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Meier, Silvio R.
Publications (6 of 6) Show all publications
Fang, X. T., Hultqvist, G., Meier, S. R., Antoni, G., Sehlin, D. & Syvänen, S. (2019). High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain. NeuroImage, 184, 881-888
Open this publication in new window or tab >>High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain
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2019 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 184, p. 881-888Article in journal (Refereed) Published
Abstract [en]

PET imaging of amyloid-beta (A beta) deposits in brain has become an important aid in Alzheimer's disease diagnosis, and an inclusion criterion for patient enrolment into clinical trials of new anti-A beta treatments. Available PET radioligands visualizing A beta bind to insoluble fibrils, i.e. A beta plaques. Levels of prefibrillar A beta forms, e.g. soluble oligomers and protofibrils, correlate better than plaques with disease severity and these soluble species are the neurotoxic form of A beta leading to neurodegeneration. The goal was to create an antibody-based radioligand, recognizing not only fibrillary A beta , but also smaller and still soluble aggregates. We designed and expressed a small recombinant bispecific antibody construct, di-scFv 3D6-8D3, targeting the A beta N-terminus and the transferrin receptor (TfR). Natively expressed at the blood-brain barrier (BBB), TfR could thus be used as a brain-blood shuttle. Di-scFv 3D6-8D3 bound to A beta 1-40 with high affinity and to TfR with moderate affinity. Di-scFv [I-124] 3D6-8D3 was injected in two transgenic mouse models overexpressing human A beta and wild-type control mice and PET scanned at 14, 24 or 72 h after injection. Di-scFv [I-124] 3D6-8D3 was retained in brain of transgenic animals while it was cleared from wild-type lacking A beta . This difference was observed from 24 h onwards, and at 72 h, 18 months old transgenic animals, with high load of A beta pathology, displayed SUVR of 2.2-3.5 in brain while wildtype showed ratios close to unity. A subset of the mice were also scanned with [C-11] PIB. Again wt mice displayed ratios of unity while transgenes showed slightly, non-significantly, elevated SUVR of 1.2, indicating improved sensitivity with novel di-scFv [I-124] 3D6-8D3 compared with [C-11] PIB. Brain concentrations of di-scFv [I-124] 3D6-8D3 correlated with soluble A beta (p < 0.0001) but not with total A beta, i.e. plaque load (p = 0.34). We have successfully created a small bispecific antibody-based radioligand capable of crossing the BBB, subsequently binding to and visualizing intrabrain A beta in vivo. The radioligand displayed better sensitivity compared with [C-11] PIB, and brain concentrations correlated with soluble neurotoxic A beta aggregates.

Keywords
Alzheimer's disease, Amyloid beta, PET, Antibody-based radioligand, Transferrin receptor, Brain
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-332464 (URN)10.1016/j.neuroimage.2018.10.011 (DOI)000449385000075 ()30300753 (PubMedID)
Funder
Swedish Research Council, 2012-1593Swedish Research Council, 2017-02413
Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2019-01-15Bibliographically approved
Meier, S. R., Syvänen, S., Hultqvist, G., Fang, X. T., Roshanbin, S., Lannfelt, L., . . . Sehlin, D. (2018). Antibody-Based In Vivo PET Imaging Detects Amyloid-beta Reduction in Alzheimer Transgenic Mice After BACE-1 Inhibition. Journal of Nuclear Medicine, 59(12), 1885-1891
Open this publication in new window or tab >>Antibody-Based In Vivo PET Imaging Detects Amyloid-beta Reduction in Alzheimer Transgenic Mice After BACE-1 Inhibition
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2018 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, no 12, p. 1885-1891Article in journal (Refereed) Published
Abstract [en]

Visualization of amyloid-beta (A beta) pathology with PET has become an important tool for making a specific clinical diagnosis of Alzheimer disease (AD). However, the available amyloid PET radioligands, such as C-11-Pittsburgh compound B, reflect levels of insoluble A beta plaques but do not capture soluble and protofibrillar A beta forms. Furthermore, the plaque load appears to be fairly static during clinical stages of AD and may not be affected by A beta-reducing treatments. The aim of the present study was to investigate whether a novel PET radioligand based on an antibody directed toward soluble aggregates of A beta can be used to detect changes in A beta levels during disease progression and after treatment with a beta-secretase (BACE-1) inhibitor. Methods: One set of transgenic mice (tg-ArcSwe, a model of A beta pathology) aged between 7 and 16 mo underwent PET with the A beta protofibril-selective radioligand I-124-RmAb158-scFv8D3 (where RmAb is recombinant mouse monoclonal antibody and scFv is single-chain variable fragment) to follow progression of A beta pathology in the brain. A second set of tg-ArcSwe mice, aged 10 mo, were treated with the BACE-1 inhibitor NB-360 for 3 mo and compared with an untreated control group. A third set of tg-ArcSwe mice, also aged 10 mo, underwent PET as a baseline group. Brain tissue was isolated after PET to determine levels of A beta by ELISA and immunohistochemistry. Results: The concentration of I-124-RmAb158-scFv8D3, as measured in vivo with PET, increased with age and corresponded well with the ex vivo autoradiography and A beta immunohistochemistry results. Mice treated with NB-360 showed significantly lower in vivo PET signals than untreated animals and were similar to the baseline animals. The decreased I-124-RmAb158-scFv8D3 concentrations in NB-360-treated mice, as quantified with PET, corresponded well with the decreased A beta levels measured in postmortem brain. Conclusion: Several treatments for AD are in phase 2 and 3 clinical trials, but the possibility of studying treatment effects in vivo on the important, nonfibrillar, forms of A beta is limited. This study demonstrated the ability of the A beta protofibril-selective radioligand I-124-RmAb158-scFv8D3 to follow disease progression and detect treatment effects with PET imaging in tg-ArcSwe mice.

Place, publisher, year, edition, pages
SOC NUCLEAR MEDICINE INC, 2018
Keywords
Alzheimer's disease, positron emission tomography (PET), antibody-based radioligand, BACE-1 inhibitor NB-360, amyloid-beta
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372378 (URN)10.2967/jnumed.118.213140 (DOI)000452015900020 ()29853653 (PubMedID)
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically approved
Syvänen, S., Fang, X. T., Hultqvist, G., Meier, S. R., Lannfelt, L. & Sehlin, D. (2017). A bispecific Tribody PET radioligand for visualization of amyloid-beta protofibrils - a new concept for neuroimaging. NeuroImage, 148, 55-63
Open this publication in new window or tab >>A bispecific Tribody PET radioligand for visualization of amyloid-beta protofibrils - a new concept for neuroimaging
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2017 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 148, p. 55-63Article in journal (Refereed) Published
Abstract [en]

Antibodies are highly specific for their target molecules, but their poor brain penetrance has restricted their use as PET ligands for imaging of targets within the CNS. The aim of this study was to develop an antibody-based radioligand, using the Tribody(TM) format, for PET imaging of soluble amyloid-beta (All) protofibrils, which are suggested to cause neurodegeneration in Alzheimer's disease. Antibodies, even when expressed in smaller engineered formats, are large molecules that do not enter the brain in sufficient amounts for imaging purposes. Hence, their transport across the blood-brain barrier (BBB) needs to be facilitated, for example through interaction with the transferrin receptor (TfR). Thus, a Fab fragment of the TfR antibody 8D3 was fused with two single chain variable fragments (scFv) of the A beta protofibril selective antibody mAb158. Five Tribody proteins (A1-A5) were generated with different linkers between the Fab-8D3 and scFv-158. All proteins bound to TfR and All protofibrils in vitro. Three of the proteins (A1-A3) were radiolabeled with iodine-125 and studied ex vivo in wild-type (wt) and transgenic mice overexpressing human All. The systemic pharmacokinetics were similar with half-lives in blood of around 9 h for all three ligands. Brain concentrations at 2 h were around 1% of the injected dose per gram brain tissue, which is similar to what is observed for small molecular radioligands and at least 10-fold higher than antibodies in general. At 72 h, transgenic mice showed higher concentrations of radioactivity in the brain than wt mice (12, 15- and 16-fold for Al, A2 and A3 respectively), except in the cerebellum, an area largely devoid of A beta pathology. A3 was then labelled with iodine-124 for in vivo positron emission tomography (PET) imaging. Brain concentrations were quantified in six different regions showing a clear distinction both quantitatively and visually between wt and transgenic mice and a good correlation with A beta pathology. We have thus produced a recombinant, bispecific protein, actively transported into the brain, for PET imaging within the CNS. In a longer perspective, this technique may enable imaging of other proteins involved in neurodegenerative diseases for which imaging agents are completely lacking today.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2017
Keywords
PET, Amyloid-beta, Antibody, Transferrin receptor, Tribody
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-320289 (URN)10.1016/j.neuroimage.2017.01.004 (DOI)000396803100006 ()28069541 (PubMedID)
Funder
Swedish Research Council, 2012-1593The Swedish Brain FoundationTorsten Söderbergs stiftelse
Available from: 2017-04-25 Created: 2017-04-25 Last updated: 2017-04-25Bibliographically approved
Fang, X., Hultqvist, G., Meier, S., Sehlin, D. & Syvänen, S. (2017). A small bispecific antibody-based construct based on bapineuzumab as a PET tracer for amyloid beta pathology in brain. Paper presented at 28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET, APR 01-04, 2017, Int Soc Cerebral Blood Flow & Metab, Berlin, GERMANY. Meeting abstract
Open this publication in new window or tab >>A small bispecific antibody-based construct based on bapineuzumab as a PET tracer for amyloid beta pathology in brain
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2017 (English)In: Meeting abstractArticle in journal, Meeting abstract (Other academic) Published
National Category
Endocrinology and Diabetes Hematology Neurology
Identifiers
urn:nbn:se:uu:diva-331029 (URN)000400157400102 ()
Conference
28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET, APR 01-04, 2017, Int Soc Cerebral Blood Flow & Metab, Berlin, GERMANY
Note

Supplement: 1, Meeting Abstract: BPS01-1

Available from: 2017-10-11 Created: 2017-10-11 Last updated: 2017-11-08
Sehlin, D., Fang, X. T., Meier, S. R., Jansson, M. & Syvänen, S. (2017). Pharmacokinetics, biodistribution and brain retention of a bispecific antibody-based PET radioligand for imaging of amyloid-beta. Scientific Reports, 7, Article ID 17254.
Open this publication in new window or tab >>Pharmacokinetics, biodistribution and brain retention of a bispecific antibody-based PET radioligand for imaging of amyloid-beta
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 17254Article in journal (Refereed) Published
Abstract [en]

Monoclonal antibodies (mAbs) have not been used as positron emission tomography (PET) ligands for in vivo imaging of the brain because of their limited passage across the blood-brain barrier (BBB). However, due to their high affinity and specificity, mAbs may be an attractive option for brain PET if their brain distribution can be facilitated. In the present study, a F(ab')(2) fragment of the amyloidbeta (A beta) protofibril selective mAb158 was chemically conjugated to the transferrin receptor (TfR) antibody 8D3 to enable TfR mediated transcytosis across the BBB. The generated bispecific protein, 8D3-F(ab')(2)-h158, was subsequently radiolabeled and used for microPET imaging of A beta pathology in two mouse models of AD. [124I]8D3-F(ab')(2)-h158 was distributed across the BBB several fold more than unmodified mAbs in general and its accumulation in the brain reflected disease progression, while its concentration in blood and other organs remained stable across all age groups studied. Cerebellum was largely devoid of 8D3-F(ab')(2)-h158 in young and middle aged mice, while mice older than 18 months also showed some accumulation in cerebellum. In a longer perspective, the use of bispecific antibodies as PET ligands may enable in vivo 'immunohistochemistry' also of other proteins in the brain for which PET radioligands are lacking.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Pharmacology and Toxicology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-343897 (URN)10.1038/s41598-017-17358-2 (DOI)000417463500053 ()29222502 (PubMedID)
Funder
Swedish Research Council, 2012-1593
Available from: 2018-03-02 Created: 2018-03-02 Last updated: 2018-03-08Bibliographically approved
Michno, W., Wehrli, P., Meier, S. R., Sehlin, D., Syvänen, S., Zetterberg, H., . . . Hanrieder, J. Chemical imaging of evolving amyloid plaque pathology and associated A beta peptide aggregation in a transgenic mouse model of Alzheimer's disease. Journal of Neurochemistry
Open this publication in new window or tab >>Chemical imaging of evolving amyloid plaque pathology and associated A beta peptide aggregation in a transgenic mouse model of Alzheimer's disease
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(English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159Article in journal (Refereed) Epub ahead of print
Abstract [en]

One of the major hallmarks of Alzheimer's disease (AD) pathology is the formation of extracellular amyloid beta (A beta) plaques. While A beta has been suggested to be critical in inducing and, potentially, driving the disease, the molecular basis of AD pathogenesis is still under debate. Extracellular A beta plaque pathology manifests itself upon aggregation of distinct A beta peptides, resulting in morphologically different plaque morphotypes, including mainly diffuse and cored senile plaques. As plaque pathology precipitates long before any clinical symptoms occur, targeting the A beta aggregation processes provides a promising target for early interventions. However, the chain of events of when, where and what A beta species aggregate and form plaques remains unclear. The aim of this study was to investigate the potential of matrix-assisted laser desorption/ionization imaging mass spectrometry as a tool to study the evolving pathology in transgenic mouse models for AD. To that end, we used an emerging, chemical imaging modality - matrix-assisted laser desorption/ionization imaging mass spectrometry - that allows for delineating A beta aggregation with specificity at the single plaque level. We identified that plaque formation occurs first in cortical regions and that these younger plaques contain higher levels of 42 amino acid-long A beta (A beta 1-42). Plaque maturation was found to be characterized by a relative increase in deposition of A beta 1-40, which was associated with the appearance of a cored morphology for those plaques. Finally, other C-terminally truncated A beta species (A beta 1-38 and A beta 1-39) exhibited a similar aggregation pattern as A beta 1-40, suggesting that these species have similar aggregation characteristics. These results suggest that initial plaque formation is seeded by A beta 1-42; a process that is followed by plaque maturation upon deposition of A beta 1-40 as well as deposition of other C-terminally modified A beta species.

Place, publisher, year, edition, pages
WILEY
Keywords
Alzheimer's disease, beta-amyloid, MALDI imaging, plaque pathology, transgenics
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-397798 (URN)10.1111/jnc.14888 (DOI)000494419200001 ()31605538 (PubMedID)
Funder
Swedish Research Council, 2014-6447Swedish Research Council, 2018-02532Swedish Research Council, 2017-00915Swedish Research Council, 2017-02413Swedish Research Council, 2018-02715Swedish Research Council, 2018-02181Knut and Alice Wallenberg FoundationEU, European Research Council, 681712The Swedish Brain FoundationÅke Wiberg FoundationStiftelsen Gamla TjänarinnorGun och Bertil Stohnes StiftelseTorsten Söderbergs stiftelseThe Dementia Association - The National Association for the Rights of the Demented
Available from: 2019-11-27 Created: 2019-11-27 Last updated: 2020-02-17Bibliographically approved
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