Evaluating the therapeutic efficacy of mono-and bivalent affibody-based fusion proteins targeting HER3 in a pancreatic cancer xenograft model
(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
- Leitao, Charles Dahlsson ; Rinne, Sara S. ; Altai, Mohamed LU ; Vorontsova, Olga ; Dunås, Finn ; Jonasson, Per ; Tolmachev, Vladimir ; Löfblom, John ; Ståhl, Stefan and Orlova, Anna
- organization
- publishing date
- 2020
- 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
-
- scopus:85088413202
- pmid:32545760
- 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
- 2024-09-20 03:01:11
@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}}, }