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Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin
KTH, School of Biotechnology (BIO), Protein Technology.
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2016 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 49, no 3, 1185-1194 p.Article in journal (Refereed) Published
Abstract [en]

Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide In-111. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)(3) purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, In-111-(HE)(3)-Z(HER2)-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

Place, publisher, year, edition, pages
2016. Vol. 49, no 3, 1185-1194 p.
Keyword [en]
Affibody molecule, immunotoxin, albumin binding domain, PE38, HER2, biodistribution, In-111
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-192970DOI: 10.3892/ijo.2016.3614ISI: 000382447300034PubMedID: 27573289Scopus ID: 2-s2.0-84978531659OAI: oai:DiVA.org:kth-192970DiVA: diva2:1004306
Funder
Swedish Research CouncilSwedish Cancer Society
Note

QC 20160930

Available from: 2016-09-30 Created: 2016-09-23 Last updated: 2017-11-30Bibliographically approved

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