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The influence of domain permutations of an albumin-binding domain-fused her2-targeting affibody-based drug conjugate on tumor cell proliferation and therapy efficacy

Yin, Wen ; Xu, Tianqi ; Altai, Mohamed LU ; Oroujeni, Maryam ; Zhang, Jie ; Vorobyeva, Anzhelika ; Vorontsova, Olga ; Vtorushin, Sergey V. ; Tolmachev, Vladimir and Gräslund, Torbjörn , et al. (2021) In Pharmaceutics 13(11).
Abstract

Human epidermal growth factor receptor 2 (HER2) is a clinically validated target for breast cancer therapy. Previously, a drug-fused HER2-targeting affinity protein construct successfully extended the survival of mice bearing HER2-expressing xenografts. The aim of this study was to evaluate the influence of the number and positioning of the protein domains in the drug conjugate. Seven HER2-targeting affibody-based constructs, including one or two affibody molecules (Z) with or without an albumin-binding domain (ABD), namely Z, Z-ABD, ABD-Z, Z-Z, Z-Z-ABD, Z-ABD-Z, and ABD-Z-Z, were evaluated on their effects on cell growth, in vivo targeting, and biodistribution. The biodistribution study demonstrated that the monomeric constructs had... (More)

Human epidermal growth factor receptor 2 (HER2) is a clinically validated target for breast cancer therapy. Previously, a drug-fused HER2-targeting affinity protein construct successfully extended the survival of mice bearing HER2-expressing xenografts. The aim of this study was to evaluate the influence of the number and positioning of the protein domains in the drug conjugate. Seven HER2-targeting affibody-based constructs, including one or two affibody molecules (Z) with or without an albumin-binding domain (ABD), namely Z, Z-ABD, ABD-Z, Z-Z, Z-Z-ABD, Z-ABD-Z, and ABD-Z-Z, were evaluated on their effects on cell growth, in vivo targeting, and biodistribution. The biodistribution study demonstrated that the monomeric constructs had longer blood retention and lower hepatic uptake than the dimeric ones. A dimeric construct, specifically ABD-Z-Z, could stimulate the proliferation of HER2 expressing SKOV-3 cells in vitro and the growth of tumors in vivo, whereas the monomeric construct Z-ABD could not. These two constructs demonstrated a therapeutic effect when coupled to mcDM1; however, the effect was more pronounced for the non-stimulating Z-ABD. The median survival of the mice treated with Z-ABD-mcDM1 was 63 days compared to the 37 days for those treated with ABD-Z-Z-mcDM1 or for the control animals. Domain permutation of an ABD-fused HER2-targeting affibody-based drug conjugate significantly influences tumor cell proliferation and therapy efficacy. The monomeric conjugate Z-ABD is the most promising format for targeted delivery of the cytotoxic drug DM1.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Affibody molecule, Albumin-binding domain, DM1, Drug conjugate, HER2, Mertansine, Targeted therapy
in
Pharmaceutics
volume
13
issue
11
article number
1974
publisher
MDPI AG
external identifiers
  • pmid:34834389
  • scopus:85120309189
ISSN
1999-4923
DOI
10.3390/pharmaceutics13111974
language
English
LU publication?
yes
id
d8e9023a-e862-466a-b667-58bd01304d09
date added to LUP
2021-12-15 12:13:35
date last changed
2024-04-20 17:48:31
@article{d8e9023a-e862-466a-b667-58bd01304d09,
  abstract     = {{<p>Human epidermal growth factor receptor 2 (HER2) is a clinically validated target for breast cancer therapy. Previously, a drug-fused HER2-targeting affinity protein construct successfully extended the survival of mice bearing HER2-expressing xenografts. The aim of this study was to evaluate the influence of the number and positioning of the protein domains in the drug conjugate. Seven HER2-targeting affibody-based constructs, including one or two affibody molecules (Z) with or without an albumin-binding domain (ABD), namely Z, Z-ABD, ABD-Z, Z-Z, Z-Z-ABD, Z-ABD-Z, and ABD-Z-Z, were evaluated on their effects on cell growth, in vivo targeting, and biodistribution. The biodistribution study demonstrated that the monomeric constructs had longer blood retention and lower hepatic uptake than the dimeric ones. A dimeric construct, specifically ABD-Z-Z, could stimulate the proliferation of HER2 expressing SKOV-3 cells in vitro and the growth of tumors in vivo, whereas the monomeric construct Z-ABD could not. These two constructs demonstrated a therapeutic effect when coupled to mcDM1; however, the effect was more pronounced for the non-stimulating Z-ABD. The median survival of the mice treated with Z-ABD-mcDM1 was 63 days compared to the 37 days for those treated with ABD-Z-Z-mcDM1 or for the control animals. Domain permutation of an ABD-fused HER2-targeting affibody-based drug conjugate significantly influences tumor cell proliferation and therapy efficacy. The monomeric conjugate Z-ABD is the most promising format for targeted delivery of the cytotoxic drug DM1.</p>}},
  author       = {{Yin, Wen and Xu, Tianqi and Altai, Mohamed and Oroujeni, Maryam and Zhang, Jie and Vorobyeva, Anzhelika and Vorontsova, Olga and Vtorushin, Sergey V. and Tolmachev, Vladimir and Gräslund, Torbjörn and Orlova, Anna}},
  issn         = {{1999-4923}},
  keywords     = {{Affibody molecule; Albumin-binding domain; DM1; Drug conjugate; HER2; Mertansine; Targeted therapy}},
  language     = {{eng}},
  number       = {{11}},
  publisher    = {{MDPI AG}},
  series       = {{Pharmaceutics}},
  title        = {{The influence of domain permutations of an albumin-binding domain-fused her2-targeting affibody-based drug conjugate on tumor cell proliferation and therapy efficacy}},
  url          = {{http://dx.doi.org/10.3390/pharmaceutics13111974}},
  doi          = {{10.3390/pharmaceutics13111974}},
  volume       = {{13}},
  year         = {{2021}},
}