Sarah Minucci1, Marc Presler1, Joshua Apgar1, Joshuaine Grant1, Paul Baverel2, Kyriaki Ioannou2, Amal Saidi3, Amelie Croset2, Andreas Bosshart2, Julien Torgue4, Michael Stumpp2
1Certara Applied BioSimulation, 2Molecular Partners AG, 3Orano Med SAS, 4Orano Med LLC
Introduction/Objectives: MP0712 is a novel radiopharmaceutical candidate composed of a Designed Ankyrin Repeat Protein (DARPin) vector targeting DLL3 and the short-lived alpha particle-emitting radioisotope ²¹²Pb¹. DLL3 is highly expressed on the tumor cell surface in neuroendocrine carcinomas such as small cell lung cancer (SCLC), with cytoplasmic localization in healthy tissues, allowing for selective delivery of radiation to tumors while reducing systemic exposure and minimizing damage to healthy tissues. The objective of this work was to explore by means of pharmacokinetic/pharmacodynamic (PK/PD) modeling the biodistribution of MP0712 to estimate ²¹²Pb radioactive absorbed doses in relevant organs, and guide the characterization of a target compound profile. Methods: A minimal physiologically-based PK/PD mouse model of DLL3-targeting molecules was developed to explore the impact of drug and target properties on the biodistribution of MP0712. The model structure included multiple compartments (blood, tumor, bone marrow, kidney and lumped other tissues), reversible drug binding to DLL3, internalization of DLL3 and drug-DLL3 complex, and subsequent ²¹²Pb ionizing radiations. The model was calibrated based on several datasets: a) mass-balanced data derived from serum exposure levels of non-radiolabelled MP0712 in mice and target expression levels obtained by flow cytometry in cell lines used in mouse xenografts, b) literature data to inform initial model parameters² ³ 4, and c) activity expressed in %ID/g (% injected dose per gram) in relevant organ tissues and excretion data obtained from several biodistribution studies in non-tumor bearing and xenograft mice. Disposition of the drug was described by a first-order elimination rate representing the catabolic clearance of DARPins, a bi-directional intercompartmental transport, and by renal excretion. The decay of ²¹²Pb was defined by a one-step disintegration with a half-life of ~10 hours resulting in the formation of stable ²°8Pb. The modeling framework included dosimetry and scaling to humans to estimate absorbed dose in grays in the tumor, bone marrow and kidney compartments. Parameter scans were performed to explore sensitive parameters actionable for target compound profile optimization. Results: The model was successfully calibrated using mouse serum PK data and tissue biodistribution data from studies performed in non-tumor bearing mice and in a MC38 human DLL3 expressing xenograft model. Renal clearance was calibrated with excretion data. The model was then verified against an independent dataset from a mice study with a lower-expressing DLL3 cell lines (NCI-H82). Scaling with the actual tissue weights was essential to normalize model predictions from %ID into %ID/g in femoral bones and kidneys, and blood-correction was required to calibrate blood-rich tissues. The blood time-course of MP0712 was adequately captured by the model to reflect a biphasic profile. The model predicted a higher tumor uptake of MP0712 compared to kidneys. A single IV dose of 20 µCi [0.16 mg/kg] ²¹²Pb-MP0712 was simulated in the hDLL3-MC38 and NCI-H82 xenograft models and AUC0-168h estimates were calculated based on total predicted radioactivity in the blood, tumor, kidney, and bone marrow. The 9-fold increase in DLL3 expression in hDLL3-MC38 tumors (compared to NCI-H82) was associated with more than a 2-fold increase in tumor activity (AUC0-168h = 0.31 vs. 0.15 µCi*day), with no change in activity predicted in healthy organs. Furthermore, the model predicted that affinity maturation of DARPin molecules for DLL3 beyond a single digit nM range may not result in significant improvement in tumor %ID/g, while onset of tumor uptake was insensitive to DLL3 receptor density per cells, tumor size, and DLL3 internalization rate. Overall, the model predicts that MP0712 has a favorable therapeutic index based on mouse data. In scaling to humans and calculating absorbed doses, the model is developed to forecast the therapeutic index for MP0712 in SCLC patients. Additional translational work is currently ongoing to further validate the model. Conclusions: A minimal physiologically-based PK/PD model linking mass dose and ²¹²Pb-ionizing radioactivity energy deposition in relevant organs was developed for MP0712 and successfully calibrated based on mouse. Our quantitative framework is aimed to serve as a translational tool to guide future designs of DARPin-based radioligand therapies for patients.
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Reference: PAGE 33 (2025) Abstr 11338 [www.page-meeting.org/?abstract=11338]
Poster: Drug/Disease Modelling - Oncology