In vitro and in vivo immunogenicity assessment of protein aggregate characteristics
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The immunogenicity risk of therapeutic protein aggregates has been extensively investigated over the past decades. While it is established that not all aggregates are equally immunogenic, the specific aggregate characteristics, which are most likely to induce an immune response, remain ambiguous. The aim of this study was to perform comprehensive in vitro and in vivo immunogenicity assessment of human insulin aggregates varying in size, structure and chemical modifications, while keeping other morphological characteristics constant. We found that flexible aggregates with highly altered secondary structure were most immunogenic in all setups, while compact aggregates with native-like structure were found to be immunogenic primarily in vivo. Moreover, sub-visible (1–100 µm) aggregates were found to be more immunogenic than sub-micron (0.1–1 µm) aggregates, while chemical modifications (deamidation, ethylation and covalent dimers) were not found to have any measurable impact on immunogenicity. The findings highlight the importance of utilizing aggregates varying in few characteristics for assessment of immunogenicity risk of specific morphological features and may provide a workflow for reliable particle analysis in biotherapeutics.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 122490 |
| Tidsskrift | International Journal of Pharmaceutics |
| Vol/bind | 631 |
| ISSN | 0378-5173 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Authors acknowledge Novo Nordisk A/S for project funding and providing material for formation of protein aggregates, human cell studies and animal studies. VF and CT acknowledge VILLUM FONDEN for supporting the project via the Villum Young Investigator Grant “Protein Superstructures as Smart Biomaterials (ProSmart)” 2018 − 2023 (Grant 19175). NSH and CT acknowledge VILLUM FONDEN (Grant 18333) and NSH acknowledge Novo Nordisk foundation grants NNF16OC0021948 and NNF14CC0001. For use of SEM, authors acknowledge the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen.
Funding Information:
Authors acknowledge Novo Nordisk A/S for project funding and providing material for formation of protein aggregates, human cell studies and animal studies. VF and CT acknowledge VILLUM FONDEN for supporting the project via the Villum Young Investigator Grant “Protein Superstructures as Smart Biomaterials (ProSmart)” 2018 − 2023 (Grant 19175). NSH and CT acknowledge VILLUM FONDEN (Grant 18333) and NSH acknowledge Novo Nordisk foundation grants NNF16OC0021948 and NNF14CC0001. For use of SEM, authors acknowledge the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen.
Publisher Copyright:
© 2022 The Author(s)
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