ArticleProceedings of the National Academy of Sciences of the United States of America2022
Interleukin-2 superkines by computational design.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Review
- Rewiring STAT signaling from the cell surface with Trikine immunotherapeutics.Science (New York, N.Y.) · 2026Article
- Article
- Designing de novo TIM barrels: insights into stabilization, diversification, and functionalization strategies.Biochemical Society transactions · 2026Review
- DF6215, an α-optimized IL-2-Fc fusion, expands immune effectors and drives robust preclinical anti-tumor activity.Cell reports. Medicine · 2026Article
- Protein engineering: status report.Protein engineering, design & selection : PEDS · 2026Review
- Selectivity of bovine interleukin-2 mutein stimulation on bovine peripheral blood mononuclear cells.The Journal of veterinary medical science · 2025Article
- Presetting CAR-T cells during ex vivo biomanufacturing.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Direct delivery of immune modulators to tumour-infiltrating lymphocytes using engineered extracellular vesicles.Journal of extracellular vesicles · 2025Article
- Regulating IL-2 Immune Signaling Function Via A Core Allosteric Structural Network.Journal of molecular biology · 2025Article
- Directed disruption of IL2 aggregation and receptor binding sites produces designer biologics with enhanced specificity and improved production capacity.Computational and structural biotechnology journal · 2025Article
- Molecular Engineering of Interleukin-2 for Enhanced Therapeutic Activity in Autoimmune Diseases.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Review
- Molecular reshaping of phage-displayed Interleukin-2 at beta chain receptor interface to obtain potent super-agonists with improved developability profiles.Communications biology · 2023Article
- Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 and IL-2R targeting strategies.Molecular cancer · 2023Review
- Advances in engineering and delivery strategies for cytokine immunotherapy.Expert opinion on drug delivery · 2023Article
- Engineering cytokine therapeutics.Nature reviews bioengineering · 2023Review
- Emerging principles of cytokine pharmacology and therapeutics.Nature reviews. Drug discovery · 2023Review
- Review
- De Novo Design of a Highly Stable Ovoid TIM Barrel: Unlocking Pocket Shape towards Functional Design.Biodesign research · 2022Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Affinity maturation of protein–protein interactions is an important approach in the development of therapeutic proteins such as cytokines. Typical experimental strategies involve targeting the cytokine-receptor interface with combinatorial libraries and then selecting for higher-affinity variants. Mutations to the binding scaffold are usually not considered main drivers for improved affinity. Here we demonstrate that computational design can provide affinity-enhanced variants of interleukin-2 (IL-2) “out of the box” without any requirement for interface engineering. Using a strategy of global IL-2 structural stabilization targeting metastable regions of the three-dimensional structure, rather than the receptor binding interfaces, we computationally designed thermostable IL-2 variants with up to 40-fold higher affinity for IL-2Rβ without any library-based optimization. These IL-2 analogs exhibited CD25-independent activities on T and natural killer (NK) cells both in vitro and in vivo, mimicking the properties of the IL-2 superkine “super-2” that was engineered through yeast surface display [A. M. Levin et al., Nature, 484, 529–533 (2012)]. Structure-guided stabilization of cytokines is a powerful approach to affinity maturation with applications to many cytokine and protein–protein interactions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.