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Interleukin-18 (IL-18) is a promising cytokine for immunotherapy. Besides exploiting the cytokine itself or mutant versions thereof for biomedical applications, bi- and multispecific antibody scaffolds can be harnessed that mimic the function of IL-18 by triggering receptor signaling. In addition to potential advantages with respect of manufacturability, a major benefit in using bispecific antibody derivatives relies in the different structure and sequence of the antibody compared to the cytokine. The activity of IL-18 is normally regulated in a negative feedback loop via IL-18 binding protein (IL-18BP) that binds with high affinities to IL-18 and prevents IL-18 from binding to its receptor. This physiological process is hijacked in certain types of cancer. We have generated VHH-derived bispecific surrogate agonists that are naturally resistant to inhibition by the decoy receptor IL-18BP. In this chapter, we detail protocols about the generation and characterization of IL-18 mimicking bispecifics.

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Generation and Characterization of Bispecific VHH-Derived Surrogate Agonists Mimicking the Function of IL-18

  • 实验方案

  • 发表日期：

    2026年

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  • Britta Lipinski,
  • Desislava Elter,
  • Paul Arras,
  • Laura Unmuth,
  • Simon Krah,
  • Achim Doerner,
  • Andreas Evers,
  • Lukas Pekar,
  • Stefan Zielonka

摘要

Interleukin-18 (IL-18) is a promising cytokine for immunotherapy. Besides exploiting the cytokine itself or mutant versions thereof for biomedical applications, bi- and multispecific antibody scaffolds can be harnessed that mimic the function of IL-18 by triggering receptor signaling. In addition to potential advantages with respect of manufacturability, a major benefit in using bispecific antibody derivatives relies in the different structure and sequence of the antibody compared to the cytokine. The activity of IL-18 is normally regulated in a negative feedback loop via IL-18 binding protein (IL-18BP) that binds with high affinities to IL-18 and prevents IL-18 from binding to its receptor. This physiological process is hijacked in certain types of cancer. We have generated VHH-derived bispecific surrogate agonists that are naturally resistant to inhibition by the decoy receptor IL-18BP. In this chapter, we detail protocols about the generation and characterization of IL-18 mimicking bispecifics.