“Negative” Impact: The Role of Payload Charge in the Physicochemical Stability of Auristatin Antibody–Drug Conjugates

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.2024.04.023

Abstract

Antibody-drug conjugates (ADCs) tend to be less stable than their parent antibodies, which is often attributed to the hydrophobic nature of their drug payloads. This study investigated how the payload charge affects ADC stability by comparing two interchain cysteine ADCs that had matched drug-to-antibody ratios and identical linkers but differently charged auristatin payloads, vcMMAE (neutral) and vcMMAF (negative). Both ADCs exhibited higher aggregation than their parent antibody under shaking stress and thermal stress conditions. However, conjugation with vcMMAF increased the aggregation rates to a greater extent than conjugation with uncharged but more hydrophobic vcMMAE. Consistent with the payload logD values, ADC-vcMMAE showed the greatest increase in hydrophobicity but minor changes in charge compared with the parent antibody, as indicated by hydrophobic interaction chromatography and capillary electrophoresis data. In contrast, ADC-vcMMAF showed a decrease in net charge and isoelectric point along with an increase in charge heterogeneity. This charge alteration likely contributed to a reduced electrostatic repulsion and increased surface activity in ADC-vcMMAF, thus affecting its aggregation propensity. These findings suggest that not only the hydrophobicity of the payload, but also its charge should be considered as a critical factor affecting the 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). “Negative” Impact: The Role of Payload Charge in the Physicochemical Stability of Auristatin Antibody–Drug Conjugates. Journal of Pharmaceutical Sciences. https://doi.org/10.1016/j.xphs.2024.04.023

MLA:

Johann, Florian, Steffen Wöll, and Henning Gieseler. "“Negative” Impact: The Role of Payload Charge in the Physicochemical Stability of Auristatin Antibody–Drug Conjugates." Journal of Pharmaceutical Sciences (2024).

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