Rationale : Tregs and IL-2

Regulatory T cells (Tregs) regulate adaptive immune responses1-2. One of their key roles is to suppress excess immune responses against a diverse range of antigens, thereby preventing autoimmune diseases and maintaining self-tolerance1. They also protect against inflammatory diseases, including atherosclerosis3, and contribute to tissue repair, modulating for example cardiac remodeling after myocardial infarction4. Thus, Tregs are considered as important therapeutic targets5–7. 

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Interleukin-2 (IL-2) is the key cytokine supporting the differentiation, survival and fitness of Tregs8. While IL-2 was initially used at high doses as a cancer drug aimed at activating effector T cells (Teffs), we pioneered the use of low-doses of IL-2 (IL-2LD) to preferentially stimulate and expand Tregs in vivo, and thus improve autoimmunity9-10-11-12-13. Large multicentre randomized controlled therapeutic trials have been initiated and will delineate the therapeutic value of 1st-generation native IL-2LD.

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Meanwhile, the pharmaceutical industry has embarked on developing 2nd-generation IL-2 muteins, with most big companies having their own program in the field. So far, they have all engineered IL-2 to (i) increase its half-life by fusing it to scaffolds made of Ig fragments and (ii) abolish its binding to the b chain of the IL-2 receptor (IL-2R), such as to limit its capacity to activate effector T cells (Teffs). Although two 2nd-generation IL-2 recently failed to show efficacy in SLE, others such molecule are still in development.