Radiolabeled Interleukin-8 to image infection and inflammation (NKG.5607)

Nowadays, in routine clinical practice gallium-67, radiolabeled autologous leukocytes and radiolabeled anti-granulocyte antibodies are used as radio-pharma-ceuticals to image infection and inflammation. Each of these techniques, although successful in many cases, has its particular disadvantages with respect to radiation burden, physiologic uptake in normal tissues, duration of the procedure. Therefore, there is a need for a safe infection/inflammation imaging agent that can be prepared off-the-shelf and can visualize infectious and inflammatory foci within six hours.
During the past decade radiolabeled receptor binding ligands have emerged as an important class of radiopharmaceuticals which promise to revolutionize nuclear medicine. Theoretically, the high binding affinity for its receptor facilitates retention of the peptide in receptor-expressing tissues, while its relative small size (e.g. as compared to antibody molecules) facilitates rapid clearance from the blood and from the nontarget tissues.
Several peptides have been proposed that could be used to image infection and inflammatory foci. Since inflammation is characterized by an influx of leukocytes, several ligands for receptors on infiltrating leukocytes (e.g. f-MetLeuPhe, IL-1RA, platelet factor 4, and others) have been tested for this application. Each of these peptides has been shown to visualize infectious foci in experimental models, however, absolute uptake of these agents in inflammatory foci is relatively low. We have shown that ¹²³I-labeled interleukin-8 (¹²³I-IL-8) localized in infectious foci much more efficiently. In a comparative study in rabbits with E. coli infection, abscess uptake of ¹²³I-IL-8 was 7 to 22-times higher than the abscess uptake of other ¹²³I-labeled receptor binding peptides (IL-1, IL-1RA or f-MetLeuPhe). Eight hours after injection of the agent abscess-to-muscle ratios exceeded 120, while with the other agents these ratios did not exceed 40. Technetium-99m is the most suitable radionuclide for scintigraphic application, due to its ideal physical characteristics, general availability and low costs. We have labeled IL-8 with Tc-99m using state-of-the-art bifunctional chelating agents. In rabbits with focal E.Coli infection, ^99mTc-IL-8 rapidly visualized the infection, with minimal retention in nontarget tissues except the kidneys. The characteristics of ^99mTc-IL-8 in these experimental studies suggest that IL-8 is an excellent vehicle for the scintigraphic imaging of infection. IL-8 is a member of the CXC-subfamily of chemokines and binds with high affinity to both CXC receptor subtypes (CXCRI and CXCRII). This project aims to explore the potential of IL-8 analoges for scintigraphic detection of infection and inflammation.
In the first part of the project IL-8 will be labeled with ^99mTc according to various indirect labeling technologies using bifunctional chelating agents. The most optimal technology (with respect to labeling efficiency, kitability, stability, in vivo behavior) will be selected to label IL-8 with ^99mTc. Subsequently, the in vivo behaviour of the ^99mTc-labeled IL-8 preparation will be optimized (reduction of kidney retention, reduction of biological effects, optimization of labeling efficiency, optimization of target/nontarget ratios). Subsequently, the potential of ^99mTc-labeled IL-8 as an agent to image infection and inflammation will be evaluated in various experimental infection models. A one-step labeling kit will be developed to allow preparation of the radiopharmaceutical in general community hospitals. In the final phase of the project, the diagnostic accuracy of the agent will be evaluated in various groups of patients and compared to conventional agents for infection and inflammation imaging (radiolabeled IgG and radiolabeled leukocytes).

De meeste resultaten van dit project zijn beschreven in onderstaande publicaties:

1. Rennen HJ, Corstens FH, Oyen WJ, Boerman OC. New concepts in infection/inflammation imaging. Q J Nucl Med. 2001;45:167-173.
2. Rennen HJ, Makarewicz J, Oyen WJ, Laverman P, Corstens FH, Boerman OC. The effect of molecular weight on nonspecific accumulation of 99mTc-labeled proteins in inflammatory foci. Nucl Med Biol. 2001;28:401-408.
3. Gratz S, Rennen HJ, Boerman OC, Oyen WJ, Corstens FH. Rapid imaging of experimental colitis with 99mTc-interleukin-8 in rabbits. J Nucl Med. 2001;42:917-923.
4. Rennen HJ, Boerman OC, Oyen WJ, Corstens FH. Imaging infection/inflammation in the new millennium. Eur J Nucl Med. 2001;28:241-252.
5. Gratz S, Rennen HJ, Boerman OC, Oyen WJ, Burma P, Corstens FH. 99mTc-interleukin-8 for imaging acute osteomyelitis. J Nucl Med. 2001;42:1257-1264.
6. Rennen HJ, Boerman OC, Oyen WJ, van der Meer JW, Corstens FH. Specific and rapid scintigraphic detection of infection with 99mTc-labeled interleukin-8. J Nucl Med. 2001;42:117-123.
7. Rennen HJ, Boerman OC, Koenders EB, Oyen WJ, Corstens FH. Labeling proteins with Tc-99m via hydrazinonicotinamide (HYNIC): optimization of the conjugation reaction. Nucl Med Biol. 2000;27:599-604.
8. Rennen H, Boerman O, Oyen W, Corstens F. Labeling method largely affects the imaging potential of interleukin-8. J Nucl Med. 2002;43:1128.
9. Rennen HJ, van Eerd JE, Oyen WJ, Corstens FH, Edwards DS, Boerman OC. Effects of coligand variation on the in vivo characteristics of Tc-99m-labeled interleukin-8 in detection of infection. Bioconjug Chem. 2002;13:370-377.
10. Rennen HJ, Oyen WJ, Cain SA, Monk PN, Corstens FH, Boerman OC. Tc-99m-labeled C5a and C5a des Arg74 for infection imaging. Nucl Med Biol. 2003;30:267-272.
11. Rennen HJ, Boerman OC, Oyen WJ, Corstens FH. Kinetics of 99mTc-labeled interleukin-8 in experimental inflammation and infection. J Nucl Med. 2003;44:1502-1509.

Er is één bedrijf bij dit project betrokken.