1. Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds
- Author
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Yang, Huilin, Ulge, Umut Y., Quijano-Rubio, Alfredo, Bernstein, Zachary J., Maestas, David R., Chun, Jung-Ho, Wang, Wentao, Lin, Jian-Xin, Jude, Kevin M., Singh, Srujan, Orcutt-Jahns, Brian T., Li, Peng, Mou, Jody, Chung, Liam, Kuo, Yun-Huai, Ali, Yasmin H., Meyer, Aaron S., Grayson, Warren L., Heller, Nicola M., Garcia, K. Christopher, Leonard, Warren J., Silva, Daniel-Adriano, Elisseeff, Jennifer H., Baker, David, and Spangler, Jamie B.
- Abstract
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.
- Published
- 2023
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