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Engineering IL-2 for immunotherapy of autoimmunity and cancer

Abstract

Preclinical studies of the T cell growth factor activity of IL-2 resulted in this cytokine becoming the first immunotherapy to be approved nearly 30 years ago by the US Food and Drug Administration for the treatment of cancer. Since then, we have learnt the important role of IL-2 in regulating tolerance through regulatory T cells (Treg cells) besides promoting immunity through its action on effector T cells and memory T cells. Another pivotal event in the history of IL-2 research was solving the crystal structure of IL-2 bound to its tripartite receptor, which spurred the development of cell type-selective engineered IL-2 products. These new IL-2 analogues target Treg cells to counteract the dysregulated immune system in the context of autoimmunity and inflammatory disorders or target effector T cells, memory T cells and natural killer cells to enhance their antitumour responses. IL-2 biologics have proven to be effective in preclinical studies and clinical assessment of some is now underway. These studies will soon reveal whether engineered IL-2 biologics are truly capable of harnessing the IL-2–IL-2 receptor pathway as effective monotherapies or combination therapies for autoimmunity and cancer.

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Fig. 1: Lymphoid cell expression of high-affinity and intermediate-affinity IL-2R.
Fig. 2: Interactions between IL-2 and IL-2R subunits and the residues crucial for their binding interface.
Fig. 3: Structural models of selected engineered IL-2 compounds.

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Acknowledgements

The authors thank A. Pugliese and A. Villarino at the University of Miami and M. Struthers at Bristol Myers Squibb for critically reading the manuscript and M. Doyle at Bristol Myers Squibb for providing the structural model of IL-2–CD25. Their research is supported by grants from the US National Institutes of Health (NIH R01AI131648 and R01AI148675) and the Florida Department of Health (21B03) and a sponsored research agreement with Bristol Myers Squibb.

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Contributions

T.R.M. conceptualized the manuscript. R.H. wrote most of the first draft and developed the figures. J.P. and K.M.L. contributed information related to the biological effects of the engineered IL-2 proteins. All authors edited the manuscript.

Corresponding author

Correspondence to Thomas R. Malek.

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Competing interests

The University of Miami, T.R.M. and R.H. have patents pending on IL-2–CD25 fusion proteins (Wo2016022671A1; T.R.M.) and their use (PCT/US20/13152; T.R.M. and R.H.) that have been licensed exclusively to Bristol Myers Squibb, and some research on IL-2–CD25 fusion proteins has been supported, in part, by a collaboration and sponsored research and licensing agreement with Bristol Myers Squibb. The other authors declare no competing interests.

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Nature Reviews Immunology thanks J. Bluestone, O. Boyman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

High-affinity IL-2R

The IL-2 receptor (IL-2R) comprising the three subunits IL-2Rα (CD25), IL-2Rβ (CD122) and the common cytokine receptor γ-chain (γc; CD132).

Intermediate-affinity IL-2R

The IL-2 receptor (IL-2R) comprising only the two subunits CD122 and CD132.

IL-2 muteins

IL-2 proteins engineered through the introduction of mutations that shift the selectivity of IL-2 towards cells expressing the high-affinity or intermediate-affinity receptor. These modifications are not aimed at increasing the half-life of IL-2.

PEGylated IL-2

Complexes of IL-2 and polyethylene glycol (PEG) in which PEG chains attach to lysine residues on IL-2 biasing its selectivity towards the high-affinity or intermediate-affinity receptor, depending on the location and number of PEG chains on IL-2. PEGylation increases the half-life of IL-2.

IL-2–anti-IL-2 immune complexes

Complexes of IL-2 and anti-IL-2 antibodies that exist as separate entities that are pre-complexed prior to administration or engineered as linked molecules. Depending on the anti-IL-2 antibody, IL-2 shows selectivity for the high-affinity or intermediate-affinity receptor. IL-2 immune complexes result in increased half-life of IL-2.

IL-2–CD25 fusion proteins

IL-2 covalently linked to CD25 via a short amino acid linker. The IL-2 component of the fusion protein is linked to CD25 in a linear or rearranged manner to generate fusion proteins that exhibit selectivity towards the high-affinity or intermediate-affinity receptor, respectively. These fusion proteins exhibit increased half-lives compared with IL-2.

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Hernandez, R., Põder, J., LaPorte, K.M. et al. Engineering IL-2 for immunotherapy of autoimmunity and cancer. Nat Rev Immunol 22, 614–628 (2022). https://doi.org/10.1038/s41577-022-00680-w

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