Evaluating the Potential of Cyclodextrins in Reducing Aggregation of Antibody–Drug Conjugates with Different Payloads

Johann F, Wöll S, Gieseler H (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Journal of Pharmaceutical Sciences Elsevier

DOI: 10.1016/j.xphs.2024.04.024

Abstract

Cyclodextrins (CDs) are versatile agents used to solubilize small drugs and stabilize proteins. This dual functionality may be particularly beneficial for antibody–drug conjugates (ADCs), as CDs may “mask” the hydrophobicity of the drug payloads. In this study, we explored the effect of CDs on the physical stability of ADCs composed of the same antibody but with different payloads (maytansinoid, auristatin, and fluorophore payloads). The aggregation of ADCs was evaluated under shaking stress conditions and elevated temperatures using size-exclusion chromatography, turbidity, and backgrounded membrane imaging. Our results showed that hydroxypropyl-(HP)-CDs effectively stabilized all ADCs during shaking stress, with increasing stabilization in the order of HPαCD < HPγCD < HPβCD at concentrations of 7.5 mM and (near) complete stabilization at 75 mM. Native CDs without surface activity also stabilized certain ADCs, although less effectively than HP-CDs under agitation stress. During quiescent incubation, the HP-CD effects were small for most ADCs. However, for an ADC with a fluorophore payload that rapidly aggregated after conjugation, HPγCD substantially reduced aggregate levels, in line with fluorescence data supporting CD–ADC interactions. In contrast, sulfobutylether-β-CD (SBEβCD) increased the aggregation rates in all ADCs under all stress conditions. In conclusion, this study highlights the potential of appropriate CD formulations to improve the physical stability of ADCs.

Authors with CRIS profile

Florian Johann Lehrstuhl für Pharmazeutische Technologie und Biopharmazie Henning Gieseler Lehrstuhl für Pharmazeutische Technologie und Biopharmazie

Additional Organisation(s)

FAU Forschungszentrum Neue Wirkstoffe (FAU NeW)

Involved external institutions

Merck KGaA DE Germany (DE)

How to cite

APA:

Johann, F., Wöll, S., & Gieseler, H. (2024). Evaluating the Potential of Cyclodextrins in Reducing Aggregation of Antibody–Drug Conjugates with Different Payloads. Journal of Pharmaceutical Sciences. https://doi.org/10.1016/j.xphs.2024.04.024

MLA:

Johann, Florian, Steffen Wöll, and Henning Gieseler. "Evaluating the Potential of Cyclodextrins in Reducing Aggregation of Antibody–Drug Conjugates with Different Payloads." Journal of Pharmaceutical Sciences (2024).

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