Challenges and Solutions in Antibody-Conjugated Drug (ADC) Bioanalysis

Antibody-drug conjugates (ADCs) have surged in popularity due to their precise targeting of cancer cells, combining the specificity of monoclonal antibodies with potent cytotoxic payloads. This approach minimizes harm to healthy cells, a key advantage over traditional chemotherapy. However, ADCs are structurally complex, with multiple forms emerging as they transform in the body, which poses challenges for bioanalysis. Accurate measurement of each component requires advanced techniques to fully understand ADC behavior and effectiveness.
Traditional ligand-binding assays (LBAs) have been widely used for ADC bioanalysis but face limitations, including low specificity and selectivity, complex critical reagents, lengthy method development, and the ability to measure only the antibody component. Liquid chromatography-mass spectrometry (LCMS) offers a promising alternative, providing precise and multiplexed bioanalysis that addresses these limitations of LBAs. In this presentation, we propose an LCMS-based strategy to quantify both the payload and antibody components, discuss associated challenges and solutions, and present several case studies.
Using UPLC coupled with a triple quadrupole MS enables accurate quantification of ADCs' complex structures, which is essential for ADC bioanalysis. LCMS offers superior bioanalytical capabilities compared to traditional LBAs, providing precise and comprehensive measurements of the total antibody, ADC, conjugated payload, and free payload. This strategy significantly streamlines the bioanalytical workflow for ADC drugs.