Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds

Huilin Yang; Umut Y Ulge; Alfredo Quijano-Rubio; Zachary J Bernstein; David R Maestas; Jung-Ho Chun; Wentao Wang; Jian-Xin Lin; Kevin M Jude; Srujan Singh; Brian T Orcutt-Jahns; Peng Li; Jody Mou; Liam Chung; Yun-Huai Kuo; Yasmin H Ali; Aaron S Meyer; Warren L Grayson; Nicola M Heller; K Christopher Garcia; Warren J Leonard; Daniel-Adriano Silva; Jennifer H Elisseeff; David Baker; Jamie B Spangler

doi:10.1038/s41589-023-01313-6

Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds

Nat Chem Biol. 2023 Sep;19(9):1127-1137. doi: 10.1038/s41589-023-01313-6. Epub 2023 Apr 6.

Authors

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 Lin⁷, Kevin M Jude⁸, Srujan Singh^{1

2}, Brian T Orcutt-Jahns⁹, Peng Li⁷, Jody Mou^{2

5}, Liam Chung^{2

10}, Yun-Huai Kuo^{1

2}, Yasmin H Ali¹¹, 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 Leonard⁷, Daniel-Adriano Silva³, Jennifer H Elisseeff^{2

5}, David Baker^{20

21}, Jamie B Spangler^{22

23

24

25

26

27

28}

Affiliations

¹ Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
² Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA.
⁴ Department of Bioengineering, University of Washington, Seattle, WA, USA.
⁵ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA, USA.
⁷ Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Department of Bioengineering, University of California, Los Angeles, CA, USA.
¹⁰ Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
¹¹ College of Medicine, Florida State University, Tallahassee, FL, USA.
¹² Department of Bioinformatics, University of California, Los Angeles, CA, USA.
¹³ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
¹⁴ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA.
¹⁵ Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA.
¹⁶ Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, USA.
¹⁷ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
¹⁸ Allergy and Clinical Immunology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
¹⁹ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
²⁰ Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
²¹ Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
²² Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA. jamie.spangler@jhu.edu.
²³ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jamie.spangler@jhu.edu.
²⁴ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jamie.spangler@jhu.edu.
²⁵ Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA. jamie.spangler@jhu.edu.
²⁶ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. jamie.spangler@jhu.edu.
²⁷ Sidney Kimmel Cancer Center, The Johns Hopkins University, Baltimore, MD, USA. jamie.spangler@jhu.edu.
²⁸ Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, MD, USA. jamie.spangler@jhu.edu.

^# Contributed equally.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cytokines*
Interleukin-4*
Signal Transduction

Substances

Interleukin-4
Cytokines

Abstract

Publication types

MeSH terms

Substances

Grants and funding