Engineering cytokines and cytokine circuits

Li, Aileen W.; Lim, Wendell A.

doi:10.1126/science.abb5607

Cited by 27 publications

(21 citation statements)

References 15 publications

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“…The cell‐targeting specificity of a protein‐ligand depends on its cognate receptor, which is often shared by a wide variety of cell types. Accordingly, engineering cell‐selectivity of ligand‐receptor interactions is important in cell‐targeting for ligand‐based therapy [3b, 6b] . We developed a SUDA system to selectively activate specific ligand–receptor signaling pathways of cell subpopulations based on multi‐input Boolean logic analysis of cell‐surface protein profiles.…”

Section: Resultsmentioning

confidence: 99%

Scan and Unlock: A Programmable DNA Molecular Automaton for Cell‐Selective Activation of Ligand‐Based Signaling

et al. 2021

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Selective modulation of ligand–receptor interaction is essential in targeted therapy. In this study, we design an intelligent “scan and unlock” DNA automaton (SUDA) system to equip a native protein‐ligand with cell‐identity recognition and receptor‐mediated signaling in a cell‐type‐specific manner. Using embedded DNA‐based chemical reaction networks (CRNs) on the cell surface, SUDA scans and evaluates molecular profiles of cell‐surface proteins via Boolean logic circuits. Therefore, it achieves cell‐specific signal modulation by quickly unlocking the protein‐ligand in proximity to the target cell‐surface to activate its cognate receptor. As a proof of concept, we non‐genetically engineered hepatic growth factor (HGF) with distinct logic SUDAs to elicit target cell‐specific HGF signaling and wound healing behaviors in multiple heterogeneous cell types. Furthermore, the versatility of the SUDA strategy was shown by engineering tumor necrotic factor‐α (TNFα) to induce programmed cell death of target cell subpopulations through cell‐specific modulation of TNFR1 signaling.

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Section: Resultsmentioning

confidence: 99%

Scan and Unlock: A Programmable DNA Molecular Automaton for Cell‐Selective Activation of Ligand‐Based Signaling

et al. 2021

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“…Several strategies have been used to engineer cytokines to improve their bioactivity and antitumor efficacy. These include: enhancing affinity by modifying cytokine/receptor interfaces; altering cytokine/receptor interactions; redirecting specificity; and improving stability in serum ( 40 ). These modified cytokines are referred to as “Superkines”, e.g., alterations in IL-2 to enhance binding affinity for IL-2Rβ resulted in an “IL-2 Superkine” that improves expansion of cytotoxic T cells resulting in superior antitumor responses ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Cancer Therapy Using an Engineered Designer Cytokine Alone and in Combination With an Immune Checkpoint Inhibitor

et al. 2022

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melanoma differentiation associated gene-7 or Interleukin-24 (mda-7, IL-24) displays expansive anti-tumor activity without harming corresponding normal cells/tissues. This anticancer activity has been documented in vitro and in vivo in multiple preclinical animal models, as well as in patients with advanced cancers in a phase I clinical trial. To enhance the therapeutic efficacy of MDA-7 (IL-24), we engineered a designer cytokine (a “Superkine”; IL-24S; referred to as M7S) with enhanced secretion and increased stability to engender improved “bystander” antitumor effects. M7S was engineered in a two-step process by first replacing the endogenous secretory motif with an alternate secretory motif to boost secretion. Among four different signaling peptides, the insulin secretory motif significantly enhanced the secretion of MDA-7 (IL-24) protein and was chosen for M7S. The second modification engineered in M7S was designed to enhance the stability of MDA-7 (IL-24), which was accomplished by replacing lysine at position K122 with arginine. This engineered “M7S Superkine” with increased secretion and stability retained cancer specificity. Compared to parental MDA-7 (IL-24), M7S (IL-24S) was superior in promoting anti-tumor and bystander effects leading to improved outcomes in multiple cancer xenograft models. Additionally, combinatorial therapy using MDA-7 (IL-24) or M7S (IL-24S) with an immune checkpoint inhibitor, anti-PD-L1, dramatically reduced tumor progression in murine B16 melanoma cells. These results portend that M7S (IL-24S) promotes the re-emergence of an immunosuppressive tumor microenvironment, providing a solid rationale for prospective translational applications of this therapeutic designer cytokine.

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“…In an important first step, Cui and coworkers have recently discovered and characterized anti-MPL diabodies with differential effects on signaling output[ 101 ], which appear to separate the dual roles of MPL signaling; HSC self-renewal and megakaryocyte differentiation. As the development of highly specific synthetic cytokines gathers pace[ 102 ] it is tempting to speculate that additional modalities targeting the MPL ECD to alter signaling output could also be achieved.…”

Section: Perspectives and Concluding Remarksmentioning

confidence: 99%

The thrombopoietin receptor: revisiting the master regulator of platelet production

Hitchcock

Hafer

Sangkhae³

et al. 2021

Platelets

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Thrombopoietin (TPO) and its receptor, MPL, are the primary regulators of platelet production and critical for hematopoietic stem cell (HSC) maintenance. Since TPO was first cloned in 1994, the physiological and pathological roles of TPO and MPL have been well characterized, culminating in the first MPL agonists being approved for the treatment of chronic immune thrombocytopenia in 2008. Dysregulation of the TPO-MPL signaling axis contributes to the pathogenesis of hematological disorders: decreased expression or function results in severe thrombocytopenia progressing to bone marrow failure, while hyperactivation of MPL signaling, either by mutations in the receptor or associated Janus kinase 2 (JAK2), results in pathological myeloproliferation. Despite its importance, it was only recently that the long-running debate over the mechanism by which TPO binding activates MPL has been resolved. This review will cover key aspects of TPO and MPL structure and function and their importance in receptor activation, discuss how these are altered in hematological disorders and consider how a greater understanding could lead to the development of better-targeted and more efficacious therapies.

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Engineering cytokines and cytokine circuits

Abstract: Learning to speak the secret language of immune cells could improve immunotherapies

Cited by 27 publications

References 15 publications

Scan and Unlock: A Programmable DNA Molecular Automaton for Cell‐Selective Activation of Ligand‐Based Signaling

Scan and Unlock: A Programmable DNA Molecular Automaton for Cell‐Selective Activation of Ligand‐Based Signaling

Enhanced Cancer Therapy Using an Engineered Designer Cytokine Alone and in Combination With an Immune Checkpoint Inhibitor

The thrombopoietin receptor: revisiting the master regulator of platelet production

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