Clinical Research Papers:

Pharmacokinetic properties of radiolabeled mutant Interleukin-2v: a PET imaging study

Siddesh V. Hartimath, Valeria Manuelli, Rolf Zijlma, Alberto Signore, Tapan K. Nayak, Anne Freimoser-Grundschober, Christian Klein, Rudi A.J.O. Dierckx and Erik F.J. _

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Oncotarget. 2018; 9:7162-7174. https://doi.org/10.18632/oncotarget.23852

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Siddesh V. Hartimath1, Valeria Manuelli1,2, Rolf Zijlma1, Alberto Signore1,2, Tapan K. Nayak3, Anne Freimoser-Grundschober4, Christian Klein4, Rudi A.J.O. Dierckx1 and Erik F.J. de Vries1

1Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

2Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy

3Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland

4Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Zurich, Schlieren, Switzerland

Correspondence to:

Erik F.J. de Vries, email: [email protected]

Keywords: Interleukin-2; activated T lymphocytes; peripheral blood mononuclear cells; animal studies; positron emission tomography

Received: February 24, 2017     Accepted: December 28, 2017     Published: January 02, 2018


Interleukin-2 (IL2) is a cytokine that can stimulate cytotoxic immune cells to attack infected and malignant cells. Unfortunately, IL2 can also cause serious immune-related toxicity. Recently, a mutant of IL2 (IL2v) with abolished CD25 binding, increased plasma half-life and less toxicity was engineered. Unlike wild-type IL2 (wt-IL2), mutant IL2v does not bind to the α-subunit (CD25) of the high affinity IL2αβγ receptor, but only to its β and γ subunit. Here, we investigated the biological properties of IL2v and compared with the wt-IL2 using fluorine-18 and PET. [18F]FB-IL2v binds specifically to IL2 receptors (IL2R) on activated human peripheral blood monocytes (hPBMCs) and is cleared mainly by the kidneys (Balb/c mice). [18F]FB-IL2v PET studies in SCID mice injected with hPBMCs revealed high uptake in the implant (0.85 ± 0.15 SUV), which was significantly reduced after pretreatment with wt-IL2 or mutant IL2v (SUV 0.26 ± 0.1 and 0.46 ± 0.1, p < 0.01). Compartment modeling and Logan graphical analysis in wistar rats inoculated with hPBMCs indicated that the binding of [18F]FB-IL2v to IL2R was reversible. The volume of distribution (VT) and the non-displaceable binding potential (BPnd) of mutant [18F]FB-IL2v in the implant were approximately 3 times lower than those of wild-type [18F]FB-IL2 (p < 0.01). Pretreatment with wt-IL2 significantly reduced the VT and BPnd of mutant [18F]FB-IL2v in the implant (p < 0.001). This demonstrates that wild-type [18F]FB-IL2 binds stronger to IL2R and has faster kinetics than [18F]FB-IL2v, which makes it less suitable as a therapeutic drug. [18F]FB-IL2v, on the other hand, seems to have better properties for use as a therapeutic drug.

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