IL-2 focus switches to stimulating T_regs

Recombinant interleukin-2 (IL-2) has been used since the early 1990s for the treatment of renal cell carcinoma and melanoma, as high-dose IL-2 has immune-stimulating properties. A spate of deals in 2017 — including Eli Lilly's acquisition of co-development rights to Nektar's NKTR-358, the acquisition of Delinia by Celgene, and a co-development agreement between ILTOO Pharma and Servier (Supplementary information S1 (table)) — illustrate growing interest in another potential therapeutic use for IL-2. This cytokine stimulates regulatory T (T_reg) cells and therefore could have applications in numerous autoimmune diseases.

Two nearly simultaneous discoveries in the 1990s catalysed research on IL-2 as an immunosuppressive agent, rather than an immune stimulant. “I think the people who do mouse studies deserve all the credit for this,” says Abul Abbas, a professor at the University of California, San Francisco, USA, who has advised ILTOO and Celgene. IL-2 was known to promote effector T (T_eff) cell function (hence its anticancer properties), but when scientists knocked out Il2 or components of its receptor in mice, they unexpectedly developed spontaneous autoimmunity. This observation coincided with the discovery of T_reg cells — a marker of which is constitutive expression of the high-affinity IL-2 receptor α-chain (IL-2Rα) — and their primary role in dampening T_eff cells and resolving inflammation. Eventually, IL-2 was found to be a key cytokine in T_reg cell development, thus explaining the mouse phenotypes (Nat. Rev. Immunol. 15, 283–294; 2015). “That's when the field of IL-2 therapeutics got turned on its head,” says Abbas.

The IL-2R can be composed of different combinations of the α- and β-chains together with the common γ-chain, leading to receptors with varying affinity for IL-2. Whereas T_reg cells constitutively express high levels of IL-2Rα, T_eff cells express this chain only transiently after stimulation and also express the lower-affinity IL-2Rβ. David Klatzmann, a professor at Pierre and Marie Curie University, Paris, France, reasoned that low-dose IL-2 could preferentially stimulate T_reg cells over T_eff cells. A pioneering phase I/IIa trial that he led showed that low-dose IL-2 promoted T_reg cell development in patients with hepatitis C virus (HCV)-induced vasculitis, which is characterized by a low number of T_reg cells (N. Engl J. Med. 22, 2067–2077; 2011). “When I saw the results of this first trial, and knowing that you can find IL-2 on the shelves of most hospitals, I thought that people would immediately realize its potential, because there is a T_reg insufficiency in many settings,” he says. ILTOO Pharma was spun out from his work. Simultaneously, another group investigating the same hypothesis — led by John Koreth at the Dana-Farber Cancer Institute, Boston, USA — reported a positive trial of low-dose IL-2 in graft-versus-host disease (N. Engl J. Med. 365, 2055–2066; 2011). Subsequent trials of low-dose IL-2 have reported positive results in diseases including type 1 diabetes (T1D) (Lancet Diabetes Endocrinol. 4, 295–305; 2013) and systemic lupus erythematosus (SLE) (Nat. Med. 22, 991–993; 2016). And in an ongoing 'disease-finding trial' led by Klatzmann that is investigating low-dose IL-2 in 14 different autoimmune, T cell- or antibody-based diseases (NCT01988506), he has found a biological response in all patients treated with the cytokine so far, leading him to describe IL-2 as “the corticosteroids of the 21st century”.

Using a low dose of IL-2 is one way to bias responses to activate T_reg cells; another is to modify IL-2 to preferentially target IL-2Rα. Delinia's lead candidate, DEL106, is a mutated version of IL-2 that preferentially binds to IL-2Rα, fused to an antibody Fc domain, whereas Nektar developed a polyethylene glycol (PEG)-conjugated version of IL-2, known as NKTR-358. Although PEGylation is normally used to extend protein half-life, Nektar recently presented data suggesting that NKTR-358 preferentially binds to IL-2Rα. These candidates are in preclinical development.

George Tsokos, a professor at Harvard Medical School, Boston, USA, highlights some potential hurdles for IL-2 therapies. Patients with SLE, a disease high on the list of potential uses for IL-2, are clinically heterogeneous, and the same is likely to be true for the molecular pathways governing T_reg cell development in these individuals. Moreover, his group found that T cells from patients with SLE have reduced sensitivity to IL-2 (Arthritis Rheumatol. 4, 808–813; 2017). Klatzmann agrees that biomarkers could be necessary and that not all patients with a biological response will necessarily have a clinical response. Nevertheless, it seems that harnessing T_reg cells could lead to much-needed new therapies for diseases such as T1D and SLE.