Clinical-grade N-(4-[18F]fluorobenzoyl)-interleukin-2 for PET imaging of activated T-cells in humans

Elly L Van Der Veen,Marjolijn N Lub-De Hooge,Petra Maarsingh,Annelies Jorritsma-Smit,Erik F J De Vries,Geke A P Hospers,Rolf Zijlma,Hendrikus H Boersma,Janet Hessels-Scheper,Inês F Antunes,Elisabeth G E De Vries

doi:10.1186/s41181-019-0062-7

Abstract

BackgroundMolecular imaging of immune cells might be a potential tool for response prediction, treatment evaluation and patient selection in inflammatory diseases as well as oncology. Targeting interleukin-2 (IL2) receptors on activated T-cells using positron emission tomography (PET) with N-(4-[18F]fluorobenzoyl)-interleukin-2 ([18F]FB-IL2) could be such a strategy. This paper describes the challenging translation of the partly manual labeling of [18F]FB-IL2 for preclinical studies into an automated procedure following Good Manufacturing Practices (GMP), resulting in a radiopharmaceutical suitable for clinical use.MethodsThe preclinical synthesis of [18F]FB-IL2 was the starting point for translation to a clinical production method. To overcome several challenges, major adaptations in the production process were executed. The final analytical methods and production method were validated and documented. All data with regards to the quality and safety of the final drug product were documented in an investigational medicinal product dossier.ResultsRestrictions in the [18F]FB-IL2 production were imposed by hardware configuration of the automated synthesis equipment and by use of disposable cassettes. Critical steps in the [18F]FB-IL2 production comprised the purification method, stability of recombinant human IL2 and the final formulation. With the GMP compliant production method, [18F]FB-IL2 could reliably be produced with consistent quality complying to all specifications.ConclusionsTo enable the use of [18F]FB-IL2 in clinical studies, a fully automated GMP compliant production process was developed. [18F]FB-IL2 is now produced consistently for use in clinical studies.

Highlights

Molecular imaging of immune cells might be a potential tool for response prediction, treatment evaluation and patient selection in inflammatory diseases as well as oncology
Technology transfer Technology transfer describes the translation of methods developed in research and development (R&D) setting to a Good Manufacturing Practices (GMP) environment (Fig. 1)
The initial transfer of the production of both [N-succinimidyl 4-[18F]fluorobenzoate (18F]SFB) and [18F]FB-IL2 to the Eckert & Ziegler synthesis module led to several issues

Summary

Introduction

Molecular imaging of immune cells might be a potential tool for response prediction, treatment evaluation and patient selection in inflammatory diseases as well as oncology. Targeting interleukin-2 (IL2) receptors on activated T-cells using positron emission tomography (PET) with N-(4-[18F]fluorobenzoyl)interleukin-2 ([18F]FB-IL2) could be such a strategy. Conclusions: To enable the use of [18F]FB-IL2 in clinical studies, a fully automated GMP compliant production process was developed. Molecular imaging of immune cells for diagnosis and therapy evaluation in inflammatory and infectious diseases has been investigated for decades, but recently this field has expanded to oncology. Many immunotherapeutics are based on the activation of effector T-cells Targeting these activated Tcells with a radiolabeled imaging probe, might be a potential molecular imaging strategy in this context. Molecular imaging of IL2 receptors using radiolabeled recombinant human IL2 could be a strategy to track activated T-cells expressing the IL2 receptor. The accumulation of [18F]FB-IL2 correlated with the number of injected activated CD25positive human T-cells (Di Gialleonardo et al, 2012b)

Methods

Results

Conclusion