A Priori Prediction of Tumor Payload Concentrations: Preclinical Case Study with an Auristatin-Based Anti-5T4 Antibody-Drug Conjugate

Abstract

Abstract. The objectives of this investigation were as follows: (a) to validate a mechanism-based pharmacokinetic (PK) model of ADC for its ability to a priori predict tumor concentrations of ADC and released payload, using anti-5T4 ADC A1mcMMAF, and (b) to analyze the PK model to find out main pathways and parameters model outputs are most sensitive to. Experiential data containing biomeasures, and plasma and tumor concentrations of ADC and payload, following A1mcMMAF administration in two different xenografts, were used to build and validate the model. The model performed reasonably well in terms of a priori predicting tumor exposure of total antibody, ADC, and released payload, and the exposure of released payload in plasma. Model predictions were within two fold of the observed exposures. Pathway analysis and local sensitivity analysis were conducted to investigate main pathways and set of parameters the model outputs are most sensitive to. It was discovered that payload dissociation from ADC and tumor size were important determinants of plasma and tumor payload exposure. It was also found that the sensitivity of the model output to certain parameters is dose-dependent, suggesting caution before generalizing the results from the sensitivity analysis. Model analysis also revealed the importance of understanding and quantifying the processes responsible for ADC and payload disposition within tumor cell, as tumor concentrations were sensitive to these parameters. Proposed ADC PK model provides a useful tool for a priori predicting tumor payload concentrations of novel ADCs preclinically, and possibly translating them to the clinic.

QSP Toolbox: Computational Implementation of Integrated Workflow Components for Deploying Multi-Scale Mechanistic Models

“…Several models have been proposed to mechanistically model ADC efficacy (43)(44)(45)(46)(47)(48)(49)(50)(51)(52), many of which have been previously reviewed (41). Mechanistic models have often been applied to investigate antibodies as a modality, although modeling studies focused on immunotoxins have also been reported (43,52).…”

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

“…75 Application of Quantitative Systems Pharmacology Modeling Quantitative systems pharmacology modeling was previously used for ADC design optimization, 76,77 prediction of tumor ADC concentrations, and increasing the understanding of intracellular ADC activation in preclinical tumor models. This information was then used to guide dose selection 78,79 and translate data from preclinical species to humans to predict clinically efficacious doses. 80,81 A multiscale, mechanism-based PK/PD model was built and validated using published brentuximab vedotin experimental data.…”

“Target-Site” Drug Metabolism and Transport

“…Of particular interest is the prediction of released payload concentrations at the site of therapeutic action, which may be significantly higher than the concentration observed in plasma (Alley et al, 2009). As direct clinical measurement of released payload concentrations through the use of tumor distribution studies is often logistically challenging, a significant effort has recently been placed on the development of in dmd.aspetjournals.org vitro or in silico techniques to predict the effect of therapeutic sitespecific catabolism on the observed target-site concentrations of ADC payloads (Shah et al, 2014). The final aspect of this symposium focused on the use of in vitro cellular assays to determine the effect of ADC catabolism at the site of therapeutic action on the observed pharmacodynamics of the ADC.…”