Cong Liu 1, Abdallah Derbalah 1, Adriana Zyla 1, Felix Stader, Armin Sepp 1
1 Certara UK Simcyp Division (Sheffiled, United Kingdom)
Objective
Monoclonal antibodies (mAbs) frequently exert their pharmacological effects by competing with endogenous ligands for binding to shared targets, thereby preventing formation of ligand–target complexes that drive downstream biological responses [1]. Although such competitive interactions often have minimal impact on systemic mAb pharmacokinetics and are therefore commonly overlooked in PBPK models, they may critically influence tissue-level pharmacodynamics when PD is governed by local ligand–receptor complex formation, particularly for soluble ligands that distribute between plasma and tissues [2].
The objective of this work was to develop a mechanistic, whole-body PBPK framework that explicitly incorporates competitive binding between therapeutic mAbs and endogenous ligands, integrating mAb disposition, ligand turnover and distribution, and target engagement within a unified structure. The interleukin-6 (IL-6)–IL-6 receptor (IL-6R) pathway was used as a representative example, comparing anti-IL-6 and anti-IL-6R strategies targeting hepatic IL-6R on hepatocytes. The model was applied to predict hepatocyte IL-6–IL-6R complex concentrations following ligand- or receptor-targeting therapy to evaluate how competitive binding and ligand redistribution influence tissue-level target engagement.
Methods
A mechanistic whole-body PBPK model was implemented in Simcyp V25 using the TP-Modulator model to incorporate competitive binding between endogenous ligands and therapeutic mAbs.
IL-6 was modelled as a soluble ligand distributed between plasma and tissue interstitial compartments. Plasma concentration and systemic removal rate were defined as inputs. IL-6 synthesis was assumed to occur in plasma to maintain whole-body mass balance, and additional local synthesis could be implemented in inflamed tissues (e.g., liver) to account for disease-driven, local cytokine production [3]. IL-6R was modelled as a membrane-bound receptor expressed on hepatocytes in liver interstitial space and on circulating immune cells; soluble IL-6R was not included in the current study. IL-6 binding to IL-6R formed a complex that underwent internalization, representing target-mediated elimination. IL-6R turnover was defined by baseline receptor concentrations and first-order degradation. Steady-state concentrations of IL-6, IL-6R, and IL-6–IL-6R complex were solved prior to mAb administration and used as initial conditions.
Following administration of anti-IL-6 or anti-IL-6R mAbs, competitive binding was implemented using their respective association and dissociation rate constants for ligand–receptor and mAb–target interactions. Anti-IL-6 formed IL-6–mAb complexes eliminated via the same elimination pathway as mAbs, whereas anti-IL-6R bound receptor-expressing sites and the complex underwent internalization and degradation.
Results
Systemic plasma concentrations of both anti-IL-6 and anti-IL-6R mAbs were minimally affected by endogenous ligand binding under baseline IL-6 levels, consistent with low circulating ligand burden relative to mAb dose [4,5].
For anti-IL-6 mAb, total plasma IL-6 increased following treatment due to the formation of IL-6–mAb complexes and reduced receptor-mediated elimination and renal elimination. In the liver interstitial space, IL-6–IL-6R complex concentrations progressively increased above baseline. This was driven by prolonged systemic persistence of IL-6 while bound to mAb, redistribution into tissues, and dissociation, allowing renewed receptor engagement. When IL-6 synthesis was assumed locally in the liver, IL-6–IL-6R complex formation was instead suppressed below baseline, as elevated interstitial IL-6 enhanced interstitial-to-vascular flux and redistribution to the systemic circulation.
For anti-IL-6R mAb, receptor blockade displaced IL-6 from endogenous complexes, increasing circulating IL-6 concentrations. In the liver, IL-6–IL-6R complex formation was initially suppressed, followed by gradual recovery and a transient rebound above baseline before returning to steady state. The rebound was driven by redistribution of accumulated systemic IL-6 into the liver interstitial space and receptor re-engagement as mAb concentrations declined. When IL-6 was synthesized locally, complex formation remained suppressed without rebound due to sustained redistribution to plasma.
Conclusion
This work demonstrates that explicit representation of endogenous ligand competition within a whole-body PBPK framework is critical for mechanistically predicting tissue-level target engagement, even when systemic mAb pharmacokinetics remain unchanged. Importantly, when soluble endogenous targets are mechanistically included, their distribution between systemic circulation and tissues is non-trivial and cannot be assumed negligible. The proposed framework is broadly applicable to systems involving soluble ligands and membrane-bound receptors and provides a quantitative platform for evaluating competitive binding effects on tissue PD responses in biologics development.
References:
[1] Begum A et al. J Pharmacokinet Pharmacodyn (2021) 48(4):447-464.
[2] Wang W et al. AAPS J. (2014) 16(1):129-39.
[3] Wang L et al. Clin Transl Sci. (2022) 15(2):464-476.
[4] Puchalski T et al. Clin Cancer Res. (2010) 16(5) :1652-61.
[5] Paccaly AJ et al. J Clin Pharmacol. (2021) 61(1):90-104.
Reference: PAGE 34 (2026) Abstr 11922 [www.page-meeting.org/?abstract=11922]
Poster: Drug/Disease Modelling - Absorption & PBPK