A modelling approach to compare ADC deconjugation and systemic elimination rates of individual drug-load species using native ADC LC-MS data from human plasma
Creators: name: Hengel, Shawna M.
name: Topletz-Erickson, Ariel R.
name: Kadry, Hossam
name: Alley, Stephen C.
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Space Science
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Mental Health

description: Native liquid chromatography mass spectrometry (LC-MS) is a commonly used approach for intact analysis of inter-chain cysteine conjugated antibody-drug conjugates (ADCs). Coupling native LC-MS with affinity capture provides a platform for intact ADC analysis from <i>in vivo</i> samples and characterisation of individual drug load species, specifically the impact of drug linker deconjugation, hydrolysis, and differential clearance in a biological system.This manuscript describes data generated from native LC-MS analysis of ADCs from human plasma, both <i>in vitro</i> incubations and clinical samples. It also details the pharmacokinetic (PK) model built to specifically characterise the disposition of individual drug load species from MMAE and MMAF interchain cysteine conjugated ADCs.<i>In vitro</i> deconjugation and hydrolysis rates were similar across both ADCs. Differential clearance of higher loaded species <i>in vivo</i> was pronounced for the MMAE conjugated ADC, while systemic elimination after accounting for deconjugation was similar across drug loads for the MMAF conjugated ADC. This is the first report of affinity capture native LC-MS analysis, and subsequent modelling of deconjugation, hydrolysis and clearance rates of individual drug load species using clinical data from cysteine conjugated ADCs. Native liquid chromatography mass spectrometry (LC-MS) is a commonly used approach for intact analysis of inter-chain cysteine conjugated antibody-drug conjugates (ADCs). Coupling native LC-MS with affinity capture provides a platform for intact ADC analysis from <i>in vivo</i> samples and characterisation of individual drug load species, specifically the impact of drug linker deconjugation, hydrolysis, and differential clearance in a biological system. This manuscript describes data generated from native LC-MS analysis of ADCs from human plasma, both <i>in vitro</i> incubations and clinical samples. It also details the pharmacokinetic (PK) model built to specifically characterise the disposition of individual drug load species from MMAE and MMAF interchain cysteine conjugated ADCs. <i>In vitro</i> deconjugation and hydrolysis rates were similar across both ADCs. Differential clearance of higher loaded species <i>in vivo</i> was pronounced for the MMAE conjugated ADC, while systemic elimination after accounting for deconjugation was similar across drug loads for the MMAF conjugated ADC. This is the first report of affinity capture native LC-MS analysis, and subsequent modelling of deconjugation, hydrolysis and clearance rates of individual drug load species using clinical data from cysteine conjugated ADCs.