Engineering a Single-Agent Cytokine/Antibody Fusion That Selectively Expands Regulatory T Cells for Autoimmune Disease Therapy

Spangler, Jamie B.; Trotta, Eleonora; Tomala, Jakub; Peck, Ariana; Young, Tracy A.; Savvides, Christina S; Silveria, Stephanie L.; Votavová, Petra; Salafsky, Joshua; Pande, Vijay S.; Kovář, Marek; Bluestone, Jeffrey A.; García, K. Christopher

doi:10.4049/jimmunol.1800578

Cited by 62 publications

(48 citation statements)

References 66 publications

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“…Additional efforts have focused on novel forms of IL2 with superior pharmacokinetics and Treg selectivity. These include a long-lived bivalent IgG-human IL2 fusion protein with N88D mutation that reduces IL2Rβ binding (Peterson et al, 2018), a polyethylene glycol (PEG)-modified murine IL2 that increases IL2 retention in the body by protection from enzymatic digestion and renal clearance (Wu et al, 2016), and a murine IL2/anti-IL2 antibody (JES6-1) conjugate (Spangler et al, 2018). Despite the effort to develop various forms of IL2 with superior pharmacokinetics and selectivity for treatment of autoimmune and inflammatory diseases, it is not clear how they affect heterogeneity of Tregs, given that Tregs exists in a variety of sub-states at different tissue sites, which are phenotypically and functionally heterogeneous.…”

Section: C4 and C8 Tregs Expand After Il-2m Stimulation Through C2 Inmentioning

confidence: 99%

Dynamic changes in the regulatory T-cell heterogeneity and function by murine IL-2 mutein

Driver

et al. 2020

Life Sci. Alliance

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The therapeutic expansion of Foxp3+ regulatory T cells (Tregs) shows promise for treating autoimmune and inflammatory disorders. Yet, how this treatment affects the heterogeneity and function of Tregs is not clear. Using single-cell RNA-seq analysis, we characterized 31,908 Tregs from the mice treated with a half-life extended mutant form of murine IL-2 (IL-2 mutein, IL-2M) that preferentially expanded Tregs, or mouse IgG Fc as a control. Cell clustering analysis revealed that IL-2M specifically expands multiple sub-states of Tregs with distinct expression profiles. TCR profiling with single-cell analysis uncovered Treg migration across tissues and transcriptional changes between clonally related Tregs after IL-2M treatment. Finally, we identified IL-2M–expanded Tnfrsf9+Il1rl1+ Tregs with superior suppressive function, highlighting the potential of IL-2M to expand highly suppressive Foxp3+ Tregs.

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Section: C4 and C8 Tregs Expand After Il-2m Stimulation Through C2 Inmentioning

confidence: 99%

Dynamic changes in the regulatory T-cell heterogeneity and function by murine IL-2 mutein

Driver

et al. 2020

Life Sci. Alliance

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“…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. clone JES6‐1), preferentially inducing the expansion of T reg cells over T conv cells.…”

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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“…The anti-IL-2 mAb JES6 prolonged the half-life of IL-2 (30), while also blocking the interaction of IL-2 with IL-2Rβ, leading to increased Treg proliferation since binding to the high-affinity IL-2Rαβγ c was preserved (29). However, until now, clinical adoption of antibody/cytokine complexes has been limited by difficulties in manufacturing them and maintaining their stability (31).…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

Engineering IL-2 to Give New Life to T Cell Immunotherapy

2021

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Interleukin-2 (IL-2) is integral to immune system regulation. Its opposing immunostimulatory and immunosuppressive actions make it an attractive therapeutic target for cancer and autoimmune diseases. A challenge in developing IL-2-directed anticancer therapies has been how to stimulate effector T cells (Teffs) without inducing regulatory T cells (Tregs) in the tumor microenvironment; conversely, IL-2 therapy for autoimmune diseases requires Treg induction without further stimulation of Teffs. High-dose IL-2 is approved for melanoma and renal cell carcinoma, but its therapeutic value is limited by a need for frequent dosing at specialist centers, its short half-life, severe toxicity, and a lack of efficacy in most patients. Re-engineered IL-2 therapeutics are designed to have longer in vivo half-lives, target specific IL-2 receptor conformations to stimulate specific T cell subsets, or localize to target tissues to optimize efficacy and reduce toxicity. We discuss recent studies that elucidate the potential of newly engineered IL-2-based therapeutics for cancer and autoimmune diseases. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Engineering a Single-Agent Cytokine/Antibody Fusion That Selectively Expands Regulatory T Cells for Autoimmune Disease Therapy

Cited by 62 publications

References 66 publications

Dynamic changes in the regulatory T-cell heterogeneity and function by murine IL-2 mutein

Dynamic changes in the regulatory T-cell heterogeneity and function by murine IL-2 mutein

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

Engineering IL-2 to Give New Life to T Cell Immunotherapy

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