4.8 Review

Emerging principles of cytokine pharmacology and therapeutics

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Summary: Cytokines are potent immunoregulatory proteins that play important roles in cancer and have the potential for cancer immunotherapy. However, the use of cytokines as therapeutics has been limited by their complex biology and toxicities. Recent advances in immune checkpoint inhibitors and combination immunotherapies have reinvigorated interest in cytokines as therapeutics.

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Summary: This study presents a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics. The researchers generated combinatorial matrices of single-chain bispecific ligands and discovered that this approach can lead to the engineering of surrogate ligands that compel assembly of non-natural receptor heterodimers. The findings demonstrate the generalizability of this approach for the discovery of diversified agonists for various ligand-receptor systems.
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Summary: Affinity maturation of protein-protein interactions is crucial in therapeutic protein development. Computational design can provide high-affinity IL-2 variants without interface engineering. Stabilizing the global IL-2 structure instead of receptor binding interfaces, we designed thermostable IL-2 variants with increased affinity for IL-2R beta, exhibiting IL-2 superkine-like activities.

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Summary: Cytokines signal through cell surface receptor dimers to initiate activation of intracellular JAKs. This study reports the cryo-electron microscopy structure of JAK1 complexed with a cytokine receptor, and investigates the role of oncogenic JAK1 mutations in signaling.

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Summary: The structural mechanism of receptor sharing used by IL-12 family cytokines can be utilized to tune the cytokine axis for therapeutics, as demonstrated by the design of IL-12 partial agonists that elicited anti-tumor immunity in vivo.
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J. Randolph Hecht et al.

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Robert A. Saxton et al.

Summary: This study engineered a high-affinity IL-22 superagonist to investigate the molecular mechanisms of the IL-22 signaling pathway. They found that precise control of IL-22 signaling can be achieved by modulating receptor expression levels and signaling bias, leading to tissue protection effects.

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Site-specific PEGylation of interleukin-2 enhances immunosuppression via the sustained activation of regulatory T cells

Bo Zhang et al.

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Summary: By determining the structure of the IL-10 receptor complex and uncovering differences in IL-10 response thresholds across immune cell populations, this study provides a mechanistic blueprint for manipulating the pleiotropic actions of IL-10. Some IL-10 variants displayed myeloid-biased activity, suppressing macrophage activation without stimulating inflammatory CD8(+) T cells, thus uncoupling the major opposing functions of IL-10.

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A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy

Eric J. Hsu et al.

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A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells

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Summary: The study introduces a novel bispecific heavy-chain only antibody that binds to and activates signaling through the heterodimeric IL-2R beta gamma receptor complex on resting T-cells and NK cells, offering a safe and effective alternative to traditional IL-2 therapy with enhanced therapeutic potential for cancer treatment.

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Caleb R. Glassman et al.

Summary: Interleukin-2 (IL-2) is a pleiotropic cytokine that mediates both pro- and anti-inflammatory functions, with different sensitivities in immune cells due to cell type and activation state-dependent expression of receptors and signaling pathway components. Using structure-based design, IL-2 variants were created to titrate maximum signal strength across cell types, leading to cell type-dependent differences in gene expression. IL-2 partial agonists can be used to calibrate intrinsic differences in response thresholds across responding cell types to narrow pleiotropic actions.
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Hon Sen Tan et al.

Summary: Oliceridine, a biased opioid agonist, activates G-protein signaling to reduce the risk of adverse effects compared to conventional opioids, but further studies are needed to confirm its safety profile and advantages.

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Fei Mo et al.

Summary: Adoptive transfer of antigen-specific T cells is a significant advancement in cancer immunotherapy, and maintaining a stem-cell-like state before transfer is beneficial for therapeutic efficacy.

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An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism

Jerod L. Ptacin et al.

Summary: The application of synthetic biology in medicine has the potential to revolutionize drug development, with engineered semi-synthetic organisms offering a new approach to creating chemically modified biologics. Through targeted chemical modifications in human IL-2, a variant named THOR-707 has been identified that shows selective engagement with IL-2 receptors, leading to enhanced immune responses in mice and significant reduction in tumor growth in preclinical models.

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Summary: The study engineered a novel immunocytokine, anti-PD1-IL15m, that targets PD1+ tumor-infiltrating lymphocytes to enhance the efficacy and safety of IL15 in cancer immunotherapy.

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Inja Waldhauer et al.

Summary: FAP-IL2v is a potent immunocytokine that enhances the efficacy of different T- and NK-cell-based cancer immunotherapies by stimulating antibody activity and promoting tumor targeting.
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Jarrod A. Dudakov et al.

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