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Facile discovery of surrogate cytokine agonists.

Yen M, Ren J, Liu Q, Glassman CR, Sheahan TP, Picton LK, Moreira FR, Rustagi A, Jude KM, Zhao X, Blish CA, Baric RS, Su LL, Garcia KC
Cell 185 1414-1430.e19 (2022)
Cited: 21 times
EuropePMC logo PMID: 35325595

Abstract

Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but natural cytokines have structural limitations as therapeutics. We present a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics amenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15, type-I interferon, and interleukin-10 receptors, we generated combinatorial matrices of single-chain bispecific ligands that exhibited diverse spectrums of functional activities, including potent inhibition of SARS-CoV-2 by surrogate interferons. Crystal structures of IL-2R:VHH complexes revealed that variation in receptor dimer geometries resulted in functionally diverse signaling outputs. This modular platform enabled engineering of surrogate ligands that compelled assembly of an IL-2R/IL-10R heterodimer, which does not naturally exist, that signaled through pSTAT5 on T and natural killer (NK) cells. This "cytokine med-chem" approach, rooted in principles of induced proximity, is generalizable for discovery of diversified agonists for many ligand-receptor systems.

Reviews - 7s2s mentioned but not cited (1)

  1. Emerging principles of cytokine pharmacology and therapeutics. Saxton RA, Glassman CR, Garcia KC. Nat Rev Drug Discov 22 21-37 (2023)

Articles - 7s2s mentioned but not cited (1)

  1. Facile discovery of surrogate cytokine agonists. Yen M, Ren J, Liu Q, Glassman CR, Sheahan TP, Picton LK, Moreira FR, Rustagi A, Jude KM, Zhao X, Blish CA, Baric RS, Su LL, Garcia KC. Cell 185 1414-1430.e19 (2022)


Reviews citing this publication (7)

  1. The JAK-STAT pathway at 30: Much learned, much more to do. Philips RL, Wang Y, Cheon H, Kanno Y, Gadina M, Sartorelli V, Horvath CM, Darnell JE, Stark GR, O'Shea JJ. Cell 185 3857-3876 (2022)
  2. Immunotherapeutic progress and application of bispecific antibody in cancer. Kang J, Sun T, Zhang Y. Front Immunol 13 1020003 (2022)
  3. Recent and future perspectives on engineering interferons and other cytokines as therapeutics. Aung T, Grubbe WS, Nusbaum RJ, Mendoza JL. Trends Biochem Sci 48 259-273 (2023)
  4. Arming CAR-T cells with cytokines and more: Innovations in the fourth-generation CAR-T development. Tang L, Pan S, Wei X, Xu X, Wei Q. Mol Ther 31 3146-3162 (2023)
  5. Engineering cytokine therapeutics. Deckers J, Anbergen T, Hokke AM, de Dreu A, Schrijver DP, de Bruin K, Toner YC, Beldman TJ, Spangler JB, de Greef TFA, Grisoni F, van der Meel R, Joosten LAB, Merkx M, Netea MG, Mulder WJM. Nat Rev Bioeng 1 286-303 (2023)
  6. Next generation of multispecific antibody engineering. Keri D, Walker M, Singh I, Nishikawa K, Garces F. Antib Ther 7 37-52 (2024)
  7. Strategies to therapeutically modulate cytokine action. Leonard WJ, Lin JX. Nat Rev Drug Discov 22 827-854 (2023)

Articles citing this publication (12)

  1. Host Kinase CSNK2 is a Target for Inhibition of Pathogenic SARS-like β-Coronaviruses. Yang X, Dickmander RJ, Bayati A, Taft-Benz SA, Smith JL, Wells CI, Madden EA, Brown JW, Lenarcic EM, Yount BL, Chang E, Axtman AD, Baric RS, Heise MT, McPherson PS, Moorman NJ, Willson TM. ACS Chem Biol 17 1937-1950 (2022)
  2. A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes. Wilder CL, Lefaudeux D, Mathenge R, Kishimoto K, Zuniga Munoz A, Nguyen MA, Meyer AS, Cheng QJ, Hoffmann A. Mol Syst Biol 19 e11294 (2023)
  3. Designing receptor agonists with enhanced pharmacokinetics by grafting macrocyclic peptides into fragment crystallizable regions. Sakai K, Sugano-Nakamura N, Mihara E, Rojas-Chaverra NM, Watanabe S, Sato H, Imamura R, Voon DC, Sakai I, Yamasaki C, Tateno C, Shibata M, Suga H, Takagi J, Matsumoto K. Nat Biomed Eng 7 164-176 (2023)
  4. Generation and engineering of potent single domain antibody-based bispecific IL-18 mimetics resistant to IL-18BP decoy receptor inhibition. Lipinski B, Unmuth L, Arras P, Becker S, Bauer C, Toleikis L, Krah S, Doerner A, Yanakieva D, Boje AS, Klausz K, Peipp M, Siegmund V, Evers A, Kolmar H, Pekar L, Zielonka S. MAbs 15 2236265 (2023)
  5. Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination. Tsutsumi N, Hwang S, Waghray D, Hansen S, Jude KM, Wang N, Miao Y, Glassman CR, Caveney NA, Janda CY, Hannoush RN, Garcia KC. Proc Natl Acad Sci U S A 120 e2218238120 (2023)
  6. Advances in engineering and delivery strategies for cytokine immunotherapy. Bohmer M, Xue Y, Jankovic K, Dong Y. Expert Opin Drug Deliv 20 579-595 (2023)
  7. CD20/TNFR1 dual-targeting antibody enhances lysosome rupture-mediated cell death in B cell lymphoma. Kim JR, Lee D, Kim Y, Kim JY. Cancer Immunol Immunother 72 1567-1580 (2023)
  8. Cattle-derived knob paratopes grafted onto peripheral loops of the IgG1 Fc region enable the generation of a novel symmetric bispecific antibody format. Yanakieva D, Vollmer L, Evers A, Siegmund V, Arras P, Pekar L, Doerner A, Valldorf B, Kolmar H, Zielonka S, Krah S. Front Immunol 14 1238313 (2023)
  9. Combination of cancer vaccine with CD122-biased IL-2/anti-IL-2 Ab complex shapes the stem-like effector NK and CD8+ T cells against tumor. Shimizu K, Ueda S, Kawamura M, Aoshima H, Satoh M, Nakabayashi J, Fujii SI. J Immunother Cancer 11 e006409 (2023)
  10. Joined at the hip: The role of light chain complementarity determining region 2 in antibody self-association. Sargunas PR, Spangler JB. Proc Natl Acad Sci U S A 119 e2208330119 (2022)
  11. Surrogate cytokine agonists: promising agents against COVID-19. Lin Z, Zuo J, He S. Signal Transduct Target Ther 7 150 (2022)
  12. The interweaved signatures of common-gamma-chain cytokines across immunologic lineages. Baysoy A, Seddu K, Salloum T, Dawson CA, Lee JJ, Yang L, Gal-Oz S, Ner-Gaon H, Tellier J, Millan A, Sasse A, Brown B, Lanier LL, Shay T, Nutt S, Dwyer D, Benoist C, Immunological Genome Project Consortium. J Exp Med 220 e20222052 (2023)


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