Oxidation-Induced Destabilization of Model Antibody-Drug Conjugates
Bücheler J, Winzer M, Weber C, Gieseler H (2019)
Publication Type: Journal article
Publication year: 2019
Journal
Book Volume: 108
Pages Range: 1236-1245
Journal Issue: 3
DOI: 10.1016/j.xphs.2018.10.039
Abstract
Oxidation of biopharmaceutics represents a major degradation pathway, which may impact bioactivity, serum half-life, and colloidal stability. This study focused on the quantification of oxidation and its effects on structure and colloidal stability for a model antibody and its lysine (ADC-L) and cysteine (ADC-C) conjugates. The effects of oxidation were evaluated by a forced degradation study using H2O2 and a shelf-life simulation, which used degrading polysorbate 80 as source for reactive oxygen species. Differential scanning fluorimetry revealed decreasing transition temperatures of the CH2 domain with rising oxidation, resulting in a loss of colloidal stability as assessed by size-exclusion high pressure liquid chromatography. The conjugation technique influences structural changes of the monoclonal antibody (mAb) and subsequently alters the impact of oxidation. ADC-C was most effected by oxidation as the CH2 domain showed the biggest destabilization on conjugation compared to the mAb and ADC-L. Quantification of Fc methionine oxidation by analytical protein A chromatography revealed 4-fold higher oxidation after 8 weeks for the ADC-C compared to the mAb. Payload degradation was observed independently of the conjugation technique used or if free in solution by ultraviolet-visible. In addition, adding antioxidants can be a suitable approach to prevent oxidation and achieve baseline stabilization of the proteins. (c) 2019 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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APA:
Bücheler, J., Winzer, M., Weber, C., & Gieseler, H. (2019). Oxidation-Induced Destabilization of Model Antibody-Drug Conjugates. Journal of Pharmaceutical Sciences, 108(3), 1236-1245. https://dx.doi.org/10.1016/j.xphs.2018.10.039
MLA:
Bücheler, Jakob, et al. "Oxidation-Induced Destabilization of Model Antibody-Drug Conjugates." Journal of Pharmaceutical Sciences 108.3 (2019): 1236-1245.
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