Bioanalytical Strategies for Antibody Drug Conjugate (ADC) Biopharmaceutical Development: Characterization of Trastuzumab-DM1 in Plasma by Affinity Mass Spectrometry

摘要

Recombinant monoclonal antibodies (MAbs) are now widely used as a treatment option in oncology, often in combination with chemotherapy. Antibody-drug conjugates (ADCs) are recombinant MAbs with covalently bound cytotoxic drugs via a linker, and represent an exciting new biotherapeutic platform. Trastuzmab-DM1 (T-DM1) is Genentech's first ADC currently under evaluation in the clinic, which contains the recombinant humanized MAb Trastuzumab linked to the cytotoxic drug maytansinoid DM1. ADCs can deliver the cytotoxic drugs specifically inside target tumor cells, minimizing the exposure to non-target cells and thereby reduce the side effects of the treatment. Analysis of ADCs in vivo has been challenging due to their complex and heterogeneous structures, together with the difficulty to separate them from the abundant background proteins in biological matrices. Our strategy has included the development of a paramagnetic bead-based affinity mass spectrometric method for the structural characterization and quantitation of ADCs in plasma.