Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells

Abstract

IL-2 immunotherapy is an attractive treatment option for certain metastatic cancers. However, administration of IL-2 to patients can lead, by ill-defined mechanisms, to toxic adverse effects including severe pulmonary edema. Here, we show that IL-2–induced pulmonary edema is caused by direct interaction of IL-2 with functional IL-2 receptors (IL-2R) on lung endothelial cells in vivo. Treatment of mice with high-dose IL-2 led to efficient expansion of effector immune cells expressing high levels of IL-2Rβγ, including CD8 + T cells and natural killer cells, which resulted in a considerable antitumor response against s.c. and pulmonary B16 melanoma nodules. However, high-dose IL-2 treatment also affected immune cell lineage marker-negative CD31 + pulmonary endothelial cells via binding to functional αβγ IL-2Rs, expressed at low to intermediate levels on these cells, thus causing pulmonary edema. Notably, IL-2–mediated pulmonary edema was abrogated by a blocking antibody to IL-2Rα (CD25), genetic disruption of CD25, or the use of IL-2Rβγ–directed IL-2/anti-IL-2 antibody complexes, thereby interfering with IL-2 binding to IL-2Rαβγ + pulmonary endothelial cells. Moreover, IL-2/anti-IL-2 antibody complexes led to vigorous activation of IL-2Rβγ + effector immune cells, which generated a dramatic antitumor response. Thus, IL-2/anti-IL-2 antibody complexes might improve current strategies of IL-2–based tumor immunotherapy.

NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

“…Subsequently, other reports described modified forms of IL2 that have attempted to favor ILRbg binding, prolong exposure, or mitigate toxicity. These include mutation of the IL2 amino acid sequence, fusion to a targeting antibody, or use of IL2/anti-IL2 antibody complexes (29)(30)(31). These alterations, like every new agent, need to be evaluated clinically.…”

Le renouveau de l’interleukine 2

“…Ces anticorps, en recouvrant le site d'interaction de l'IL-2 avec la chaîne α de son récepteur, dirigent spécifiquement la cytokine vers le complexe dimérique. Les complexes anti-IL-2/IL-2 ainsi formés se révèlent avoir à faibles doses des activités anti-tumorales augmentées par rapport à des doses fortes d'IL-2, avec des effets secondaires très réduits [35]. Une stratégie alternative repose sur l'utilisation de l'IL-15 qui, comme l'IL-2, utilise les chaînes IL-2Rβ (CD122) et IL-2Rγ (CD132) du récepteur comme éléments de liaison et de transduction de signal.…”

Expression, Identification and Characterize of CD25-Binding Epitope Modified Human IL-2 in Pichia pastoris

“…The most common manifestation of IL-2 toxicity is capillary leak syndrome, resulting in a hypovolemic state and fluid accumulation in the extravascular space [13]. Krieg et al [7] discovered that VLS were mainly caused by IL-2Rabc non-immune cells activated by IL-2 in vivo. As IL-2-mediated VLS mainly depends on IL2Rabc ?…”

“…The main side effect was vascular leak syndrome (VLS) [5,6]. Krieg et al [7] found that the VLS was induced by interaction between IL-2 and IL-2Rabc. Thus, this experiment designed a new recombinant human IL-2 (rhIL-2) to block the binding of IL-2 and IL-2abc and to minimize the side effect of IL-2.…”