Insight into Mechanism of IL-2-Induced Toxicity Provides Rationale for Improved Treatment Strategy using IL-2/mAb Complexes (38.8)

Abstract IL-2 immunotherapy is used against certain metastatic cancers and for patients infected with human immunodeficiency virus. However, administration of IL-2 can lead to serious side effects including pulmonary edema, the pathogenesis of which is ill-defined. Here, we provide data showing that IL-2 may bind directly to CD25 on lung endothelial cells and thus cause toxicity and pulmonary edema. Thus, lung endothelial cells express CD25 under steady-state conditions, and expression levels of CD25 on these cells increase in vivo upon injection of mice with IL-2. Activation of CD25+ lung endothelial cells and of IL-2 receptor-positive NK cells and T cells leads to pulmonary edema upon IL-2 treatment. Significantly, co-administration of anti-CD25 antibody along with IL-2 treatment is able to completely abrogate IL-2-induced pulmonary edema despite considerable proliferation of NK cells and T cells. Similarly, knocking out CD25 on non-immune cells or obscuring the CD25-binding epitope of IL-2 by the use of selective immune complexes of IL-2 plus anti-IL-2 antibody (IL-2/mAb) is able to prevent IL-2-induced pulmonary edema. Notably, IL-2-mediated toxic effects are also evident on a human lung cell line and can be abrogated using the anti-CD25 antibody daclizumab or IL-2/mAb complexes. Moreover, IL-2/mAb complexes are very efficient in generating anti-tumor responses in vivo against syngeneic local or metastatic tumor nodules. Thus, CD25+ endothelial cells play a crucial role in IL-2-mediated vascular leak syndrome and this can be circumvented by the use of IL-2/mAb complexes.