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Selection of an optimal cysteine-containing peptide-based chelator for labeling of affibody molecules with (188)Re.
KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
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2014 (Engelska)Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 87, s. 519-28Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of (188)Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all (188)Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The (188)Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of (188)Re-ZHER2:V2 (3.1 ± 0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental (188)Re-ZHER2:2395 (172 ± 32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of (188)Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.

Ort, förlag, år, upplaga, sidor
2014. Vol. 87, s. 519-28
Nyckelord [en]
Affibody, Affinity discrimination, Cell surface display, FACS, Gram positive, Staphylococcus carnosus, immunoglobulin G, membrane protein, antibody combining site, article, binding affinity, cell interaction, cellular distribution, evaluation, fluorescence activated cell sorting, nonhuman, priority journal, protein domain, protein expression, protein localization, protein targeting, signal transduction, Staphylococcus, Staphylococcus carnosus, surface property, Amino Acid Sequence, Antibody Affinity, Flow Cytometry, Immunoglobulin G, Molecular Sequence Data, Mutation, Peptide Library, Protein Structure, Tertiary, Recombinant Proteins, Sequence Alignment, Staphylococcal Protein A, Staphylococcus, Transformation, Bacterial, Posibacteria, Staphylococcus carnosus
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Övrig annan medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:kth:diva-160037DOI: 10.1016/j.ejmech.2014.09.082ISI: 000363431300049PubMedID: 25282673Scopus ID: 2-s2.0-84907818093OAI: oai:DiVA.org:kth-160037DiVA, id: diva2:788325
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QC 20150213

Tillgänglig från: 2015-02-13 Skapad: 2015-02-13 Senast uppdaterad: 2017-12-04Bibliografiskt granskad

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Löfblom, JohnStåhl, Stefan

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Wållberg, HelenaLöfblom, JohnStåhl, Stefan
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