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Syvänen, Stina
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Publications (10 of 55) Show all publications
Sehlin, D., Syvänen, S., Ballanger, B., Barthel, H., Bischof, G. N., Boche, D., . . . Willbold, D. (2019). Engineered antibodies: new possibilities for brain PET?. European Journal of Nuclear Medicine and Molecular Imaging, 46(13), 2848-2858
Open this publication in new window or tab >>Engineered antibodies: new possibilities for brain PET?
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2019 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no 13, p. 2848-2858Article, review/survey (Refereed) Published
Abstract [en]

Almost 50 million people worldwide are affected by Alzheimer's disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood-brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand's pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Transferrin receptor 1 (TfR1)-mediated transcytosis, Alzheimer's disease (AD), Amyloid-beta (A beta), Antibody, Blood-brain barrier (BBB), Positron emission tomography (PET)
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-401995 (URN)10.1007/s00259-019-04426-0 (DOI)000502971900023 ()31342134 (PubMedID)
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2020-01-10Bibliographically approved
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
Zysk, M., Clausen, F., Aguilar, X., Sehlin, D., Syvänen, S. & Erlandsson, A. (2019). Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease. Journal of Alzheimer's Disease, 72(1), 161-180
Open this publication in new window or tab >>Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 72, no 1, p. 161-180Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting over 10% of the elderly population. Epidemiological evidence indicates that traumatic brain injury (TBI) is an important risk factor for developing AD later in life. However, which injury-induced processes that contribute to the disease onset remains unclear. The aim with the present study was to identify cellular processes that could link TBI to AD development, by investigating the chronic impact of two different injury models, controlled cortical impact (CCI) and midline fluid percussion injury (mFPI). The trauma was induced in 3-month-old tg-ArcSwe mice, carrying the Arctic mutation along with the Swedish mutation, and the influence of TBI on AD progression was analyzed at 12- and 24-weeks post-injury. The long-term effect of the TBI on memory deficiency, amyloid-beta (A beta) pathology, neurodegeneration and inflammation was investigated by Morris water maze, PET imaging, immunohistochemistry, and biochemical analyses. Morris water maze analysis demonstrated that mice subjected to CCI or mFPI performed significantly worse than uninjured tg-ArcSwe mice, especially at the later time point. Moreover, the injured mice showed a late upregulation of reactive gliosis, which concurred with a more pronounced A beta pathology, compared to uninjured AD mice. Our results suggest that the delayed glial activation following TBI may be an important link between the two diseases. However, further studies in both experimental models and human TBI patients will be required to fully elucidate the reasons why TBI increases the risk of neurodegeneration.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Alzheimer's disease, amyloid-beta, inflammation, Morris water maze, neurodegeneration astrocytes, PET, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-400408 (URN)10.3233/JAD-190572 (DOI)000500780700014 ()31561367 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationThe Swedish Brain Foundation
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved
Stenler, S., Roshanbin, S., Yilmaz Ugur, C., Rostami, J., Aguilar, X., Erlandsson, A., . . . Hultqvist, G. (2019). Over the BBB and into the cell: Pursuing intracellular targets for immunotherapy of Parkinson’s disease. In: : . Paper presented at 15th annual PEGS: The Essential Protein Engineering & Cell Therapy Summit, Boston, USA, April 8-12 2019.
Open this publication in new window or tab >>Over the BBB and into the cell: Pursuing intracellular targets for immunotherapy of Parkinson’s disease
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2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

The aim of our research is to modify therapeutic antibodies so that they can reach their dementia target inside cells located on the other side of the blood brain barrier. While the aggregates associated with Alzheimer’s are located extracellularly and thus readily available for antibodies that have crossed the BBB barrier, this is not the case for Parkinson’s disease. In this study, we focus on developing a peptide shuttle that can deliver antibodies not only over the BBB but also into neuronal cells where the Tau and a-synuclein aggregates can be found.

For this purpose, we have investigated the use of a peptide which binds to a receptor that co- localizes with the aggregates. Our in-house experience suggests that the peptide is not an efficient BBB transporter despite the fact that some groups have used it as such, but that it might be more suitable as a transporter for intracellular delivery.

We have successfully expressed recombinant antibodies with the peptide on the N-terminal of an antibody targeting the aggregates associated with Parkinson’s disease. Our initial studies indicate that the tyrosine on the N-terminal of the peptide needs to be free and unmodified to be able to enhance uptake into neuronal cells. This hinders the use of the normal labelling method which attaches radiolabelled iodine to tyrosines where the affinity for peptide target would be destroyed. We have been pursuing alternative methods, such as using click chemistry to attach the peptide which will leave the antibody free to be radiolabelled, as well as methods to detect unlabelled antibodies in vivo and in vitro.

We have assessed the peptide-assisted increase in uptake in appropriate neuronal cell line models. Furthermore, we have studied uptake and retention in brain in mouse models for Parkinson’s disease.

Keywords
Protein drug design, blood-brain-barrier, neurodegenerative diseases, immunotherapy, antibody-based drugs
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-401539 (URN)
Conference
15th annual PEGS: The Essential Protein Engineering & Cell Therapy Summit, Boston, USA, April 8-12 2019
Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-01-22Bibliographically approved
Michno, W., Nyström, S., Wehrli, P., Lashley, T., Brinkmalm, G., Guerard, L., . . . Hanrieder, J. (2019). Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1–40 deposition underlies plaque polymorphism in progressing Alzheimer's disease pathology. Journal of Biological Chemistry, 294(17), 6719-6732
Open this publication in new window or tab >>Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1–40 deposition underlies plaque polymorphism in progressing Alzheimer's disease pathology
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2019 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 294, no 17, p. 6719-6732Article in journal (Refereed) Published
Abstract [en]

Amyloid- (A) pathology in Alzheimer's disease (AD) is characterized by the formation of polymorphic deposits comprising diffuse and cored plaques. Because diffuse plaques are predominantly observed in cognitively unaffected, amyloid-positive (CU-AP) individuals, pathogenic conversion into cored plaques appears to be critical to AD pathogenesis. Herein, we identified the distinct A species associated with amyloid polymorphism in brain tissue from individuals with sporadic AD (s-AD) and CU-AP. To this end, we interrogated A polymorphism with amyloid conformation-sensitive dyes and a novel in situ MS paradigm for chemical characterization of hyperspectrally delineated plaque morphotypes. We found that maturation of diffuse into cored plaques correlated with increased A1-40 deposition. Using spatial in situ delineation with imaging MS (IMS), we show that A1-40 aggregates at the core structure of mature plaques, whereas A1-42 localizes to diffuse amyloid aggregates. Moreover, we observed that diffuse plaques have increased pyroglutamated Ax-42 levels in s-AD but not CU-AP, suggesting an AD pathology-related, hydrophobic functionalization of diffuse plaques facilitating A1-40 deposition. Experiments in tgAPP(Swe) mice verified that, similar to what has been observed in human brain pathology, diffuse deposits display higher levels of A1-42 and that A plaque maturation over time is associated with increases in A1-40. Finally, we found that A1-40 deposition is characteristic for cerebral amyloid angiopathy deposition and maturation in both humans and mice. These results indicate that N-terminal Ax-42 pyroglutamation and A1-40 deposition are critical events in priming and maturation of pathogenic A from diffuse into cored plaques, underlying neurotoxic plaque development in AD.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2019
Keywords
amyloid-beta (A), Alzheimer disease, mass spectrometry (MS), imaging, protein aggregation, neurodegeneration, pyroglutamation, plaque polymorphism, hyperspectral imaging, transgenic mice, pyroglutamic acid
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-383851 (URN)10.1074/jbc.RA118.006604 (DOI)000467394700011 ()30814252 (PubMedID)
Available from: 2019-05-24 Created: 2019-05-24 Last updated: 2019-05-24Bibliographically 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
Olsen, M., Aguilar, X., Sehlin, D., Fang, X. T., Antoni, G., Erlandsson, A. & Syvänen, S. (2018). Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease. Molecular Imaging and Biology, 20(4), 605-614
Open this publication in new window or tab >>Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease
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2018 (English)In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 20, no 4, p. 605-614Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (A beta) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-l-[C-11]deprenyl ([C-11]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during A beta pathology progression. APP(ArcSwe) mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [C-11]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. A beta and GFAP levels were also measured with ELISA in brain homogenates. The intrabrain levels of aggregated A beta and reactive astrocytes were found to be elevated in APP(ArcSwe) compared with WT mice. GFAP and vimentin expression increased with age, i.e., with A beta pathology, in the APP(ArcSwe) mice. This was not the case for in vivo marker [C-11]DED that showed elevated binding of the same magnitude in APP(ArcSwe) mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP. MAO-B levels are increased early in A beta pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant A beta plaque formation. Thus, [C-11]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of AD progression but does not measure the total extent of astrogliosis at advanced stages of A beta pathology.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
PET, Amyloid-beta, Astrocytes, Astrogliosis, MAO-B, GFAP, Vimentin, [C-11]DED
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-361033 (URN)10.1007/s11307-017-1153-z (DOI)000438457800010 ()29297157 (PubMedID)
Funder
The Swedish Brain FoundationGun och Bertil Stohnes Stiftelse
Available from: 2018-09-21 Created: 2018-09-21 Last updated: 2018-09-21Bibliographically approved
Gustafsson, S., Gustavsson, T., Roshanbin, S., Hultqvist, G., Hammarlund-Udenaes, M., Sehlin, D. & Syvänen, S. (2018). Blood-Brain Barrier Integrity in a Mouse Model of Alzheimer’s Disease With or Without Acute 3D6 Immunotherapy. Neuropharmacology, 143, 1-9
Open this publication in new window or tab >>Blood-Brain Barrier Integrity in a Mouse Model of Alzheimer’s Disease With or Without Acute 3D6 Immunotherapy
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2018 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 143, p. 1-9Article in journal (Refereed) Published
Abstract [en]

The blood-brain barrier (BBB) is suggested to be compromised in Alzheimer's disease (AD). The concomitant presence of vascular amyloid beta (AD) pathology, so called cerebral amyloid angiopathy (CAA), also predisposes impairment of vessel integrity. Additionally, immunotherapy against A beta may lead to further damage of the BBB. To what extent this affects the BBB passage of molecules is debated. The current study aimed to investigate BBB integrity to large molecules in transgenic mice displaying abundant A beta pathology and age matched wild type animals, with or without acute anti-A beta antibody treatment. Animals were administered a single i.v. injection of PBS or 3D6 (10 mg/kg), i.e. the murine version of the clinically investigated A beta antibody bapineuzumab, supplemented with [(125)]3D6. Three days post injections, a 4 kDa FITC and a 150 kDa Antonia Red dextran were administered i.v. to all animals. After termination, fluorescent detection in brain and serum was used for the calculation of dextran brain-to-blood concentration ratios. Further characterization of antibody fate and the presence of CAA were investigated using radioactivity measurements and Congo red staining. BBB passage of large molecules was equally low in wild type and transgenic mice, suggesting an intact BBB despite A beta pathology. Neither was the BBB integrity affected by acute 3D6 treatment. However, CAA was confirmed in the transgenes and local antibody accumulations were observed in the brain, indicating CAA-antibody interactions. The current study shows that independently of A beta pathology or acute 3D6 treatment, the BBB is intact, without extensive permeability to large molecules, including the 3D6 antibody.

National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-347199 (URN)10.1016/j.neuropharm.2018.09.001 (DOI)000453493200001 ()30201212 (PubMedID)
Funder
Swedish Research Council, 2017-02413Magnus Bergvall FoundationGun och Bertil Stohnes StiftelseStiftelsen Gamla Tjänarinnor
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2019-01-11Bibliographically approved
Syvänen, S., Hultqvist, G., Gustavsson, T., Gumucio, A., Laudon, H., Söderberg, L., . . . Sehlin, D. (2018). Efficient clearence of A beta protofibrils in A beta PP-transgenic mice treated with a brain-penetrating bifunctional antibody. Alzheimer's Research & Therapy, 10, Article ID 49.
Open this publication in new window or tab >>Efficient clearence of A beta protofibrils in A beta PP-transgenic mice treated with a brain-penetrating bifunctional antibody
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2018 (English)In: Alzheimer's Research & Therapy, E-ISSN 1758-9193, Vol. 10, article id 49Article in journal (Refereed) Published
Abstract [en]

Background: Amyloid-beta (A beta) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer's disease (AD) Despite recent progress targeting aggregated forms of A beta, low antibody brain penetrance remains a challenge In the piesent study, we used transferrin receptor (TfR)-mediated transcytosis to facilitate brain uptake of our previously developed A beta protofibril-selective mAb158, with the aim of increasing the efficacy of immunotherapy directed toward soluble A beta protofibills. Methods: A beta protein precursor (A beta PP)-transgenic mice (tg-ArcSwe) were given a single dose of mAb158, modified for TfR-mediated transcytosis (RmAb158-scFvSDB), in companson with an equimolar dose or a tenfold higher dose of unmodified recombinant mAb158 (RmAb158) Soluble A beta protofibrills and total A beta in the brain were measured by enzyme-linked immunosorbent assay (ELISA) Brain distribution of radiolabeled antibodies was visualized by positron emission tomography (PET) and ex vivo autoiadiography. Results: ELISA analysis of Tris-buffered saline brain extracts demonstrated a 40% reduction of soluble A beta protofibrils in both RmAb158-scFv8D3- and high-dose RmAb158-treated mice, whereas there was no A beta protofibril reduction in mice treated with a low dose of RmAb158. Further, ex vivo autoradiography and PET imaging revealed diffeient brain distribution patterns of RmAb158-scFv8D3 and RmAb158, suggesting that these antibodies may affect A beta levels by different mechanisms. Conclusions: With a combination of biochemical and imaging analyses, this study demonstrates that antibodies engineered to be transported across the blood brain barrier can be used to increase the efficacy of A beta immunotherapy. This strategy may allow for decreased antibody doses and thereby reduced side effects and treatment costs.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2018
Keywords
Alzheimer's disease (AD), Immunotherapy, Amyloid-beta (A beta), Oligomers, Protofibrils, Monoclonal antibody, Blood-brain barrier (BBB), Transferrin receptor (TfR)-mediated transcytosis
National Category
Geriatrics
Identifiers
urn:nbn:se:uu:diva-357268 (URN)10.1186/S13195-018-0377-8 (DOI)000432929200004 ()29793530 (PubMedID)
Funder
Vinnova, 2016-04050Swedish Research Council, 2017-02413
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2019-05-09Bibliographically approved
Eriksson, J., Fang, X. T., Hultqvist, G., Olberg, D. E., Antoni, G., Lannfelt, L., . . . Syvänen, S. (2018). [F-18]Tetrazine-trans-cyclooctene mediated labelling of antibodies for PET imaging of amyloid-beta. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S643-S643
Open this publication in new window or tab >>[F-18]Tetrazine-trans-cyclooctene mediated labelling of antibodies for PET imaging of amyloid-beta
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S643-S643Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372958 (URN)000449266206054 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-01-24Bibliographically approved
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