In vitro and in vivo immunogenicity assessment of protein aggregate characteristics
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In vitro and in vivo immunogenicity assessment of protein aggregate characteristics. / Thorlaksen, Camilla; Schultz, Heidi S.; Gammelgaard, Simon K.; Jiskoot, Wim; Hatzakis, Nikos S.; Nielsen, Flemming S.; Solberg, Helene; Foderà, Vito; Bartholdy, Christina; Groenning, Minna.
In: International Journal of Pharmaceutics, Vol. 631, 122490, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - In vitro and in vivo immunogenicity assessment of protein aggregate characteristics
AU - Thorlaksen, Camilla
AU - Schultz, Heidi S.
AU - Gammelgaard, Simon K.
AU - Jiskoot, Wim
AU - Hatzakis, Nikos S.
AU - Nielsen, Flemming S.
AU - Solberg, Helene
AU - Foderà, Vito
AU - Bartholdy, Christina
AU - Groenning, Minna
N1 - Publisher Copyright: © 2022 The Author(s)
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Aggregate
KW - Anti-drug antibody
KW - Human insulin
KW - Immunogenicity
KW - Particles
U2 - 10.1016/j.ijpharm.2022.122490
DO - 10.1016/j.ijpharm.2022.122490
M3 - Journal article
C2 - 36521637
AN - SCOPUS:85144782464
VL - 631
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
SN - 0378-5173
M1 - 122490
ER -
ID: 331584560