Raju Prasad Sharma1, Karen Aalbers1,2, Swantje Völler1, Sieto Bosgra1
1Genmab B.V., 2Leiden Academic Centre for Drug Research, Leiden University
Introduction: Immuno-oncology leverages monoclonal antibodies (mAbs) and related modalities (e.g., antibody-drug conjugates, bispecific antibodies) to target tumor-associated antigens. Physiologically based pharmacokinetic (PBPK) models provide a robust framework to analyze tissue-specific target expression and dynamics, characterize antibody disposition, and predict local target engagement [1]. For optimal efficacy, mAbs must accumulate at the tumor site in sufficient amount. However, targets that also exist in a soluble form—either through extracellular domain shedding, release in membrane vesicles, or alternative splicing of variants lacking transmembrane regions [2] can interfere with this process. Soluble targets are present in plasma at levels that can vary widely—from low concentrations to markedly elevated levels, depending on the target and cancer type. They can act as a binding sink, competing with tumor-cell surface antigens for mAb binding, thereby altering effective target engagement. Consequently, a critical gap remains in our understanding of the source, distribution, clearance, and interactions of these soluble antigens—free or antibody-bound—across key physiological compartments, including the tumor microenvironment. Objectives: The aim of this study is to develop a general PBPK modeling framework that integrates antigen shedding dynamics and evaluating their interactions with various antibody modalities for optimizing dosing strategies in immuno-oncology therapies. • Describe the disposition of the soluble receptor using data of proteins of different sizes (13-150 kDa) • Integrate the binding kinetics of the soluble receptor and the antibody within the mPBPK model framework. • Elucidate the impact of shed antigens on mAb and related modalities pharmacokinetics (PK) and pharmacodynamics (PD) Methods: • A physiology-based antigen biokinetic model was developed to simulate the distribution and clearance of proteins of different sizes (13-150 kDa) obtained from literature data [3]. This model was adapted to describe the distribution of a soluble target within the same size range. • Parameter ranges (including vascular reflection coefficient, pinocytosis, target density, tumor volume and shedding rate) that can explain plasma soluble target concentrations were identified. • The antigen biokinetic model was integrated into a PBPK framework. In this integrated model, free soluble target interacts with antibodies to form complexes that circulate across all compartments. • We simulated various antibody modalities—exploring ubiquitous target scenarios for mAbs (e.g., monovalent versus bivalent binding) and tumor-restricted target scenarios for ADCs and bispecific antibodies —to comprehensively evaluate the impact of soluble antigen on antibody target engagement and dosing strategies. • Simulations were performed using RxODE and pksensi packages in R. Results: The physiology-based antigen biokinetic model accurately captures the observed protein data. We successfully developed an integrated framework incorporating antigen shedding dynamics. Simulations indicated that free shed antigen levels in the tumor microenvironment can be several hundred-fold higher than in plasma, depending on target localization, expression and shedding rate. While systemic mAb concentrations remain largely unaffected, high local soluble antigen levels reduce the free mAb fraction in the tumor interstitial fluid. Target engagement analyses revealed that mAbs preferentially bind to membrane-bound antigens due to avidity effects. In tumor-restricted scenarios—common for ADCs, high TME soluble receptor may persist; however bivalent binding to membrane receptor with avidity may ensure sufficient membrane target engagement and delivery of the payload. For Ab that bind to the TAA monovalently, achieving intended target engagement in presence of high soluble receptor may face greater challenges. Conclusion: The integrated framework indicates that although systemic mAb exposure remains stable, high local concentrations of shed antigens in the tumor microenvironment reduce the availability of free mAb for target engagement. The effect varies by antibody modality; bivalent binding overcomes this challenge through avidity, whereas monovalent binding may be less effective. These findings underscore the importance of incorporating antigen shedding dynamics into dosing strategies in immuno-oncology.
1. Cao, Y., Balthasar, J.P. and Jusko, W.J., 2013. Second-generation minimal physiologically-based pharmacokinetic model for monoclonal antibodies. Journal of pharmacokinetics and pharmacodynamics, 40, pp.597-607. 2. Park, E.J. and Lee, C.W., 2024. Soluble receptors in cancer: mechanisms, clinical significance, and therapeutic strategies. Experimental & Molecular Medicine, 56(1), pp.100-109. 3. Li, Z., Li, Y., Chang, H.P., Yu, X. and Shah, D.K., 2021.Two-pore physiologically based pharmacokinetic model validation using whole-body biodistribution of trastuzumab and different-size fragments in mice. Journal of Pharmacokinetics and Pharmacodynamics, 48, pp.743–762.
Reference: PAGE 33 (2025) Abstr 11675 [www.page-meeting.org/?abstract=11675]
Poster: Methodology - New Modelling Approaches