Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft Model
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...
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doaj-148da783456d45d6a6e536a64f9360172020-11-25T02:30:02ZengMDPI AGPharmaceutics1999-49232020-06-011255155110.3390/pharmaceutics12060551Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft ModelCharles Dahlsson Leitao0Sara S. Rinne1Mohamed Altai2Olga Vorontsova3Finn Dunås4Per Jonasson5Vladimir Tolmachev6John Löfblom7Stefan Ståhl8Anna Orlova9Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 106 91 Stockholm, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, SwedenAffibody AB, 171 65 Solna, SwedenAffibody AB, 171 65 Solna, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, SwedenDepartment of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 106 91 Stockholm, SwedenDepartment of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 106 91 Stockholm, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, SwedenHuman 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.https://www.mdpi.com/1999-4923/12/6/551affibody moleculesHER3albumin-binding domainseribantumabtherapyMM-121 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Charles Dahlsson Leitao Sara S. Rinne Mohamed Altai Olga Vorontsova Finn Dunås Per Jonasson Vladimir Tolmachev John Löfblom Stefan Ståhl Anna Orlova |
spellingShingle |
Charles Dahlsson Leitao Sara S. Rinne Mohamed Altai Olga Vorontsova Finn Dunås Per Jonasson Vladimir Tolmachev John Löfblom Stefan Ståhl Anna Orlova Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft Model Pharmaceutics affibody molecules HER3 albumin-binding domain seribantumab therapy MM-121 |
author_facet |
Charles Dahlsson Leitao Sara S. Rinne Mohamed Altai Olga Vorontsova Finn Dunås Per Jonasson Vladimir Tolmachev John Löfblom Stefan Ståhl Anna Orlova |
author_sort |
Charles Dahlsson Leitao |
title |
Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft Model |
title_short |
Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft Model |
title_full |
Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft Model |
title_fullStr |
Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft Model |
title_full_unstemmed |
Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft Model |
title_sort |
evaluating the therapeutic efficacy of mono- and bivalent affibody-based fusion proteins targeting her3 in a pancreatic cancer xenograft model |
publisher |
MDPI AG |
series |
Pharmaceutics |
issn |
1999-4923 |
publishDate |
2020-06-01 |
description |
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. |
topic |
affibody molecules HER3 albumin-binding domain seribantumab therapy MM-121 |
url |
https://www.mdpi.com/1999-4923/12/6/551 |
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