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Generation and evaluation of antibody agents for molecular imaging of CD44v6 expressing cancers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Marika Nestor)
KTH.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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(English)Manuscript (preprint) (Other academic)
Keyword [en]
scFv, recombinant antibody formats, CD44v6, squamous cell carcinoma, molecular imaging
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-316722OAI: oai:DiVA.org:uu-316722DiVA: diva2:1081597
Available from: 2017-03-14 Created: 2017-03-14 Last updated: 2017-03-20
In thesis
1. Targeting molecules for diagnostics of Head and Neck squamous cell carcinoma
Open this publication in new window or tab >>Targeting molecules for diagnostics of Head and Neck squamous cell carcinoma
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

To personalize treatment for cancer, correct staging of the primary tumor, nodal disease and metastatic disease is of essence. By targeting tumor specific receptors with radiolabeled antibodies, specificity and accuracy of imaging may be improved. Radio-immunodiagnostics can potentially detect small volume disease, occult metastasis and recurrent cancer in treated tissue. This thesis focuses on evaluation of radio-immunoconjugates directed towards CD44v6, which is a surface receptor overexpressed in many head and neck squamous cell carcinomas. At the outset, the monoclonal chimeric antibody cMab U36 and its cleavage products Fab’ and F(ab’)2 were labeled with 125I and assessed in vitro and in vivo (paper I). The best distribution pattern and tumor to organ ratio was achieved with F(ab’)2. Due to the immunological responses humans can develop towards chimeric antibodies, they are not optimal for clinical use, and subsequently fully human antibody fragments were developed. AbD15179, which is a monovalent fragment, was labeled with 111In and 125I and evaluated in vitro and in mice bearing CD44v6-expressing tumors. Tumor to organ ratios were improved compared to cMab U36 derived fragments, and 111In-AbD15179 displayed a more favorable distribution compared to 125I-AbD15179 (Paper II). A bivalent Fab-dHXL, AbD19384 derived from AbD15179, was then constructed and labeled with 125I and evaluated in cell- and biodistribution studies. Furthermore, an imaging study in a small animal PET was performed with 124I-AbD19384 (Paper III). Uptake in kidneys was reduced and liver uptake increased compared to AbD15179 reflecting the larger molecule. The high CD44v6 expressing tumor was clearly visualized with maximum uptake at 48 hours post injection.In paper IV human single chain fragments towards CD44v6v were selected, and the top candidates A11 and H12 were further evaluated in vitro and in vivo. Single chain fragments are small molecules exhibiting fast clearance and high affinity to the target. The study proved this by demonstrating superior tumor to blood ratios of radiolabeled A11 and H12 compared to previously studied molecules. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1319
Keyword
HNSCC, CD44v6, radio-immunodiagnosis, immuno-PET, tumor targeting, antibodies, antibody fragments
National Category
Otorhinolaryngology
Research subject
Oto-Rhino-Laryngology
Identifiers
urn:nbn:se:uu:diva-315210 (URN)978-91-554-9864-1 (ISBN)
Public defence
2017-05-12, Skoogsalen, Ing. 78-79 Akademiska sjukhuset, Uppsala, 09:00 (Swedish)
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Supervisors
Available from: 2017-04-20 Created: 2017-03-20 Last updated: 2017-04-20

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