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Cellular effects of HER3-specific affibody molecules
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
KTH, Skolan för bioteknologi, Avdelningen för molekylär bioteknologi.
Affibody AB.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
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2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 6, s. e40023-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Recent discoveries have led to the recognition of the epidermal growth factor receptor HER3 as a key player in cancer, and consequently this receptor has gained increased interest as a target for cancer therapy. Although practically devoid of kinase activity, signaling via this receptor is often seen in tumours resistant to EGFR or HER2 therapy. Here, we show that two HER3-specific affibody molecules, Z5416 and Z5417, reduce heregulin-induced cell growth of the breast cancer cells MCF-7 and, to a lesser extent, SKBR‑3 cells. These affibody molecules have earlier been shown to block binding of the natural ligand heregulin (HRG) to HER3, which was confirmed here in cellular studies. Further, both Z5416 and Z5417 blocked HRG-induced HER3 and HER2 phosphorylation in MCF-7 cells, but only HER3 phosphorylation in SKBR-3 cells which have constantly active HER2.. These findings demonstrate that Z5416 and Z5417 exert an anti-proliferative effect on two breast cancer cells with either high or low HER2 expression, by inhibiting HRG-induced phosphorylation of HER3. The promising results presented in this study indicate that the HER3-binding affibody molecules may be suitable candidates for future therapy of cancers in which the interaction between HER3 and HRG plays an important role.

Ort, förlag, år, upplaga, sidor
2012. Vol. 7, nr 6, s. e40023-
Nyckelord [en]
HER3, heregulin, Affibody, proliferation
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-156734DOI: 10.1371/journal.pone.0040023ISI: 000305892100176OAI: oai:DiVA.org:uu-156734DiVA, id: diva2:433089
Tillgänglig från: 2011-08-08 Skapad: 2011-08-08 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
Ingår i avhandling
1. Cellular Studies of HER-family Specific Affibody Molecules
Öppna denna publikation i ny flik eller fönster >>Cellular Studies of HER-family Specific Affibody Molecules
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The human epidermal growth-factor like receptor (HER) family of receptor tyrosine kinases are important targets for cancer therapy. The family consists of four members - EGFR, HER2, HER3 and HER4 - that normally transfer stimulatory signals from extracellular growth factors to the intracellular signalling network. Over-activation of these receptors leads to uncontrolled cell proliferation and is seen in several types of tumours. The aim of the studies reported in this thesis was to study the uptake and effects of affibody molecules against EGFR, HER2 and HER3 in cultured cells. Affibody molecules are affinity proteins originally derived from one of the domains of protein A, and their small size and robust structure make them suitable agents for tumour targeting and therapy.

Papers I and II of this thesis concern EGFR-specific affibody molecules, which were shown to be more similar to the antibody cetuximab than the natural ligand EGF in terms of cellular uptake, binding site and internalisation rate. In addition, fluorescence-based methods for the quantification of internalisation were evaluated.

In the studies reported in papers III and IV, HER2-specific affibody molecules were utilised as carriers of radionuclides. Paper III reports that different cell lines exhibit different radiosensitivities to 211At-labelled affibody molecules; radiosensitivity was found to correlate with cell geometry and the rate of internalisation. Paper IV discusses the use of 17-AAG, an agent that induces HER2 internalisation and degradation, to force the internalisation of 211At- and 111In-labelled affibody molecules.

Papers V and VI describe the selection and maturation of HER3-specific affibody molecules, which were found to compete with the receptor’s natural ligand, heregulin, for receptor binding. These affibody molecules were demonstrated to inhibit heregulin-induced HER3 activation and cell proliferation.

The studies summarised in this paper will hopefully contribute to a better understanding of these affibody molecules and bring them one step closer to being helpful tools in the diagnosis and treatment of cancer.

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 ; 688
Nyckelord
EGFR, HER2, HER3, Affibody, internalisation, tumour targeting
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-156730 (URN)978-91-554-8119-3 (ISBN)
Disputation
2011-09-24, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 10:15 (Svenska)
Opponent
Handledare
Tillgänglig från: 2011-09-02 Skapad: 2011-08-08 Senast uppdaterad: 2016-11-22Bibliografiskt granskad

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