Antibodies to Interleukin-2 Elicit Selective T Cell Subset Potentiation through Distinct Conformational Mechanisms

Abstract

SUMMARY Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates immune cell homeostasis, and has been used to treat a range of disorders such as cancer and autoimmune disease. IL-2 signals via interleukin-2 receptor-β (IL-2Rβ):IL-2Rγ heterodimers on cells expressing high (regulatory T cells, Treg) or low (effector cells) amounts of IL-2Rα (CD25). When complexed with IL-2, certain anti-cytokine antibodies preferentially stimulate expansion of Treg (JES6-1) or effector (S4B6) cells, offering a strategy for targeted disease therapy. We found that JES6-1 sterically blocked the IL-2:IL-2Rβ and IL-2:IL-2Rγ interactions, but also allosterically lowered the IL-2:IL-2Rα affinity through a ‘triggered exchange’ mechanism favoring IL-2Rαhi Treg cells, creating a positive feedback loop for IL-2Rαhi cell activation. Conversely, S4B6 sterically blocked the IL-2:IL-2Rα interaction, while also conformationally stabilizing the IL-2:IL-2Rβ interaction, thus stimulating all IL-2 responsive immune cells, particularly IL-2Rβhi effector cells. Our insights provide a molecular blueprint for engineering selectively potentiating therapeutic antibodies.

Interleukin-2: Biology, Design and Application

“…These data would rather argue against IL-2R crosslinking by IL-2/ S4B6 complexes. For IL-2/JES6-1 complexes, STAT5 phosphorylation was reduced in CD25 + YT-1 human NK cells compared with IL-2 in vitro [13], although another report using in vitro stimulation of total mouse splenocytes suggested that, compared with IL-2, IL-2/JES6-1 complexes led to increased STAT5 phosphorylation in CD4 + T cells [71]. In line with the former Recent structural data not only provide evidence for the steric aspects of the abovementioned model but also suggest mild antagonistic and allosteric forces at work (Figure 3).…”

“…phosphorylation [13] and lower proliferation of wild-type and CD25 À/À memory-phenotype mouse CD8 + T cells [9]. These data would rather argue against IL-2R crosslinking by IL-2/ S4B6 complexes.…”

“…IL-2/JES6-1 complexes are also stimulatory for ILC2 that express trimeric IL-2Rs, which contributes to IL-5 production and eosinophilia [30,57]. IL-2/JES6-1 complexes have shown promising results in the prevention of pancreatic [56] and skin [58] allograft rejection as well as in the treatment of several autoimmune and inflammatory diseases in mice, including type 1 diabetes in nonobese diabetic mice [59], experimental autoimmune encephalomyelitis (a model of multiple sclerosis) [56], experimental myasthenia [60], collagen-induced arthritis [61], dextran sodium sulfate-induced acute colitis [13], and T cell-mediated allergic airway disease [62]. Interestingly, administration of IL-2/JES6-1 complexes also improved the pathology of some metabolic, cardiovascular, and degenerative disorders, such as murine obesity-induced inflammation and insulin resistance ('type 2 diabetes') [63], atherosclerosis in high-fat diet-fed apolipoprotein E-deficient animals [64], and the mdx mouse model of Duchenne muscular dystrophy [65], that feature inflammatory infiltrates and are thus amenable to suppression by CD25 + Foxp3 + Treg cells.…”

“…Furthermore, clinical trials using low-dose IL-2 have demonstrated IL-2's potential in expanding Treg cells and modulating immune pathologies [11,12]. Four recent publications exemplify this development and have motivated this review, in that they provide structural insight into the selective IL-2-mediated modulation of immune responses using IL-2/monoclonal antibody (mAb) complexes [13], highlight the possibility of using IL-2 muteins to antagonize, rather than stimulate, IL-2R-induced signals [14], and report novel data on the clinical use of low-dose IL-2 therapy in organ-specific and systemic autoimmune disease [15,16].…”

Le renouveau de l’interleukine 2

“…Une autre stratégie développée plus récemment chez la souris, a consisté à utiliser un anticorps dirigé contre l'IL-2 (le JES6-1) qui, par une conjonction d'effets stériques et allostériques, modifie la capacité de l'IL-2 à recruter ses chaînes réceptrices et lui confère une forte sélec-tivité pour les cellules exprimant la chaîne α [40,41]. L'intérêt de ces molécules a été validé chez la souris dans plusieurs modèles d'inflammation chronique ou de maladies auto-immunes [42].…”