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Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. (Vladimir Tolmachev)
KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. (Anna Orlova)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. (Vladimir Tolmachev)
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2016 (engelsk)Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 49, nr 3, s. 1185-1194Artikkel i tidsskrift (Fagfellevurdert) 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 111In. 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, 111In-(HE)3-ZHER2-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.

sted, utgiver, år, opplag, sider
2016. Vol. 49, nr 3, s. 1185-1194
Emneord [en]
Affibody molecule; immunotoxin; albumin binding domain; PE38; HER2; biodistribution; In-111
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-302638DOI: 10.3892/ijo.2016.3614ISI: 000382447300034PubMedID: 27573289OAI: oai:DiVA.org:uu-302638DiVA, id: diva2:962978
Forskningsfinansiär
Swedish Research CouncilSwedish Cancer SocietyTilgjengelig fra: 2016-09-07 Laget: 2016-09-07 Sist oppdatert: 2018-01-10bibliografisk kontrollert

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