Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds,Nature Chemical Biology

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Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2023-04-06 , DOI: 10.1038/s41589-023-01313-6
Huilin Yang _{1,

2} , Umut Y Ulge _{3,

4} , Alfredo Quijano-Rubio _{3,

4} , Zachary J Bernstein _{2,

5} , David R Maestas _{2,

5} , Jung-Ho Chun _{3,

6} , Wentao Wang _{2,

5} , Jian-Xin Lin ₇ , Kevin M Jude ₈ , Srujan Singh _{1,

2} , Brian T Orcutt-Jahns ₉ , Peng Li ₇ , Jody Mou _{2,

5} , Liam Chung _{2,

10} , Yun-Huai Kuo _{1,

2} , Yasmin H Ali ₁₁ , Aaron S Meyer _{9,

12,

13,

14} , Warren L Grayson _{1,

2,

5,

15,

16} , Nicola M Heller _{17,

18} , K Christopher Garcia _{8,

19} , Warren J Leonard ₇ , Daniel-Adriano Silva ₃ , Jennifer H Elisseeff _{2,

5} , David Baker _{3,

20} , Jamie B Spangler _{1,

2,

5,

10,

21,

22,

23}

Affiliation

Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA.
Department of Bioengineering, University of Washington, Seattle, WA, USA.
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA, USA.
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Bioengineering, University of California, Los Angeles, CA, USA.
Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
College of Medicine, Florida State University, Tallahassee, FL, USA.
Department of Bioinformatics, University of California, Los Angeles, CA, USA.
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA.
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA.
Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, USA.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
Allergy and Clinical Immunology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sidney Kimmel Cancer Center, The Johns Hopkins University, Baltimore, MD, USA.
Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

The interleukin-4 (IL-4) cytokine plays a critical role in modulating immune homeostasis. Although there is great interest in harnessing this cytokine as a therapeutic in natural or engineered formats, the clinical potential of native IL-4 is limited by its instability and pleiotropic actions. Here, we design IL-4 cytokine mimetics (denoted Neo-4) based on a de novo engineered IL-2 mimetic scaffold and demonstrate that these cytokines can recapitulate physiological functions of IL-4 in cellular and animal models. In contrast with natural IL-4, Neo-4 is hyperstable and signals exclusively through the type I IL-4 receptor complex, providing previously inaccessible insights into differential IL-4 signaling through type I versus type II receptors. Because of their hyperstability, our computationally designed mimetics can directly incorporate into sophisticated biomaterials that require heat processing, such as three-dimensional-printed scaffolds. Neo-4 should be broadly useful for interrogating IL-4 biology, and the design workflow will inform targeted cytokine therapeutic development.

中文翻译：

通过模块化从头支架设计细胞类型特异性超稳定 IL-4 模拟物

白细胞介素 4 (IL-4) 细胞因子在调节免疫稳态中发挥着关键作用。尽管人们对利用这种细胞因子作为天然或工程形式的治疗剂非常感兴趣，但天然 IL-4 的临床潜力因其不稳定性和多效性而受到限制。在这里，我们基于从头设计的 IL-2 模拟支架设计了 IL-4 细胞因子模拟物（称为 Neo-4），并证明这些细胞因子可以在细胞和动物模型中重现 IL-4 的生理功能。与天然 IL-4 相比，Neo-4 非常稳定，并且仅通过 I 型 IL-4 受体复合物发出信号，从而提供了以前无法获得的关于通过 I 型与 II 型受体的差异 IL-4 信号传导的见解。由于其超稳定性，我们通过计算设计的模拟物可以直接融入需要热处理的复杂生物材料中，例如三维打印支架。Neo-4 应该广泛用于研究 IL-4 生物学，并且设计工作流程将为靶向细胞因子治疗的开发提供信息。

更新日期：2023-04-06

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