Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15

Interleukin-2 (IL-2) and interleukin-15 (IL-15) are T-cell tropic factors t hat share beta and gamma c subunits of their receptors on T/NK-cells, Altho ugh these two cytokines share receptor components, the IL-15R alpha molecul e is expressed constitutively by various tissue cells, whereas the IL-2R al pha expression is mostly restricted to activated mononuclear cells. Consequ ently, we postulated that the biodistribution of IL-15 might be different f rom that of IL-2 and that individual alpha chains play an important role in this respect. This study investigated the differences between IL-2 and IL- 15 in pharmacokinetics, biodistribution, and their tumor-targeting abilitie s. It found that only IL-2 showed specific binding to a protein, alpha(2)-m acroglobulin, which may be the reason that IL-2 displays longer blood clear ance than IL-15. Upon injection of these cytokines into mice, we observed t hat IL-15 accumulated significantly more than IL-2 in kidney, spleen, and b one. These are all tissues that express IL-15 receptor alpha but not IL-2 r eceptor alpha. To evaluate the tumor-targeting ability of each cytokine, we used nude mice xenografted with three A431 tumors, parental and cells tran sfected with alpha subunit of the receptor for either IL-2 or IL-15. When examined using radioiodinated IL-2 or IL-15, each cytokine accumulated on the target cells, expressing its respective alpha chain, suggesting tha t the expression of the alpha chains is sufficient to define specific biodi stribution of IL-2 and IL-15, although these cytokines share the beta and g amma c molecules of their receptors. IL-15 displayed better target-specific accumulation and more rapid clearance from the circulation than did IL-2, and thus it can be considered to be a novel and unique therapeutic agent.