Joint publication by Ulrike Protzer and Matthias Feige: Modeling of the human interleukin 12:receptor complex allows to engineer attenuated cytokine variants
Liebl K, Aschenbrenner I, Schiller L, Kerle A, Protzer U, Feige MJ. Modeling of the human interleukin 12:receptor complex allows to engineer attenuated cytokine variants. Mol Immunol. 2023 Oct;162:38-44. doi: 10.1016/j.molimm.2023.08.010. Epub 2023 Aug 26. PMID: 37639747.

Abstract

Interleukin 12 (IL-12) plays major roles in immune defense against intracellular pathogens. By activating T cells and increasing antigen presentation, it is also a very potent anti-tumor molecule. Strong immune activation and systemic toxicity, however, so far limit its potential therapeutic use. Building on recent experimental structures of IL-12 related cytokine:receptor complexes, we here provide a high-resolution computational model of the human IL-12:receptor complex. We design attenuated IL-12 variants with lower receptor binding affinities based on molecular dynamics simulations, and subsequently validate them experimentally. These variants show reduced activation of natural killer cells while maintaining T cell activation. This immunological signature is important to develop IL-12 for cancer treatment, where natural killer cells contribute to severe side-effects. Taken together, our study provides detailed insights into structure and dynamics of the human IL-12:receptor complex and leverages them for engineering attenuated variants to elicit fewer side-effects while maintaining relevant biological activity.

Keywords: Cytokine engineering; IL-12; Interleukin; Interleukin receptor; Molecular dynamics.

References

https://pubmed.ncbi.nlm.nih.gov/37639747/

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