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Protein interactions with HER-family receptors can have different characteristics depending on the hosting cell line
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
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2012 (Engelska)Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 40, nr 5, s. 1677-1682Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Cell lines are common model systems in the development of therapeutic proteins and in the research on cellular functions and dysfunctions. In this field, the protein interaction assay is a frequently used tool for assessing the adequacy of a protein for diagnostic and therapeutic purposes. In this study, we investigated the extent to which the interaction characteristics depend on the choice of cell line for HER-family receptors. The interaction characteristics of two therapeutic antibodies (trastuzumab and cetuximab) and one Affibody molecule (ZHER2:342), interacting with the intended receptor were characterized with high precision using an automated real-time interaction method, in different cell lines (HaCaT, A431, HEP-G2, SKOV3, PC3, DU-145). Clear differences in binding affinity and kinetics, up to one order of magnitude, were found for the interaction of the same protein binding to the same receptor on different cells for all three proteins. For HER-family receptors, it is therefore important to refer to the measured affinity for a protein-receptor interaction together with the hosting cell line. The ability to accurately measure affinity and kinetics of a protein-receptor interaction on cell lines of different origins may increase the understanding of underlying receptor biology, and impact the selection of candidates in the development of therapeutic or diagnostic agents.

Ort, förlag, år, upplaga, sidor
2012. Vol. 40, nr 5, s. 1677-1682
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-164998DOI: 10.3892/ijo.2011.1307ISI: 000302273400041PubMedID: 22200885OAI: oai:DiVA.org:uu-164998DiVA, id: diva2:471167
Tillgänglig från: 2012-01-01 Skapad: 2012-01-01 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
Ingår i avhandling
1. Preclinical Development of Imaging Agents for HER2 Expression in Prostate Cancer Using Radiolabeled Affibody Molecules
Öppna denna publikation i ny flik eller fönster >>Preclinical Development of Imaging Agents for HER2 Expression in Prostate Cancer Using Radiolabeled Affibody Molecules
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

This thesis is focused on pre-clinical evaluation of in vivo detection of HER2-expression in prostate cancer (PCa) patients and on the possibility of using targeted molecular imaging to personalize treatment of disseminated PCa. The work is divided into three distinct parts: (1) the establishment of a preclinical model for further studies, (2) imaging of HER2 in a murine model of PCa and (3) exploration of new treatment regimes against PCa. The characterized cell line panel reflect the heterogeneity of PCa in a way that one cell line never could, and is crucial for a better understanding of different developmental stages during the progression toward androgen independence. The possibility of molecular detection of HER2 in PCa was determined in vitro using 111In-labeled CHX-A’’DTPA-trastuzumab and anti-HER2 ABY-025 affibody molecules. A novel real-time assay for radiolabeled tracer kinetics on living cells was evaluated, in an attempt to bring early developmental work a step closer to the target environment (imaging in living systems). The second part demonstrated the possibility of imaging PCa xenografts, despite the low expression levels, and that  ABY-025 is better adapted for this than the therapeutic anti-HER2 antibody trastuzumab. The study also demonstrated that a residualizing radiometal-label further improves imaging contrast. A comparative study of a HER2-binding affibody molecule N-terminally conjugated to DOTA, NOTA or NODAGA highlighted the influence of the chelator on biodistribution and emphasized the importance of taking into account potential metastatic sited during tracer development. The final study used the previously established in vitro model to explore the hypothesis of using molecular imaging of HER2 to identify PCa patients that may benefit from complemental treatment.

One conclusion from this thesis is that for imaging of PCa, molecular biological context and expression of the molecular target are equally important to consider. Another, that evaluation of response to treatment also need to consider the effect on the overall phenotypic profile, and consequently what this could mean for the efficacy of the treatment. The results of this thesis are in a larger perspective related to how the heterogeneity of tumors may affect the models used for diagnostics and monitoring of cancer in general.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2013. s. 66
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 179
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Farmaceutisk vetenskap; Biomedicinsk strålningsvetenskap
Identifikatorer
urn:nbn:se:uu:diva-207256 (URN)978-91-554-8764-5 (ISBN)
Disputation
2013-11-08, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2013-10-17 Skapad: 2013-09-11 Senast uppdaterad: 2018-01-11

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