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May 3, 20260 citations

Ion Mobility-Mass Spectrometry and Collision Induced Unfolding Reveal Linker-Payload Effects on Antibody-Drug Conjugate Higher-Order Structure and Stability.

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DMDevin M. MakeyMEMarion H. EmmertHHHang Hu

Key Points

  • The research aims to investigate how different linker-payload configurations affect the higher-order structure and stability of antibody-drug conjugates (ADCs).
  • Utilized ion mobility-mass spectrometry (IM-MS) and collision induced unfolding (CIU) techniques.
  • Analyzed ADCs with various drug-to-antibody ratios (DARs) and positional isomers.
  • Measured root-mean-square deviation values to evaluate higher-order structure disruption.
  • Conjugation at interchain cysteine residues caused greater disruption of the ADC's higher-order structure compared to site-specific conjugates.
  • Differences in conformation and stability were noted among ADCs with varying DARs.
  • IM-MS and CIU proved effective as high-throughput assays for characterizing ADCs during development.

Abstract

) of the ADC was observed. Conjugation at interchain cysteine residues disrupted the HOS of the ADC to a greater extent compared to site-specific conjugates, as evidenced by higher root-mean-square deviation values. CIU data revealed differences in conformation and stability in ADCs with different DARs and different positional isomers with the same DAR. These findings demonstrate the utility of IM-MS and CIU as a high-throughput, information-rich assay for probing the HOS and stability of ADCs during their discovery and development.

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Cite This Study

Makey et al. (2026) studied this question.

synapsesocial.com/papers/69f6e5308071d4f1bdfc5fb3https://doi.org/10.1021/acs.bioconjchem.6c00018
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