whole-body Single-photon emission computed tomography (SPECT) scanning at 72 h after injection. Following post-mortem isolation, the brains of tg-ArcSwe and WT mice were sectioned, and the spatial distribution of biAb was further investigated with autoradiography. Results: All three [ 111 In]biAb variants displayed similar blood pharmacokinetics and brain uptake at 2 h after administration. Radiolabelling did not compromise affinity, and all variants showed good stability, especially the DOTA-Tz variant. Whole-body SPECT scanning indicated high liver, spleen, and bone accumulation of all [ 111 In]biAb variants. Subsequent ex vivo measurement of organ retention confirmed SPECT data, with retention in the 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 that WT mice, despite the absence of Aβ, exhibited comparable brain concentrations of [ 111 In]biAb as those found in the tg-ArcSwe brain. Conclusions: The successful 111 In-labelling of biAb with retained binding to TfR and Aβ, and retained ability to enter the brain, demonstrated that 111 In can be used to generate radioligands for brain imaging. A high degree of [ 111 In]biAb in bone marrow and intracellular accumulation in brain tissue indicated some off-target interactions or potential interaction with intrabrain TfR resulting in a relatively high non-specific background signal. Competing Interests: The authors report no conflict of interest. (© 2024 The Author(s).) |
| Databáze: | MEDLINE |
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