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Efficient and inexpensive transient expression of multispecific multivalent antibodies in expi293 cells
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap. (Geriatrics)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap. (Geriatrics)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap. (Geriatrics)
Vise andre og tillknytning
2017 (engelsk)Inngår i: Biological Procedures Online, ISSN 1480-9222, E-ISSN 1480-9222Artikkel i tidsskrift (Fagfellevurdert) Published
sted, utgiver, år, opplag, sider
2017.
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-332463OAI: oai:DiVA.org:uu-332463DiVA, id: diva2:1153158
Tilgjengelig fra: 2017-10-27 Laget: 2017-10-27 Sist oppdatert: 2017-11-29
Inngår i avhandling
1. Preclinical PET imaging of Alzheimer's disease progression
Åpne denne publikasjonen i ny fane eller vindu >>Preclinical PET imaging of Alzheimer's disease progression
2017 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Amyloid PET imaging with [11C]PIB enabled detection of Aβ for the first time in vivo. However, [11C]PIB is a small molecule that binds only the insoluble Aβ plaque. Rather, the soluble Aβ aggregates are considered the cause of Alzheimer’s disease (AD). As such, a more sensitive and specific PET tracer is needed for tracking longitudinal AD pathology.

Soluble Aβ aggregates likely interact with the metabotropic glutamate receptor 5 (mGluR5) to cause neurotoxic effects. However, with [11C]ABP688 PET we were unable to detect aberrant mGluR5 binding in AD mouse models, although we find elevated mGluR5 protein levels with immunoblotting.

Antibodies are highly specific large molecules that can bind specifically to soluble Aβ aggregates, thus they can be a good marker for AD pathology. Unfortunately, due to their large size they cannot cross the blood-brain barrier (BBB). However, it is possible to shuttle antibodies into the brain by taking advantage of endogenous transporter systems on the BBB. By creating bispecific antibodies binding both to soluble Aβ aggregates and to the transferrin receptor (BBB target), we successfully transported the antibody into the brain and could visually detect soluble Aβ aggregates with PET.

Recombinant expression further improved and optimized antibody design, creating smaller bispecific antibody-based constructs that had better pharmacokinetic properties allowing for earlier PET scanning (1 day instead of 3), and more sensitive signal.

Lastly, using TCO-tetrazine click chemistry, we indirectly labeled our antibodies with fluorine-18, and could successfully perform PET already 11 h post-injection with a fluorine-18 labeled antibody.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 59
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1395
Emneord
Alzheimer's disease, transgenic mice, PET, antibody-based tracer, mGluR5, ABP688, di-scFv, amyloid-β
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-333220 (URN)978-91-513-0151-8 (ISBN)
Disputas
2018-01-19, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2017-12-21 Laget: 2017-11-10 Sist oppdatert: 2018-03-08

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