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Imaged capillary isoelectric focusing method development for charge variants of high DAR ADCs. | LitMetric

Imaged capillary isoelectric focusing method development for charge variants of high DAR ADCs.

Anal Chim Acta

Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd, No. 666 Xinhua Avenue, Chengdu Cross-Strait Science and Technology Industry Development Park, Wenjiang District, Chengdu, Sichuan Province, PR China.

Published: November 2024

AI Article Synopsis

  • Charge heterogeneity is essential for the quality of therapeutics like antibody-drug conjugates (ADCs), but creating effective methods for high drug-to-antibody ratios (DAR) is difficult due to increased complexity.
  • The study focuses on optimizing imaged capillary isoelectric focusing (icIEF) methods by analyzing various parameters such as solubilizers and focusing time to improve resolution and stability for high DAR ADCs.
  • This research is the first thorough investigation into icIEF method development for charge variant assessment in high DAR ADCs, offering valuable insights into their unique properties.

Article Abstract

Background: Charge heterogeneity is a critical quality attribute for therapeutic biologics including antibody-drug conjugates (ADCs). Developing an ion exchange chromatography (IEX) or an imaged capillary isoelectric focusing (icIEF) method for ADCs with high drug-to-antibody ratio (DAR) is challenging because of the increased hydrophobicity from the payload-linker, DAR heterogeneity, and payload-linker instability. A sub-optimal method can be poorly stability-indicating due to the inability to discern contributions from charge and size variants conjugated with different number of drugs/payloads. Systematic strategy and guidance on charge variant method development is highly desired for high DAR ADCs with various complex structures.

Results: This work encompasses the development and optimization of icIEF methods for high DAR ADCs of various DAR values (4-8) and payload linker chemistry. Method optimization focuses on improving resolution and stability indicating capabilities and differentiating contributions from the protein and payload-linker. Types, proportion, and combination of solubilizers and carrier ampholytes, as well as focusing parameters were interrogated. Our findings show that the structural units of the linker, the DAR, and the payload chemistry prescribe the selection of buffer, solubilizer, and ampholyte. We demonstrate that a stronger denaturant or solubilizer is needed for high DAR ADCs with polyethylene glycol (PEG)-containing linker structure compared to peptide linker. For unstable payload-linker, buffer system enhances sample stability which is vital to method robustness. In addition, a longer isoelectric focusing time is necessary for an ADC than its corresponding antibody to reach optimal focusing.

Significance: To the best of our knowledge, this is the first comprehensive study on icIEF method development for charge variant determination of high DAR ADCs with unique physicochemical properties.

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Source
http://dx.doi.org/10.1016/j.aca.2024.343176DOI Listing

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