A de novo IL2/IL15 mimic has improved antitumor activity and reduced toxicity compared with native IL2.

  • Major finding: A de novo IL2/IL15 mimic has improved antitumor activity and reduced toxicity compared with native IL2.

  • Concept: Design of a hyperstable mimic that binds IL2Rβγc but not IL2Rα avoids challenges of IL2 variants.

  • Impact: This approach may be broadly useful for enhancing efficacy and reducing toxicity of biologically active molecules.


Recombinant interleukin-2 (IL2) is an effective immunotherapy in several human cancers, but its high toxicity and tendency to induce the proliferation of immunosuppressive regulatory T cells (Treg) has limited its broader clinical use. Approaches to improve the therapeutic properties of IL2 have typically involved mutating or modifying the naturally occurring protein to reduce its interaction with IL2 receptor alpha (IL2Rα), but such approaches cannot completely eliminate IL2Rα binding, often result in reduced stability and potency, and carry the risk of inducing immune responses that cross-react with endogenous IL2. To circumvent shortcomings associated with incremental mutation or modifications of native IL2, Silva and colleagues developed a computational de novo protein design method wherein an idealized, stable globular protein structure without an IL2Rα interaction surface was built around the known IL2/IL15–IL2Rβγc interaction surface. Several rounds of optimization for stability and high IL2Rβγc affinity led to the development of Neo-2/15, a de novo IL2/IL15 mimic with little sequence identity to native IL2. Neo-2/15 has a higher affinity for IL2Rβγc and is significantly more stable than native IL2 or the IL2 variant super-2. Neo-2/15 also more potently activated T cells in vitro, led to reduced expansion of Tregs in vivo, and was not immunogenic. Neo-2/15 significantly delayed tumor growth and extended survival alone or in combination without the toxicity seen with native IL2, and led to a significant increase in intratumoral CD8:Treg ratios. This approach to de novo protein design thus has the potential to lead to safer, more effective IL2-based immunotherapy and can potentially be used to improve the therapeutic properties of other proteins.

Silva DA, Yu S, Ulge UY, Spangler JB, Jude KM, Labão-Almeida C, et al. De novo design of potent and selective mimics of IL-2 and IL-15. Nature 2019;565:186–91.

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