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

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. [(18)F]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). [(18)F]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 [(18)F]FB-IL2v to IL2R was reversible. The volume of distribution (V(T)) and the non-displaceable binding potential (BP(nd)) of mutant [(18)F]FB-IL2v in the implant were approximately 3 times lower than those of wild-type [(18)F]FB-IL2 (p < 0.01). Pretreatment with wt-IL2 significantly reduced the V(T) and BPnd of mutant [(18)F]FB-IL2v in the implant (p < 0.001). This demonstrates that wild-type [(18)F]FB-IL2 binds stronger to IL2R and has faster kinetics than [18F]FB-IL2v, which makes it less suitable as a therapeutic drug. [(18)F]FB-IL2v, on the other hand, seems to have better properties for use as a therapeutic drug.