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Evaluating the therapeutic efficacy of mono-and bivalent affibody-based fusion proteins targeting HER3 in a pancreatic cancer xenograft model

Leitao, Charles Dahlsson ; Rinne, Sara S. ; Altai, Mohamed LU ; Vorontsova, Olga ; Dunås, Finn ; Jonasson, Per ; Tolmachev, Vladimir ; Löfblom, John ; Ståhl, Stefan and Orlova, Anna (2020) In Pharmaceutics 12(6).
Abstract

Human epidermal growth factor receptor 3 (HER3) has been increasingly scrutinized as a potential drug target since the elucidation of its role in mediating tumor growth and acquired therapy resistance. Affibody molecules are so-called scaffold proteins with favorable biophysical properties, such as a small size for improved tissue penetration and extravasation, thermal and chemical stability, and a high tolerance to modifications. Additionally, affibody molecules are efficiently produced in prokaryotic hosts or by chemical peptide synthesis. We have previously evaluated the biodistribution profiles of five mono-and bivalent anti-HER3 affibody molecules (designated as 3) fused to an albumin-binding domain (designated as A), 3A, 33A, 3A3,... (More)

Human epidermal growth factor receptor 3 (HER3) has been increasingly scrutinized as a potential drug target since the elucidation of its role in mediating tumor growth and acquired therapy resistance. Affibody molecules are so-called scaffold proteins with favorable biophysical properties, such as a small size for improved tissue penetration and extravasation, thermal and chemical stability, and a high tolerance to modifications. Additionally, affibody molecules are efficiently produced in prokaryotic hosts or by chemical peptide synthesis. We have previously evaluated the biodistribution profiles of five mono-and bivalent anti-HER3 affibody molecules (designated as 3) fused to an albumin-binding domain (designated as A), 3A, 33A, 3A3, A33, and A3, that inhibit ligand-dependent phosphorylation. In the present study, we examined the therapeutic efficacy of the three most promising variants, 3A, 33A, and 3A3, in a direct comparison with the HER3-targeting monoclonal antibody seribantumab (MM-121) in a preclinical BxPC-3 pancreatic cancer model. Xenografted mice were treated with either an affibody construct or MM-121 and the tumor growth was compared to a vehicle group. Receptor occupancy was estimated by positron emission tomography/computed tomography (PET/CT) imaging using a HER3-targeting affibody imaging agent [68Ga]Ga-(HE)3-Z08698-NODAGA. The affibody molecules could inhibit ligand-dependent phosphorylation and cell proliferation in vitro and demonstrated tumor growth inhibition in vivo comparable to that of MM-121. PET/CT imaging showed full receptor occupancy for all tested drug candidates. Treatment with 3A and 3A3 affibody constructs was more efficient than with 33A and similar to the anti-HER3 antibody seribantumab, showing that the molecular design of affibody-based therapeutics targeting HER3 in terms of the relative position of functional domains and valency has an impact on therapeutic effect.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Affibody molecules, Albumin-binding domain, HER3, MM-121, Seribantumab, Therapy
in
Pharmaceutics
volume
12
issue
6
article number
551
pages
15 pages
publisher
MDPI AG
external identifiers
  • pmid:32545760
  • scopus:85088413202
ISSN
1999-4923
DOI
10.3390/pharmaceutics12060551
language
English
LU publication?
yes
id
6f712c47-0c60-4784-b56c-29aef9d967ca
date added to LUP
2020-08-05 09:18:24
date last changed
2024-06-26 20:14:31
@article{6f712c47-0c60-4784-b56c-29aef9d967ca,
  abstract     = {{<p>Human epidermal growth factor receptor 3 (HER3) has been increasingly scrutinized as a potential drug target since the elucidation of its role in mediating tumor growth and acquired therapy resistance. Affibody molecules are so-called scaffold proteins with favorable biophysical properties, such as a small size for improved tissue penetration and extravasation, thermal and chemical stability, and a high tolerance to modifications. Additionally, affibody molecules are efficiently produced in prokaryotic hosts or by chemical peptide synthesis. We have previously evaluated the biodistribution profiles of five mono-and bivalent anti-HER3 affibody molecules (designated as 3) fused to an albumin-binding domain (designated as A), 3A, 33A, 3A3, A33, and A3, that inhibit ligand-dependent phosphorylation. In the present study, we examined the therapeutic efficacy of the three most promising variants, 3A, 33A, and 3A3, in a direct comparison with the HER3-targeting monoclonal antibody seribantumab (MM-121) in a preclinical BxPC-3 pancreatic cancer model. Xenografted mice were treated with either an affibody construct or MM-121 and the tumor growth was compared to a vehicle group. Receptor occupancy was estimated by positron emission tomography/computed tomography (PET/CT) imaging using a HER3-targeting affibody imaging agent [<sup>68</sup>Ga]Ga-(HE)<sub>3</sub>-Z<sub>08698</sub>-NODAGA. The affibody molecules could inhibit ligand-dependent phosphorylation and cell proliferation in vitro and demonstrated tumor growth inhibition in vivo comparable to that of MM-121. PET/CT imaging showed full receptor occupancy for all tested drug candidates. Treatment with 3A and 3A3 affibody constructs was more efficient than with 33A and similar to the anti-HER3 antibody seribantumab, showing that the molecular design of affibody-based therapeutics targeting HER3 in terms of the relative position of functional domains and valency has an impact on therapeutic effect.</p>}},
  author       = {{Leitao, Charles Dahlsson and Rinne, Sara S. and Altai, Mohamed and Vorontsova, Olga and Dunås, Finn and Jonasson, Per and Tolmachev, Vladimir and Löfblom, John and Ståhl, Stefan and Orlova, Anna}},
  issn         = {{1999-4923}},
  keywords     = {{Affibody molecules; Albumin-binding domain; HER3; MM-121; Seribantumab; Therapy}},
  language     = {{eng}},
  number       = {{6}},
  publisher    = {{MDPI AG}},
  series       = {{Pharmaceutics}},
  title        = {{Evaluating the therapeutic efficacy of mono-and bivalent affibody-based fusion proteins targeting HER3 in a pancreatic cancer xenograft model}},
  url          = {{http://dx.doi.org/10.3390/pharmaceutics12060551}},
  doi          = {{10.3390/pharmaceutics12060551}},
  volume       = {{12}},
  year         = {{2020}},
}