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A DAR sensitive hybrid LBA-LC-MS/MS assay for quantitation of conjugated payload from a non-cleavable ADC in human
Yongjun Xue1, Eric Ma2, Brian Melo1
1Precision Medicine, Bioanalytical & Translational Sciences, Bristol Myers Squibb, Princeton, NJ, USA.
Background:
Quantitating antibody drug conjugates (ADCs) with traditional ligand binding assays (LBAs) requires cytotoxic payload targeting reagents, which may be needed for ADC capture/detection. LBAs are drug antibody ratio insensitive (DAR insensitive) and prone to under- or over-estimating DAR species.
Methods:
This hybrid LBA LC MS/MS assay measures concentrations for a novel ADC drug (BMS-X) with an engineered, site‑specific, non-cleavable linker, and a unique payload. Recombinant target protein-extracellular domain fused with mouse IgG-Fc was used for ADC pull down in human serum. Pepsin digestion released unique toxin linker peptide complexes for two conjugation sites.
Results And Conclusions:
This novel, validated DAR-sensitive hybrid-LCMS PK assay measured payload-conjugated BMS-X levels in human serum, quantitated surrogate analytes for both unique conjugation sites, and was used to support a first-in-human clinical trial.
