Mechanistic modelling of tumor uptake & interstitial receptor occupancy of PRS-344/S095012 using preclinical positron emission tomography data
Glenn Gauderat (1), Marjolijn N. Lub-de Hooge (2), Lucia Pattarini (3), Aizea Morales-Kastresana (4), Marc Huisman (5), Marleen Richter (4), Nicole Andersen (4), Thomas Jaquin (4), Johanna Verneau (6), Agathe Lepissier (7) , Najah Harouki Crochemore (8), Alix Scholer-Dahirel (7), Sylvain Fouliard (1), Claudia A.J. van Winkel (9)
(1) Department of Translational Pharmacometrics, Institut de Recherches Internationales Servier, Suresnes, France, (2) Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, (3) Institut de Recherches Servier, Center for Therapeutic Innovation Oncology, Croissy-sur-Seine, France., (4) Pieris Pharmaceuticals, Hallbergmoos, Munich, Germany, (5) Department of Radiology and nuclear medicine, University Medical Center Amsterdam, Amsterdam, the Netherlands, (6) Department of translational research, Institut de Recherches Internationales Servier, Suresnes, France, (7) Institut de Recherches Internationales Servier Oncology R&D Unit, Suresnes, France, (8) Department of Clinical Pharmacology, Institut de Recherches Internationales Servier, Suresnes, France, (9) Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Introduction:
PRS-344/S095012 is a bispecific antibody-Anticalin® fusion protein (referred to as MabcalinTM protein) targeting 4-1BB (CD137) and programmed death-ligand 1 (PD-L1). 4-1BB co-stimulation and PD-L1 blockade lead to a synergistic antitumoral T cell response in the tumor microenvironment. 4-1BB is expressed as a monomer and requires multimerization by PRS-344/S095012 via binding to PD-L1 for effective signaling and T cell co-stimulation. Therefore, a bell-shaped relationship is expected between the maximal 4-1BB stimulation (ternary complex concentrations) and drug concentrations [1] [2]. On the other hand, the optimal dose for PD-1/PD-L1 axis inhibition is expected to correspond to doses leading to high PD-L1 receptor occupancy (RO) at the biophase. A first-in-human dose escalation study is currently ongoing to evaluate the safety and tolerability of PRS-344/S095012 administered as intravenous infusion to patients with solid tumors. In this context, tumor RO for each PRS-344/S095012 arm is an important endpoint to adequately select the dose for further clinical development.
Objectives:
The objective of the analysis is to use preclinical tumor positron emission tomography (PET) data to develop a mechanistic model allowing dynamic predictions of RO in the tumor interstitial space.
Methods:
A PET study performed in mice was used to develop the model. As PRS‑344/S095012 lacks cross-reactivity to murine 4-1BB and PD-L1, a C57BL/6J mice group engrafted with murine MC38 cells and administered with PRS-344/S095012 was used to inform tumor distribution in absence of binding. To assess PD-L1 and 4-1BB‑driven tumor uptake, a surrogate version of PRS-344/S095012 (msPRS-344/S095012) that binds to murine PD-L1 was generated and administered to human 4-1BB transgenic knock-in mice engrafted with the same tumor cell line.
Mice were administered intravenously with a single dose (10 mg/kg) of a mix of unlabeled and Zirconium-89 labeled PRS-344/S095012 (n=6) or msPRS-344/S095012 (n=12). PET imaging and blood sampling were performed 1, 2, 4 or 7 days after injection. To confirm the accuracy of PET quantification, the mice body radioactivity measured in PET was compared to the mice radioactivity measured with a dose calibrator. Blood PK and standardized uptake values (SUV) measured in heart were also compared with the same objective.
Plasma PK and tumor SUVs were used to develop a plasma PK-tumor uptake model. The tumor uptake model was adapted from the model published by Huisman et al. [3], a model following mechanistic principles identified in several studies aiming at describing the main determinants of antibody tumor distribution [4] [5] [6] [7]. The receptor degradation rate, the receptor-drug complex internalization rate and the plasma volume fraction of the tumor were fixed to values published by Huisman et al. [3], the equilibrium dissociation constant (KD) was determined by surface plasmon resonance and a constant mix of labeled and unlabeled compound was assumed.
Results:
A strong correlation was observed between PET and other radioactivity measurement methods. Lower tumor SUVs were observed in the PRS-344/S095012 (non-binding) group as compared to the msPRS-344/S095012 (binding) group, with tumor SUVs increasing up to 7 days after administration with msPRS-344/S095012.
The interstitial volume fraction of the tumor was estimated at 33%, the extravasation rate was estimated at 0.021 h-1 and receptor concentrations were estimated at 28 nM. Model simulations allowed to visualize the expected time course of tumor SUV and corresponding tumor RO with different doses. Increasing the doses, the saturation of the plasma target-mediated drug disposition first leads to more sustained plasma exposure and higher tumor SUVs. However, further increasing the dose leads to the saturation of the target-mediated tumor uptake and therefore a decrease in tumor SUVs (SUVs are dose-normalized).
Conclusion:
The dose-dependent tumor uptake of antibodies could be assessed with a minimal set of assumptions using PET data directly reflecting the tumor uptake saturation. The advantage of this data with the presented tumor uptake model is that tumor saturation is directly observed in the tumor SUV data, while more complex models usually rely on assumptions about the antibody and the receptor concentrations at the biophase. The model can be used to predict the time course of tumor RO at increasing dose levels and with different dosing schedules.
References:
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