Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin

Mohamed Altai, Hao Liu, Anna Orlova, Vladimir Tolmachev, Torbjörn Gräslund

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

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-ABDPE38X8 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.

Original languageEnglish
Pages (from-to)1185-1194
Number of pages10
JournalInternational Journal of Oncology
Volume49
Issue number3
DOIs
Publication statusPublished - Sep 2016
Externally publishedYes

Keywords

  • In
  • Affibody molecule
  • Albumin binding domain
  • Biodistribution
  • HER2
  • Immunotoxin
  • PE38

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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