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The HER2-binding Affibody Molecule (ZHER2:342)2 Increases Radiosensitivity in SKBR-3 cells
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 11, s. e49579-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We have previously shown that the HER2-specific affibody molecule (ZHER2:342)2 inhibits proliferation of SKBR-3 cells. Here, we continue to investigate its biological effects in vitro by studying receptor dimerization and clonogenic survival following irradiation. We found that (ZHER2:342)2 sensitizes the HER2-overexpressing cell line SKBR-3 to ionizing radiation. The survival after exposure to (ZHER2:342)2 and 8 Gy (S8Gy 0.006) was decreased by a factor of 4 compared to the untreated (S8Gy 0.023). The low HER2-expressing cell line MCF-7 was more radiosensitive than SKBR-3 but did not respond to (ZHER2:342)2. Treatment by (ZHER2:342)2 strongly increased the levels of dimerized and phosphorylated HER2 already after 5 minutes of stimulation. The monomeric ZHER2:342 does not seem to be able to induce receptor phosphorylation and dimerization or sensitize cells to irradiation.

Ort, förlag, år, upplaga, sidor
2012. Vol. 7, nr 11, s. e49579-
Nyckelord [en]
HER2, Affibody molecule, receptor dimerization, receptor phosphorylation
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Biomedicinsk strålningsvetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-160169DOI: 10.1371/journal.pone.0049579ISI: 000311151900167PubMedID: 23166716OAI: oai:DiVA.org:uu-160169DiVA, id: diva2:449056
Tillgänglig från: 2011-10-19 Skapad: 2011-10-17 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
Ingår i avhandling
1. EGFR- and HER2-Binding Affibody Molecules: Cellular studies of monomeric, dimeric and bispecific ligands
Öppna denna publikation i ny flik eller fönster >>EGFR- and HER2-Binding Affibody Molecules: Cellular studies of monomeric, dimeric and bispecific ligands
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Abnormal expression and signaling of the ErbB receptors is associated with the development and progression of several forms of cancer. In this thesis, new ErbB-targeting affibody molecules are evaluated regarding their cellular effects in vitro. Since ligand binding to an ErbB receptor might have an impact on the cell it is important to be aware of these effects as they may have consequences for the continued growth of the tumor when used in vivo. The affibody molecules are intended for tumor targeting with the prospect of clinical use in imaging or therapy.

Three types of affibody molecules were studied, HER2-binding, EGFR-binding and bispecific binders that target both EGFR and HER2. The HER2-targeting (ZHER2:342)2 showed promising characteristics. It sensitized SKBR-3 cells to irradiation and decreased cell growth to the same extent as the clinically approved antibody Herceptin. The monomeric version, ZHER2:342, did not induce any large effects on intracellular signaling or biological outcome. This makes (ZHER2:342)2 interesting for therapy purposes, while ZHER2:342 may be better suited for imaging.

The bispecific affibody molecules were all able to simultaneously bind to both EGFR and HER2, but none of the six constructs resulted in any large effects on cellular outcome. Interestingly, all three monovalent binders are more functional when positioned at the N-terminal part of the construct and the (S4G)3 linker renders higher affinity of the bispecific binders compared to (G4S)3. Tumors that co-express several ErbB receptors are often more aggressive and associated with a worse prognosis, suggesting that the total ErbB expression pattern might be more informative than the expression level of one receptor regarding cancer prognosis and prediction of response to targeted therapies. Bispecific ligands could thus be used as imaging agents with prognostic value. Another aspect of dual targeting is the possibility of increased tumor specificity since tumors are more likely than healthy tissue to express high amounts of two receptors.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2011. s. 67
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 715
Nyckelord
EGFR, HER2, Affibody molecule, cell signaling, receptor dimerization
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Biomedicinsk strålningsvetenskap
Identifikatorer
urn:nbn:se:uu:diva-160173 (URN)978-91-554-8195-7 (ISBN)
Disputation
2011-12-03, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15 (Svenska)
Opponent
Handledare
Tillgänglig från: 2011-11-11 Skapad: 2011-10-17 Senast uppdaterad: 2011-11-23Bibliografiskt granskad

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