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Generation and evaluation of bispecific affibody molecules for simultaneous targeting of EGFR and HER2
KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
Vise andre og tillknytning
2012 (engelsk)Inngår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 23, nr 9, s. 1802-1811Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Coexpression of several ErbB receptors has been found in many cancers and has been linked with increased aggressiveness of tumors and a worse patient prognosis. This makes the simultaneous targeting of two surface receptors by using bispecific constructs an increasingly appreciated strategy. Here, we have generated six such bispecific targeting proteins, each comprising two monomeric affibody molecules with specific binding to either of the two human epidermal growth factor receptors, EGFR and HER2, respectively. The bispecific constructs were designed with (i) alternative positioning (N- or C-terminal) of the different affibody molecules, (ii) two alternative peptide linkers (Gly 4Ser) 3 or (Ser 4Gly) 3, and (iii) affibody molecules with different affinity (nanomolar or picomolar) for HER2. Using both Biacore technology and cell binding assays, it was demonstrated that all six constructs could bind simultaneously to both their target proteins. N-terminal positioning of the inherent monomeric affibody molecules was favorable to promote the binding to the respective target. Interestingly, bispecific constructs containing the novel (Ser 4Gly) 3 linker displayed a higher affinity in cell binding, as compared to constructs containing the more conventional linker, (Gly 4Ser) 3. It could further be concluded that bispecific constructs (but not the monomeric affibody molecules) induced dimer formation and phosphorylation of EGFR in SKBR3 cells, which express fairly high levels of both receptors. It was also investigated whether the bispecific binding would influence cell growth or sensitize cells for ionizing radiation, but no such effects were observed.

sted, utgiver, år, opplag, sider
2012. Vol. 23, nr 9, s. 1802-1811
Emneord [en]
bispecific affibody molecule, epidermal growth factor receptor, epidermal growth factor receptor 2, peptides and proteins, unclassified drug
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-103554DOI: 10.1021/bc3000645ISI: 000308833600011Scopus ID: 2-s2.0-84866357369OAI: oai:DiVA.org:kth-103554DiVA, id: diva2:560453
Forskningsfinansiär
VinnovaSwedish Research Council
Merknad

QC 20121015

Tilgjengelig fra: 2012-10-15 Laget: 2012-10-15 Sist oppdatert: 2017-12-07bibliografisk kontrollert

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Ståhl, Stefan

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