Development and Evaluation of Interleukin-2-Derived Radiotracers for PET Imaging of T Cells in Mice

• Published in: Journal of Nuclear Medicine Vol. 61; no. 9; pp. 1355 - 1360
• Main Authors: van der Veen, Elly L, Suurs, Frans V, Cleeren, Frederik, Bormans, Guy, Elsinga, Philip H, Hospers, Geke A P, Lub-de Hooge, Marjolijn N, de Vries, Elisabeth G E, de Vries, Erik F J, Antunes, Inês F
• Format: Journal Article
• Language: English
• Published: United States Society of Nuclear Medicine 01.09.2020
• Subjects: Aluminum; Animals; BALB 3T3 Cells; Binding; Bone marrow; Coinjection; Cytokines; Drug Discovery; Fluorides; Fluorine isotopes; Fluorine Radioisotopes - chemistry; Gallium; Gallium Radioisotopes - chemistry; Humans; Image contrast; Immunodeficiency; In vivo methods and tests; Inoculation; Interleukin 2; Interleukin-2 - chemistry; Interleukin-2 - pharmacokinetics; Interleukins; Kidneys; Leukocytes (mononuclear); Liver; Lymph nodes; Lymphocytes; Lymphocytes T; Lymphoid tissue; Mice; Molecular Imaging; Peripheral blood mononuclear cells; Positron emission; Positron-Emission Tomography - methods; Radioactive Tracers; Radiochemistry; Radiolabelling; Spleen; Stability analysis; T-Lymphocytes - metabolism; Target recognition; Tissue Distribution; Tomography; Xenografts; Xenotransplantation; radiopharmaceuticals; interleukin-2; PET imaging; T cells; immunotherapy
• ISSN: 0161-5505; 1535-5667; 2159-662X
• DOI: 10.2967/jnumed.119.238782

Recently, -(4- F-fluorobenzoyl)-interleukin-2 ( F-FB-IL2) was introduced as a PET tracer for T cell imaging. However, production is complex and time-consuming. Therefore, we developed 2 radiolabeled IL2 variants, namely aluminum F-fluoride-(restrained complexing agent)-IL2 ( F-AlF-RESCA-IL2) and Ga-gallium-(1,4,7-triazacyclononane-4,7-diacetic acid-1-glutaric acid)-IL2 ( Ga-Ga-NODAGA-IL2), and compared their in vitro and in vivo characteristics with F-FB-IL2. Radiolabeling of F-AlF-RESCA-IL2 and Ga-Ga-NODAGA-IL2 was optimized, and stability was evaluated in human serum. Receptor binding was studied with activated human peripheral blood mononuclear cells (hPBMCs). Ex vivo tracer biodistribution in immunocompetent BALB/cOlaHsd (BALB/c) mice was performed at 15, 60, and 90 min after tracer injection. In vivo binding characteristics were studied in severe combined immunodeficient (SCID) mice inoculated with activated hPBMCs in Matrigel. Tracer was injected 15 min after hPBMC inoculation, and a 60-min dynamic PET scan was acquired, followed by ex vivo biodistribution studies. Specific uptake was determined by coinjection of tracer with unlabeled IL2 and by evaluating uptake in a control group inoculated with Matrigel only. Ga-Ga-NODAGA-IL2 and F-AlF-RESCA-IL2 were produced with radiochemical purity of more than 95% and radiochemical yield of 13.1% ± 4.7% and 2.4% ± 1.6% within 60 and 90 min, respectively. Both tracers were stable in serum, with more than 90% being intact tracer after 1 h. In vitro, both tracers displayed preferential binding to activated hPBMCs. Ex vivo biodistribution studies on BALB/c mice showed higher uptake of F-AlF-RESCA-IL2 than of F-FB-IL2 in liver, kidney, spleen, bone, and bone marrow. Ga-Ga-NODAGA-IL2 uptake in liver and kidney was higher than F-FB-IL2 uptake. In vivo, all tracers revealed uptake in activated hPBMCs in SCID mice. Low uptake was seen after a blocking dose of IL2 and in the Matrigel control group. In addition, F-AlF-RESCA-IL2 yielded the highest-contrast PET images of target lymph nodes. Production of F-AlF-RESCA-IL2 and Ga-Ga-NODAGA-IL2 is simpler and faster than that of F-FB-IL2. Both tracers showed good in vitro and in vivo characteristics, with high uptake in lymphoid tissue and hPBMC xenografts.