Clinical-grade N-(4-[18F]fluorobenzoyl)-interleukin-2 for PET

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

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18F-IL2 for clinical PET

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

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


EJNMMI Radiopharmacy and Chemistry, Dec 2019, 4,15. doi: 10.1186/s41181-019-0062-7.

Abstract

Background

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. 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.

Methods

The 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.

Results

Restrictions 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.

Conclusions

To 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.

18F-IL2 FOR CLINICAL PET
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Ga-NODAGA-IL2 for imaging activated T-cells

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[Ga-68]Ga-NODAGA-IL2 for imaging activated T-cells. (Conference Abstract)

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Conference Abstract: 68Ga-NODAGA-IL2 for T-cell imaging

[Ga-68]Ga-NODAGA-IL2 for imaging activated T-cells. (Conference Abstract)

Antunes, I., van der Veen, E. L., Suurs, F. V., Dierckx, R. A. J. O., Lub-de Hooge, M. N., de Vries, E. G. E. & de Vries, E. F. J.


Oct-2019, In : European Journal of Nuclear Medicine and Molecular Imaging. 46, SUPPL 1, p. S702 1 p.

32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) - Barcelona, Spain Duration: 12-Oct-2019 - 16-Oct-2019

CONFERENCE ABSTRACT: 68GA-NODAGA-IL2 FOR T-CELL IMAGING
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Tracers for non-invasive radionuclide imaging of immune

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Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

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PET tracers for immune checkpoint imaging

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Peter Wierstra, Gerwin Sandker, Erik Aarntzen, Martin Gotthardt, Gosse Adema, Johan Bussink, René Raavé & Sandra Heskamp.


EJNMMI Radiopharmacy and Chemistry volume 4,29 (2019). doi: 10.1186/s41181-019-0078-z.

Abstract

Immunotherapy with checkpoint inhibitors demonstrates impressive improvements in the treatment of several types of cancer. Unfortunately, not all patients respond to therapy while severe immune-related adverse effects are prevalent. Currently, patient stratification is based on immunotherapy marker expression through immunohistochemical analysis on biopsied material. However, expression can be heterogeneous within and between tumor lesions, amplifying the sampling limitations of biopsies. Analysis of immunotherapy target expression by non-invasive quantitative molecular imaging with PET or SPECT may overcome this issue. In this review, an overview of tracers that have been developed for preclinical and clinical imaging of key immunotherapy targets, such as programmed cell death-1, programmed cell death ligand-1, IDO1 and cytotoxic T lymphocyte-associated antigen-4 is presented. We discuss important aspects to consider when developing such tracers and outline the future perspectives of molecular imaging of immunotherapy markers..

PET TRACERS FOR IMMUNE CHECKPOINT IMAGING
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Synthesis and Evaluation of Zirconium-89 Labelled

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Synthesis and Evaluation of Zirconium-89 Labelled and Long-Lived GLP-1 Receptor Agonists for PET Imaging

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89Zr labeled long lived GLP-1 receptor agonist

Synthesis and Evaluation of Zirconium-89 Labelled and Long-Lived GLP-1 Receptor Agonists for PET Imaging

Christian Borch Jacobsen, René Raavé, Marie Østergaard Pedersen, Pierre Adumeau, Mathieu Moreau, Ibai Valverde, Inga Bjørnsdottir, Jesper Bøggild Kristensen, Mette Finderup Grove, Kirsten Raun, James McGuire, Victor Goncalves, Sandra Heskamp, Franck Denat, Magnus Gustafsson


Nuclear Medicine and Biology 2019 Dec 4. doi: 10.1016/j.nucmedbio.2019.11.006.

Abstract

Introduction

Lately, zirconium-89 has shown great promise as a radionuclide for PET applications of long circulating biomolecules. Here, the design and synthesis of protracted and long-lived GLP-1 receptor agonists conjugated to desferrioxamine and labelled with zirconium-89 is presented with the purpose of studying their in vivo distribution by PET imaging. The labelled conjugates were evaluated and compared to a non-labelled GLP-1 receptor agonist in both in vitro and in vivo assays to certify that the modification did not significantly alter the peptides' structure or function. Finally, the zirconium-89 labelled peptides were employed in PET imaging, providing visual verification of their in vivo biodistribution.

Methods

The evaluation of the radiolabelled peptides and comparison to their non-labelled parent peptide was performed by in vitro assays measuring binding and agonistic potency to the GLP-1 receptor, physicochemical studies aiming at elucidating change in peptide structure upon bioconjugation and labelling as well as an in vivo food in-take study illustrating the compounds' pharmacodynamic properties. The biodistribution of the labelled GLP-1 analogues was determined by ex vivo biodistribution and in vivo PET imaging.

Results

The results indicate that it is surprisingly feasible to design and synthesize a protracted, zirconium-89 labelled GLP-1 receptor agonist without losing in vitro potency or affinity as compared to a non-labelled parent peptide. Physicochemical properties as well as pharmacodynamic properties are also maintained. The biodistribution in rats show high accumulation of radiolabelled peptide in well-perfused organs such as the liver, kidney, heart and lungs. The PET imaging study confirmed the findings from the biodistribution study with a significant high uptake in kidneys and presence of activity in liver, heart and larger blood vessels.

Conclusions and advances in knowledge

This initial study indicates the potential to monitor the in vivo distribution of long-circulating incretin hormones using zirconium-89 based PET.

89ZR LABELED LONG LIVED GLP-1 RECEPTOR AGONIST
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PET of 89Zr-Pembrolizumab in Cynomolgus

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PET/CT Imaging of 89Zr-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys

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PET of 89Zr-Pembrolizumab in Cynomolgus

PET/CT Imaging of 89Zr-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys

Wenping Li, Yuchuan Wang, Daniel Rubins, Idriss Bennacef, Marie Holahan, Hyking Haley, Mona Purcell, Liza Gantert, SuChun Hseih, Michael Judo, Wolfgang Seghezzi, Shuli Zhang, Elly L. van der Veen, Marjolijn N. Lub-de Hooge, Elisabeth G.E. de Vries, Jeffrey L. Evelhoch, Michael Klimas, Eric D. Hostetler


Molecular Imaging and Biology 2020 Oct 26. doi: 10.1007/s11307-020-01558-w

Abstract

Purpose:

Programmed cell death-1 receptor (PD-1) and its ligand (PD-L1) are the targets for immunotherapy in many cancer types. Although PD-1 blockade has therapeutic effects, the efficacy differs between patients. Factors contributing to this variability are PD-L1 expression levels and immune cells present in tumors. However, it is not well understood how PD-1 expression in the tumor microenvironment impacts immunotherapy response. Thus, imaging of PD-1-expressing immune cells is of interest. This study aims to evaluate the biodistribution of Zirconium-89 (89Zr)-labeled pembrolizumab, a humanized IgG4 kappa monoclonal antibody targeting PD-1, in healthy cynomolgus monkeys as a translational model of tracking PD-1- positive immune cells.

Procedures:

Pembrolizumab was conjugated with the tetrafluorophenol-N-succinyl desferal- Fe(III) ester (TFP-N-sucDf) and subsequently radiolabeled with 89Zr. Four cynomolgus monkeys with no previous exposure to humanized monoclonal antibodies received tracer only or tracer co-injected with pembrolizumab intravenously over 5 min. Thereafter, a static whole-body positron emission tomography (PET) scan was acquired with 10 min per bed position on days 0, 2, 5, and 7. Image-derived standardized uptake values (SUVmean) were quantified by region of interest (ROI) analysis.

Results:

89Zr-N-sucDf-pembrolizumab was synthesized with high radiochemical purity (>99 %) and acceptable molar activity (>7 MBq/nmol). In animals dosed with tracer only, 89Zr-N-sucDf-pembrolizumab distribution in lymphoid tissues such as mesenteric lymph nodes, spleen, and tonsils increased over time. Except for the liver, low radiotracer distribution was observed in all non-lymphoid tissue including the lung, muscle, brain, heart, and kidney. When a large excess of pembrolizumab was co-administered with a radiotracer, accumulation in the lymph nodes, spleen, and tonsils was reduced, suggestive of target-mediated accumulation.

Conclusions:

89Zr-N-sucDf-pembrolizumab shows preferential uptake in the lymphoid tissues including the lymph nodes, spleen, and tonsils. 89Zr-N-sucDf-pembrolizumab may be useful in tracking the distribution of a subset of immune cells in non-human primates and humans.

Trial registration:

ClinicalTrials.gov; Identifier: NCT02760225

PET of 89Zr-Pembrolizumab in Cynomolgus
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