Quantum weak measurement biosensor for label-free drug-to-antibody ratio determination of T-DXd

Antibody-drug conjugates (ADCs) demand precise drug-to-antibody ratio (DAR) characterization to ensure therapeutic efficacy, safety, and regulatory compliance. However, conventional DAR methods such as UV-Vis spectroscopy, hydrophobic interaction chromatography, and mass spectrometry are often destructive, label-dependent, or incapable of real-time analysis under physiologically relevant conditions. Here, we present a quantum weak measurement (QWM)-based Mach-Zehnder interferometric biosensor that enables label-free in-vitro DAR quantification of trastuzumab deruxtecan (T-DXd) on fixed human epidermal growth factor receptor 2 (HER2)-overexpressing SKBR3 cell substrates. Weak-value amplification enhances the phase sensitivity of the interferometer, allowing picomolar-level detection of T-DXd and real-time monitoring of HER2-targeted binding and dithiothreitol-induced DXd payload release within a unified optical platform. Calibration experiments yield an excellent linear response with a sensitivity of 3.166 × 10 10 nm · M −1 and a detection limit of 1.31 × 10 −12 M. By combining T-DXd adsorption and DXd release measurements, the QWM sensor determines a DAR of (7.3 ± 0.26), in good agreement with nominal specifications. The interferometric readout operates without fluorescent or enzymatic labels and avoids harsh digestion of the antibody scaffold, while requiring only microliter-scale sample volumes. Beyond T-DXd, this modular quantum biosensing architecture is adaptable to other ADCs and protein-drug conjugates as a complementary tool for precision biopharmaceutical characterization and quality control.