Autoimmune disease

A human antibody selectively targets regulatory T cells

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At low doses, IL-2 induces the proliferation and functional activation of regulatory T (Treg) cells, which suppress autoimmune responses and transplant rejection in mouse models. In a new paper in Nature Medicine, Trotta et al. identified a human anti-IL-2 antibody that mimics these effects and might be useful for treating human autoimmune diseases.

Previous studies in mice and humans have reported that low-dose IL-2 induces the expansion of Treg cells, which controls the immunopathology of autoimmune diseases such as type 1 diabetes. At high doses, however, IL-2 treatment also induces the unwanted expansion of effector T (Teff) cells. However, a mouse monoclonal antibody (JES6-1) that binds to mouse IL-2 and alters its affinity for CD25 (a component of the trimeric IL-2 receptor (IL-2R) that is expressed at different levels by Treg cells and Teff cells) improves the selectivity of IL-2 treatment so that Treg cells are preferentially upregulated.

To generate human monoclonal antibodies that bind to human IL-2 (hIL-2), the researchers first screened a proprietary phage display library. They then carried out IL-2 binding assays, monitored the selective activation of IL-2–IL-2R signalling and studied binding between human anti-IL-2 antibody–hIL-2 complexes and different IL-2R receptor subunits to select antibodies that (in a complex with hIL-2) selectively promote Treg cell proliferation. The antibody F5111.2 minimally reduced the response of Treg cells to hIL-2 while substantially reducing IL-2 signalling in Teff cells. Interestingly, structural analysis of the F5111.2 antigen-binding fragment (Fab) in complex with hIL-2 revealed that, although the binding site in IL-2 and the conformational change induced by antibody binding differed between F5111.2 and JES6-1, the overall effect of these antibodies on IL-2 was similar, suggesting a conserved biology.

In vivo analyses in a humanized mouse model of type 1 diabetes (NOD mice) revealed that the F5111.2–hIL-2 complex produced a selective increase in the Treg cell population compared with other immune cells. Importantly, treating NOD mice with the F5111.2–hIL-2 complex for 5 days led to diabetes remission in 50% of mice after 1 week and maintained normoglycaemia in most mice after 4 weeks, compared with minimal effect of an isotype-matched antibody–hIL-2 complex or low-dose hIL-2. Similar therapeutic efficacy was also demonstrated in mouse models of experimental autoimmune encephalitis and graft-versus-host disease.

“an effective immunotherapy for autoimmune diseases in humans would likely require targeting multiple axes of the immune system”

The authors conclude that an effective immunotherapy for autoimmune diseases in humans would likely require targeting multiple axes of the immune system, such as depletion of Teff cells combined with enhancement of Treg cells.

References

  1. 1

    Trotta, E. et al. A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism. Nat. Med. https://doi.org/10.1038/s41591-018-0070-2 (2018)

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Otto, G. A human antibody selectively targets regulatory T cells. Nat Rev Drug Discov 17, 546 (2018). https://doi.org/10.1038/nrd.2018.122

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