Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Inhibiting HER3-Mediated Tumor Cell Growth with Affibody Molecules Engineered to Low Picomolar Affinity by Position-Directed Error-Prone PCR-Like Diversification
Show others and affiliations
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, e62791- p.Article in journal (Refereed) Published
Abstract [en]

The HER3 receptor is implicated in the progression of various cancers as well as in resistance to several currently used drugs, and is hence a potential target for development of new therapies. We have previously generated Affibody molecules that inhibit heregulin-induced signaling of the HER3 pathways. The aim of this study was to improve the affinity of the binders to hopefully increase receptor inhibition efficacy and enable a high receptor-mediated uptake in tumors. We explored a novel strategy for affinity maturation of Affibody molecules that is based on alanine scanning followed by design of library diversification to mimic the result from an error-prone PCR reaction, but with full control over mutated positions and thus less biases. Using bacterial surface display and flow-cytometric sorting of the maturation library, the affinity for HER3 was improved more than 30-fold down to 21 PM. The affinity is among the higher that has been reported for Affibody molecules and we believe that the maturation strategy should be generally applicable for improvement of affinity proteins. The new binders also demonstrated an improved thermal stability as well as complete refolding after denaturation. Moreover, inhibition of ligand-induced proliferation of HER3-positive breast cancer cells was improved more than two orders of magnitude compared to the previously best-performing clone. Radiolabeled Affibody molecules showed specific targeting of a number of HER3-positive cell lines in vitro as well as targeting of HER3 in in vivo mouse models and represent promising candidates for future development of targeted therapies and diagnostics.

Place, publisher, year, edition, pages
2013. Vol. 8, no 5, e62791- p.
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-202922DOI: 10.1371/journal.pone.0062791ISI: 000318852400011PubMedID: 23675426OAI: oai:DiVA.org:uu-202922DiVA: diva2:634530
Available from: 2013-07-01 Created: 2013-07-01 Last updated: 2017-12-06Bibliographically approved

Open Access in DiVA

fulltext(838 kB)242 downloads
File information
File name FULLTEXT01.pdfFile size 838 kBChecksum SHA-512
f344cc202d0884b4ed3c7fb326a0b31a61dc032b4672f07957cc1913e3452567c02831c6a00609b21a8b08a6074cc89789b119f5da901e6194b5a3341e0521eb
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Frejd, Fredrik Y.Varasteh, ZohrehOrlova, AnnaTolmachev, Vladimir

Search in DiVA

By author/editor
Frejd, Fredrik Y.Varasteh, ZohrehOrlova, AnnaTolmachev, Vladimir
By organisation
Biomedical Radiation SciencesPreclinical PET Platform
In the same journal
PLoS ONE
Cancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar
Total: 242 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 712 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf