Factors influencing transferrin receptor-mediated brain delivery: Evaluating preclinical antibody-based proteins for PET imaging in Alzheimer’s disease

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Faresjö Melander, Rebecca,1990-Uppsala universitet,Geriatrik,Molecular Geriatrics (author)

Factors influencing transferrin receptor-mediated brain delivery : Evaluating preclinical antibody-based proteins for PET imaging in Alzheimer’s disease

BookEnglish2023

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Uppsala :Acta Universitatis Upsaliensis,2023
83 s.
electronicrdacarrier

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LIBRIS-ID:oai:DiVA.org:uu-494103
ISBN:9789151316857
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-494103URI

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Language:English
Summary in:English &language:-1_t

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Subject category:vet swepub-contenttype
Subject category:dok swepub-publicationtype

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Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,1651-6206 ;1893

Notes

Antibody-based proteins targeting amyloid-beta (Aβ) could be used as radioligands in positron emission tomography (PET) to study Alzheimer’s disease (AD) pathology in the living brain. The prospective advantages of antibody-based PET are to detect pathology earlier, with higher sensitivity, and to evaluate treatment effects of emerging immunotherapies against Aβ. However, antibodies and other proteins are too large to cross the blood-brain barrier (BBB). This can be circumvented by fusing antibodies with transferrin-receptor (TfR) binders that penetrate the BBB via receptor-mediated transcytosis. In this thesis, I evaluated different bispecific antibody-based proteins that bind both TfR and Aβ. The overall aim was to determine which factors are important for TfR-mediated brain delivery of these proteins and their use as PET radioligands. In paper I, we studied a large, high TfR-avidity antibody compared with a smaller antibody fragment fusion with lower TfR avidity. The small antibody had fast elimination from blood and was cleared from the brain earlier than the large antibody, thus providing better signal-to-noise ratio for brainPET. In paper II, antibody-like proteins (affibodies), even smaller than the previously studied antibody, had enhanced TfR-mediated brain delivery but had an imbalance in binding to TfR and Aβ. This resulted in poor pathology-related retention of 125I-radiolabeled affibodies. In paper III, we observed that aged mice had poorer brain delivery of the bispecific antibody, mAb3D6-scFv8D3, compared with young mice. Age was also related to increased blood cell binding of the bispecific antibody, and a lower dose resulted in higher relative delivery to the brain parenchyma. In paper IV, we evaluated single domain llama-based antibodies, VHHs, which bound both mouse and human TfR, and were characterized by rapid elimination from blood and brain. The VHHs were fused to an Aβ binding antibody fragment, scFv3D6, which enabled increased brain retention of the 125I-radiobeled antibodies in an AD mouse model, and, thus, provided high contrast to healthy controls.In conclusion, antibody format, size, mouse age, dose, and TfR binding were important factors influencing brain delivery and retention.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinsk bioteknologi Medicinsk bioteknologi hsv//swe
MEDICAL AND HEALTH SCIENCES Medical Biotechnology Medical Biotechnology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
brain delivery
bispecific antibody
transferrin receptor
Alzheimer's Disease
amyloid-beta
aging
single domain antibody
PET
Biofarmaci
Biopharmaceutics
Neurology
Neurologi
Molekylär medicin
Molecular Medicine
Biofarmaci
Biopharmaceutics

Added entries (persons, corporate bodies, meetings, titles ...)

Syvänen, Stina,ProfessorUppsala universitet,Institutionen för folkhälso- och vårdvetenskap(Swepub:uu)stsyv838 (thesis advisor)
Sehlin, Dag,Associate Professor,1976-Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap(Swepub:uu)daseh499 (thesis advisor)
Thorne, Robert,Associate ProfessorUniversity of Minnesota - Department of Pharmaceutics/Denali Therapeutics, Biology Discovery, South San Francisco, USA (opponent)
Uppsala universitetGeriatrik (creator_code:org_t)

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