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4C-O1-P-0940 PDF
Characterization of the active catabolite formed in vivo from an Antibody Drug Conjugate with an Eg5 Inhibitor Payload and Stable Linker Design
The characterization of the small molecule payload of an Antibody Drug Conjugate (ADC) is important in understanding its efficacy and potential toxicity. In this presentation, we describe the use of mass spectrometry to identify and characterize the active catabolite formed in vivo for an ADC containing an Eg5 inhibitor payload conjugated to trastuzumab, a Her2-targeting antibody, via a stable linker. In a mouse xenograft PK/PD study, the ADC was dosed at 10 mg/kg, tumors were flash frozen and then analyzed using LC/MS/MS and MALDI Imaging MS. Only the active Eg5 small molecule attached to cysteine via the stable linker was observed in both plasma and tumor. No other amino acids were found to be attached to cysteine indicating complete proteolytic digestion. Free payload was not observed, demonstrating good linker stability. MALDI Imaging MS showed a general distribution of the cysteine catabolite throughout tumors that was consistent with IHC staining for human IgG. A strong PK/PD correlation was observed for the active cysteine catabolite in tumor tissue. The combined results of this study indicated that this Eg5 ADC worked according to design, by selective accumulation in tumors, intracellular catabolism to create an active cysteine-linker-payload molecule, and induction of cell cycle arrest.