IL-2/CD25: A Long-Acting Fusion Protein That Promotes Immune Tolerance by Selectively Targeting the IL-2 Receptor on Regulatory T Cells

Ward, Natasha C.; Yu, Aixin; Moro, Alejandro; Ban, Yuguang; Chen, Xi; Hsiung, Sunnie; Keegan, James; Arbanas, Jaren; Loubeau, Martine; Thankappan, Anil; Yamniuk, Aaron P.; Davis, Jonathan H.; Struthers, Mary; Malek, Thomas R.

doi:10.4049/jimmunol.1800907

Cited by 73 publications

(83 citation statements)

References 51 publications

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“…resents an immunotherapy to selectively expand Treg cells to promote tolerance in patients with autoimmunity, and analogous to RLI, this IL-2-IL-2Ra fusion protein had greater in vivo efficacy for Treg expansion and control of autoimmunity than recombinant IL-2 (Ward et al, 2018). Biochemical and functional studies support a model in which IL-2 interacts with CD25 in trans to form inactive headto-tail dimers that slowly dissociate into an active monomer.…”

Section: G C Family Cytokines and Translational Advancesmentioning

confidence: 88%

“…In vivo, the fusion protein is long-lived and selectively stimulates Treg cells. In female NOD mice, it increased Treg cells within the pancreas and reduced the instance of spontaneous diabetes, suggesting the potential for clinical development for use in autoimmunity or other disorders of an overactive immune response (Ward et al, 2018).…”

Section: G C Family Cytokines and Translational Advancesmentioning

confidence: 99%

“…Interestingly, however, RLI is relatively ineffective on exhausted T cells and accordingly is most effective when combined with anti-PDL1. Correspondingly to RLI, a single-chain IL-2/IL-2Ra agonist has also now been generated (Ward et al, 2018). Low-dose IL-2 rep- On the left are shown IL-2 superkine (H9), anti-IL-2 antibody complexed with IL-2 (S4B6-IL-2 or JES6-IL-2), and IL-15Ra-IL-15 complex (RLI or BiG) enhancing the action.…”

Section: G C Family Cytokines and Translational Advancesmentioning

confidence: 99%

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The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

2019

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The common cytokine receptor g chain, g c , is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding g c results in X-linked severe combined immunodeficiency in humans, and g c family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.

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Section: G C Family Cytokines and Translational Advancesmentioning

confidence: 88%

Section: G C Family Cytokines and Translational Advancesmentioning

confidence: 99%

Section: G C Family Cytokines and Translational Advancesmentioning

confidence: 99%

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The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

2019

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“…To circumvent these issues, one approach is the engineering of IL‐2 superagonists to improve durability and selectivity through increased affinity, prolonged half‐life and lower doses. One example is IL‐2/CD25 fusion proteins, where IL‐2 is bound to CD25 by a non‐cleavable linker to increase the persistence of IL‐2 and reduce binding to the intermediate‐affinity IL‐2R . Another investigated compound is IL‐2‐anti‐IL‐2 monoclonal antibody immune complexes (IL‐2IC) , where IL ‐ 2 is bound to the IL‐2IC antibody such that the CD25‐binding epitope is exposed and the CD122 (IL‐2Rβ)‐binding epitope is blocked (e.g.…”

Section: Treg Cell Dysfunction In Human Diseasementioning

confidence: 99%

Mechanisms of human FoxP3+ Treg cell development and function in health and disease

Attias

Al-Aubodah

Piccirillo

2019

Clinical and Experimental Immunology

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Summary Regulatory T (Treg) cells represent an essential component of peripheral tolerance. Given their potently immunosuppressive functions that is orchestrated by the lineage‐defining transcription factor forkhead box protein 3 (FoxP3), clinical modulation of these cells in autoimmunity and cancer is a promising therapeutic target. However, recent evidence in mice and humans indicates that Treg cells represent a phenotypically and functionally heterogeneic population. Indeed, both suppressive and non‐suppressive Treg cells exist in human blood that are otherwise indistinguishable from one another using classical Treg cell markers such as CD25 and FoxP3. Moreover, murine Treg cells display a degree of plasticity through which they acquire the trafficking pathways needed to home to tissues containing target effector T (Teff) cells. However, this plasticity can also result in Treg cell lineage instability and acquisition of proinflammatory Teff cell functions. Consequently, these dysfunctional CD4+FoxP3+ T cells in human and mouse may fail to maintain peripheral tolerance and instead support immunopathology. The mechanisms driving human Treg cell dysfunction are largely undefined, and obscured by the scarcity of reliable immunophenotypical markers and the disregard paid to Treg cell antigen‐specificity in functional assays. Here, we review the mechanisms controlling the stability of the FoxP3+ Treg cell lineage phenotype. Particular attention will be paid to the developmental and functional heterogeneity of human Treg cells, and how abrogating these mechanisms can lead to lineage instability and Treg cell dysfunction in diseases like immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, type 1 diabetes, rheumatoid arthritis and cancer.

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“…However, although injection of IL‐2 expands the circulating T reg cell population, it also expands effector cells such as natural killer (NK) cells or eosinophils—thus indicating the lack of T reg specificity . This has been overcome through the development of an IL‐2/anti‐IL‐2 complex that can specifically promote the binding of IL‐2 to the high‐affinity receptor of IL‐2 that is expressed by activated T reg cells and promote T reg cell expansion in vivo without modifying other effector cells .…”

Section: Targeting Foxp3+ Treg Cells For the Control Of Autoimmune Rementioning

confidence: 99%

The role of FOXP3+ regulatory T cells in human autoimmune and inflammatory diseases

Mohr

Atif

Balderas

et al. 2019

Clinical and Experimental Immunology

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CD4 + regulatory T cells (T reg ) expressing the forkhead box protein 3 (FOXP3)transcription factor (T regs ) are instrumental for the prevention of autoimmune diseases. There is increasing evidence that the human T regulatory population is highly heterogeneous in phenotype and function. Numerous studies conducted in human autoimmune diseases have shown that T reg cells are impaired either in their suppressive function, in number, or both. However, the contribution of the FOXP3 + T reg subpopulations to the development of autoimmunity has not been delineated in detail. Rare genetic disorders that involve deficits in T reg function can be studied to develop a global idea of the impact of partial or complete deficiency in a specific molecular mechanism involved in T reg function. In patients with reduced T reg numbers (but no functional deficiency), the expansion of autologous T reg cells could be a suitable therapeutic approach: either infusion of invitro autologous expanded cells, infusion of interleukin (IL)-2/anti-IL-2 complex, or both. T reg biology-based therapies may not be suitable in patients with deficits of T reg function, unless their deficit can be corrected in vivo/in vitro.Finally, it is critical to consider the appropriate stage of autoimmune diseases at which administration of T reg cellular therapy can be most effective. We discuss conflicting data regarding whether T reg cells are more effectual at preventing the initiation of autoimmunity, ameliorating disease progression or curing autoimmunity itself.

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IL-2/CD25: A Long-Acting Fusion Protein That Promotes Immune Tolerance by Selectively Targeting the IL-2 Receptor on Regulatory T Cells

Cited by 73 publications

References 51 publications

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

Mechanisms of human FoxP3+ Treg cell development and function in health and disease

The role of FOXP3+ regulatory T cells in human autoimmune and inflammatory diseases

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