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<p>Loncastuximab tesirine is a cysteine-linked antibody–drug conjugate composed of an anti-CD19 monoclonal antibody linked to the PBD dimer payload SG3249 via a protease-cleavable linker, enabling targeted release of a highly cytotoxic DNA cross-linking agent. NAC-SG3249, a thiol adduct formed with N-acetylcysteine, serves as an important indicator of payload release and ADC stability. In this study, mass spectrometry techniques were employed to systematically investigate the stability and related small-molecule impurities of this ADC. Quantitative analysis of the free payload showed good linearity over 0.05–100 ng/mL (R² ≥ 0.991), with an LLOQ of 0.05 ng/mL, accuracy of 80%–120%, and precision below 5%, and the results were consistent between HRMS and TQMS, both methods can achieve effective quantification. Potential payload-related impurities were further characterized based on predicted hydrolysis pathways using targeted MRM analysis. Forced degradation studies under acidic, alkaline, photolytic, and thermal conditions revealed multiple degradation products using a highly sensitive nanoLC–HRMS method, with alkaline conditions producing the greatest number of impurities. Clinical trial number: not applicable.</p>

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Investigation of Payloads and Related Impurities in the cysteine-linked Antibody-Drug Conjugate Using Mass Spectrometry Techniques

  • 期刊论文

  • 发表日期：

    2026年7月21日

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  • Gang Wu,
  • Gangling Xu,
  • Yue Zhao,
  • Tie Gao,
  • Yongbo Ni,
  • Xiaolei Lv,
  • Hongxu Chen,
  • Meng Li,
  • Jialiang Du,
  • Chuanfei Yu

摘要

Loncastuximab tesirine is a cysteine-linked antibody–drug conjugate composed of an anti-CD19 monoclonal antibody linked to the PBD dimer payload SG3249 via a protease-cleavable linker, enabling targeted release of a highly cytotoxic DNA cross-linking agent. NAC-SG3249, a thiol adduct formed with N-acetylcysteine, serves as an important indicator of payload release and ADC stability. In this study, mass spectrometry techniques were employed to systematically investigate the stability and related small-molecule impurities of this ADC. Quantitative analysis of the free payload showed good linearity over 0.05–100 ng/mL (R² ≥ 0.991), with an LLOQ of 0.05 ng/mL, accuracy of 80%–120%, and precision below 5%, and the results were consistent between HRMS and TQMS, both methods can achieve effective quantification. Potential payload-related impurities were further characterized based on predicted hydrolysis pathways using targeted MRM analysis. Forced degradation studies under acidic, alkaline, photolytic, and thermal conditions revealed multiple degradation products using a highly sensitive nanoLC–HRMS method, with alkaline conditions producing the greatest number of impurities. Clinical trial number: not applicable.