Human IL-2 Mutein with Higher Antitumor Efficacy Than Wild Type IL-2

Abstract

IL-2 has been used for the treatment of melanoma and renal cell carcinoma, but this therapy has limited efficacy and severe toxicity. Currently, it is assumed that part of the limited efficacy is due to the IL-2–driven preferential expansion of regulatory T cells, which dampen the antitumor immunity. In this study, we characterize a human IL-2 mutant with higher antitumor efficacy and lower toxicity than wild type human IL-2 (wtIL-2). The mutant differs from wtIL-2 by four mutations at the interface with the α subunit of IL-2R. The IL-2 mutant induces in vitro proliferation of CD8+CD44hi and NK1.1 cells as efficiently as does wtIL-2, but it shows a reduced capacity to induce proliferation of CD4+Foxp3+ regulatory T cells. The IL-2 mutant shows a higher antimetastatic effect than does wtIL-2 in several transplantable tumor models: the experimental metastasis model of MB16F0 melanoma and the experimental and spontaneous metastasis models for the mouse pulmonary carcinoma 3LL-D1222. Relevantly, the IL-2 mutant also exhibits lower lung and liver toxicity than does wtIL-2 when used at high doses in mice. In silico simulations, using a calibrated mathematical model, predict that the properties of IL-2 mutein are a consequence of the reduction, of at least two orders of magnitude, in its affinity for the α subunit of IL-2R (CD25). The human IL-2 mutant described in the present work could be a good candidate for improving cancer therapy based on IL-2.

Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: Overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines

“…EMD 521873 (Selectikine) is an immunocytokine that targets the necrotic core of tumors fused with two D20T mutated IL-2 moieties with increased affinity for CD25 that binds preferentially the high affinity IL-2R 47,48 . Carmenate and colleagues described an untargeted IL-2 mutein with reduced CD25 affinity using different mutations than the ones used in IL2v 49 . This mutein differs from IL-2 by four mutations in the CD25 interface, and its CD25 binding is not completely abolished.…”

Fine epitope specificity of antibodies against interleukin-2 explains their paradoxical immunomodulatory effects

“…The mutein is strongly immunostimulatory and evokes potent antitumor responses. 31 In total, the evidence indicates that masking a particular IL-2 antigenic region by immunoenhancing antibodies (the α chain interface) would result in functional masking of a crucial property of IL-2: its ability to promote tolerance, 1 allowing its other facet (enhancement of immune responses) to be fully evident. In such a way, the balance between regulatory and effector cells would be altered, resulting in exacerbated effector responses, as has been described for the immunostimulatory antibody S4B6 in the context of anti-viral vaccination, 7 and anti-tumor responses.…”

Le renouveau de l’interleukine 2

“…Cette amélioration clinique est fortement corrélée à une infiltration par des lymphocytes Treg dans la peau au niveau de ces zones [29]. Un patient atteint de lupus érythémateux disséminé (SLE) et réfractaire à de multiples molécules/essais thérapeutiques a été également traité par de faibles No-a IL-2), portant sur sa région d'interaction avec la chaîne α de son récepteur [34] (Figure 3A), conduit à une baisse de son affinité pour le récepteur trimérique tout en conservant celle pour le récepteur hétérodimère. No-a IL-2 conserve les propriétés antitumorales de l'IL-2, mais avec des effets toxiques amoindris.…”