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Blood-Brain Barrier Integrity in a Mouse Model of Alzheimer’s Disease With or Without Acute 3D6 Immunotherapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (tPKPD)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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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.

Place, publisher, year, edition, pages
2018. Vol. 143, p. 1-9
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-347199DOI: 10.1016/j.neuropharm.2018.09.001ISI: 000453493200001PubMedID: 30201212OAI: oai:DiVA.org:uu-347199DiVA, id: diva2:1193721
Funder
Swedish Research Council, 2017-02413Magnus Bergvall FoundationGun och Bertil Stohnes StiftelseStiftelsen Gamla TjänarinnorAvailable from: 2018-03-27 Created: 2018-03-27 Last updated: 2022-03-06Bibliographically approved
In thesis
1. Translational Aspects of Blood-Brain Barrier Transport and Brain Distribution of Drugs in Health and Disease
Open this publication in new window or tab >>Translational Aspects of Blood-Brain Barrier Transport and Brain Distribution of Drugs in Health and Disease
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A high unmet medical need in the area of CNS diseases coincides with high failure rates in CNS drug development. Efficient treatment of CNS disease is constrained by limited entrance of drugs into the brain owing to the blood-brain barrier (BBB), which separates brain from blood. Insufficient inter-species translation and lack of methods to evaluate therapeutic, unbound, drug concentrations in human brain also contribute to development failure. Further disease related changes in BBB properties and tissue composition raise a concern of altered drug neuropharmacokinetics (neuroPK) during disease. This calls for the evaluation of translational aspects of neuroPK parameters in health and disease, and exploration of strategies for neuroPK translations between rodents and humans.

Positron emission tomography (PET) enables corresponding PK analysis in various species, although being restricted to measuring total, i.e. both unbound and nonspecifically bound, drug concentrations. However, the current work shows that PET can be used for the estimation of unbound, active, brain concentrations and for assessment of drug BBB transport, if compensation is made for intra-brain drug distribution and binding. Adapted PET designs could be applied in humans where rat estimates of drug intra-brain distribution may be used with reasonable accuracy for concentration conversions in healthy humans, but preferably not in Alzheimer’s disease (AD) patients. As shown in this thesis, a high variability in nonspecific drug tissue binding was observed in AD compared to rats and human controls that might lead to unacceptable bias of outcome values if used in PET. Furthermore, heterogeneity in drug tissue binding among brain regions in both rodents and humans was detected and must be considered in regional investigations of neuroPK. By the use of transgenic animal models of amyloid beta and alpha-synuclein pathology, the work further suggests that the BBB is able to uphold sufficient capacity for the transport of small molecular drugs and integrity towards large molecules despite the presence of hallmarks representative of neurodegenerative diseases.

This thesis work provides insight into neurodegenerative disease impact on neuroPK and contributes with translational strategies for neuroPK evaluation from preclinical investigations to the clinic, aimed to aid drug development and optimal disease management.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 254
Keywords
Blood-brain barrier, Neurovascular unit, Pharmacokinetics, Neurodegenerative disease, Drug transport, Brain tissue binding, Positron emission tomography, Brain regions
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-347204 (URN)978-91-513-0294-2 (ISBN)
Public defence
2018-05-18, B21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-04-26 Created: 2018-03-27 Last updated: 2018-10-08
2. Brain distribution of a bispecific antibody targeting Aβ
Open this publication in new window or tab >>Brain distribution of a bispecific antibody targeting Aβ
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is characterised by aberrant protein aggregation in the brain with subsequent synaptic loss, neuroinflammation, and brain atrophy that ultimately clinically manifests as cognitive impairment. Histopathological findings in AD are extracellular plaques of the protein amyloid-beta (Aβ), Aβ in blood vessels (CAA), and intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau. The FDA recently approved the antibody aducanumab for AD treatment, and several antibodies are now in clinical phase 3 trials, demonstrating that Aβ-directed immunotherapy is a viable treatment option in AD. 

In this thesis we evaluated the therapeutic Aβ antibodies 3D6 and RmAb158 in comparison with the bispecific RmAb158-scFv8D3, which penetrates the blood-brain barrier (BBB) by transferrin receptor mediated transcytosis. Emphasis lies in antibody brain uptake and intra brain distribution, in their use as potential treatment options in AD and how such treatment affects BBB integrity. 

Vascular disturbances are common side effects of anti-Aβ immunotherapy. However, we demonstrated that the BBB permeability of large molecules is unchanged following acute 3D6 treatment in an Aβ mouse model (paper I). Next, brain uptake and distribution of radioiodinated RmAb158 and its bispecific variant RmAb158-scFv8D3 were investigated with SPECT in an Aβ mouse model. Due to its active transport across BBB, RmAb158-scFv8D3 had a higher brain uptake than RmAb158, resulting in greater total brain exposure, and higher concentration at Aβ plaques (paper II). In paper III, we labelled RmAb158-scFv8D3 with the radiometal indium-111 (111In), using chelators CHX-A”-DTPA or DOTA, and SPECT was used to investigate brain retention and biodistribution. The 111In-labelled bispecific antibody entered the brain, and although brain retention was higher in Aβ mice, the wild type (wt) background was high. SPECT revealed high bone uptake of all tracers, and subsequent ex vivo measurement pinpointed retention to the bone marrow. With the knowledge gained from paper II, we addressed whether RmAb158-scFv8D3 would improve treatment efficacy in different treatment regimes. We also assessed the immunogenicity of different antibody constructs upon chronic administration (paper IV). As all tested bispecific antibody constructs elicited a humoral response, immune cell depletion was necessary before repeated antibody treatment. Overall, long-term treatment of RmAb158-scFv8D3 did lower total brain Aβ but compared with RmAb158, it did not improve treatment efficacy.

In conclusion, acute anti-Aβ immunotherapy did not negatively affect BBB integrity, and bispecific antibodies displayed improved brain distribution and long-term accumulation at parenchymal Aβ. However, this did not translate into an added treatment effect in a chronic therapeutic setting.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2022. p. 66
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1817
Keywords
Alzheimer's disease, amyloid-beta, blood-brain barrier, single-photon emission computed tomography (SPECT), bispecific antibody, immunotherapy
National Category
Neurosciences
Research subject
Molecular Medicine; Neuroscience
Identifiers
urn:nbn:se:uu:diva-469103 (URN)978-91-513-1436-5 (ISBN)
Public defence
2022-04-22, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds Väg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2022-03-31 Created: 2022-03-06 Last updated: 2022-03-31

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Gustafsson, SofiaRoshanbin, SaharHultqvist, GretaHammarlund-Udenaes, MargaretaSehlin, DagSyvänen, Stina

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