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Liebl, K.* ; Aschenbrenner, I.* ; Schiller, L. ; Kerle, A.* ; Protzer, U. ; Feige, M.J.*

Modeling of the human interleukin 12:receptor complex allows to engineer attenuated cytokine variants.

Mol. Immunol. 162, 38-44 (2023)

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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.

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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.

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