Agitation-Induced Aggregation of Lysine- And Interchain Cysteine-Linked Antibody-Drug Conjugates
Johann F, Wöll S, Winzer M, Gieseler H (2024)
Publication Type: Journal article
Publication year: 2024
Journal
Book Volume: 113
Pages Range: 1265-1274
Journal Issue: 5
DOI: 10.1016/j.xphs.2023.12.003
Abstract
Drug conjugation to an antibody can affect its stability, which depends on factors such as the conjugation technique used, drug-linker properties, and stress encountered. This study focused on the effects of agitation stress on the physical stability of two lysine (ADC-K) and two interchain cysteine (ADC-C) conjugates of an IgG1 monoclonal antibody (mAb) linked to either ∼4 MMAE or DM1 payloads. During agitation, all antibody–drug conjugates (ADCs) exhibited higher aggregation than the mAb, which was dependent on the conjugation technique (aggregation of ADC-Ks > ADC-Cs) and drug-linker (aggregation of ADCs with MMAE > ADCs with DM1). The aggregation propensities correlated well with higher self-interaction, hydrophobicity, and surface activity of ADCs relative to the mAb. The intermediate reduced mAb (mAb-SH) showed even higher aggregation than the final product ADC-Cs. However, blocking mAb-SH's free thiols with N-ethylmaleimide (NEM) strongly reduced its aggregation, suggesting that free thiols should be minimized in cysteine ADCs. Further, this study demonstrates that a low-volume surface tension method can be used for estimating agitation-induced aggregation of ADCs in early development phases. Identifying liabilities to agitation stress and their relationship to biophysical properties may help optimize ADC stability.
Authors with CRIS profile
Florian Johann
Lehrstuhl für Pharmazeutische Technologie und Biopharmazie
Henning Gieseler
Lehrstuhl für Pharmazeutische Technologie und Biopharmazie
Additional Organisation(s)
Involved external institutions
Germany (DE)How to cite
APA:
Johann, F., Wöll, S., Winzer, M., & Gieseler, H. (2024). Agitation-Induced Aggregation of Lysine- And Interchain Cysteine-Linked Antibody-Drug Conjugates. Journal of Pharmaceutical Sciences, 113(5), 1265-1274. https://doi.org/10.1016/j.xphs.2023.12.003
MLA:
Johann, Florian, et al. "Agitation-Induced Aggregation of Lysine- And Interchain Cysteine-Linked Antibody-Drug Conjugates." Journal of Pharmaceutical Sciences 113.5 (2024): 1265-1274.
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