Blocking IL-2 Signal In Vivo with an IL-2 Antagonist Reduces Tumor Growth through the Control of Regulatory T Cells

Carmenate, Tania; Ortíz, Yaquelín; Enamorado, Michel; García-Martínez, Karina; Avellanet, Janet; Moreno, Ernesto; Graça, Luís; León, Kalet

doi:10.4049/jimmunol.1700433

Cited by 42 publications

(29 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…K35E -the mutation most frequently selected during panning- was chosen for further experiments. Display levels of a variety of IL-2-derived muteins already described 10,11,14,32 containing K35E were also increased by 6-30-fold. K35E not only improved the levels, but also increased the antigenicity (measured with several anti-IL-2 mAbs) and receptor binding ability (to human and mouse CD25) to different extents (Fig.…”

Section: Resultsmentioning

confidence: 61%

“…A “superkine” with increased affinity for CD122 -the beta receptor subunit constitutively expressed in NK and T cells- also has an enhanced effector potential 11 . A variety of IL-2-based antagonists have been generated by disrupting its signalling ability 12–14 . IL-2 engineering does not only target receptor interactions, as fusion to antibody variable and/or Fc domains also modulates its pharmacological properties through changes in bio distribution and plasma half-life, and acquisition of effector functions 15–19 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Directed evolution of super-secreted variants from phage-displayed human Interleukin-2

Rojas

Carmenate

Santo-Tomás

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

Selection from a phage display library derived from human Interleukin-2 (IL-2) yielded mutated variants with greatly enhanced display levels of the functional cytokine on filamentous phages. Introduction of a single amino acid replacement selected that way (K35E) increased the secretion levels of IL-2-containing fusion proteins from human transfected host cells up to 20-fold. Super-secreted (K35E) IL-2/Fc is biologically active in vitro and in vivo, has anti-tumor activity and exhibits a remarkable reduction in its aggregation propensity- the major manufacturability issue limiting IL-2 usefulness up to now. Improvement of secretion was also shown for a panel of IL-2-engineered variants with altered receptor binding properties, including a selective agonist and a super agonist that kept their unique properties. Our findings will improve developability of the growing family of IL-2-derived immunotherapeutic agents and could have a broader impact on the engineering of structurally related four-alpha-helix bundle cytokines.

show abstract

Section: Resultsmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Directed evolution of super-secreted variants from phage-displayed human Interleukin-2

Rojas

Carmenate

Santo-Tomás

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…③Tregs affect effector cell function by interfering with cell metabolism mainly in the following three ways: (1) Deprivation of IL-2 in the TME, and the proliferation of Tregs and effector T cells require the maintenance of IL-2 levels. Tregs compete with effector T cells and consume a large amount of IL-2, resulting in the deficiency of IL-2 in the TME, thus inhibiting the growth of effector T cells [ 26 , 50 ]. (2) CD39 and CD73 are nucleases constitutionally expressed in human and mouse Tregs.…”

Section: Classifications and Functions Of Tregsmentioning

confidence: 99%

“…Although IL-2 is important for effector T cell function, it has been hypothesized that therapies blocking IL-2 signals weaken Tregs activity, promoting immune responses using anti–IL-2 or anti–IL-2R Abs. Treatment with an IL-2 mutein reduces Tregs numbers and impairs tumour growth in mice [ 50 ]. Patients over 60 years old responded more efficiently to anti-PD-1, and the likelihood of generating a response to anti-PD-1 treatment increased with age.…”

Section: Tumour Immunotherapy Strategies Targeting Tregsmentioning

confidence: 99%

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

et al. 2020

View full text Add to dashboard Cite

Regulatory T cells (Tregs) characterized by the expression of the master transcription factor forkhead box protein p3 (Foxp3) suppress anticancer immunity, thereby hindering protective immunosurveillance of tumours and hampering effective antitumour immune responses in tumour-bearing hosts, constitute a current research hotspot in the field. However, Tregs are also essential for the maintenance of the immune tolerance of the body and share many molecular signalling pathways with conventional T cells, including cytotoxic T cells, the primary mediators of tumour immunity. Hence, the inability to specifically target and neutralize Tregs in the tumour microenvironment without globally compromising self-tolerance poses a significant challenge. Here, we review recent advances in characterizing tumour-infiltrating Tregs with a focus on the functional roles of costimulatory and inhibitory receptors in Tregs, evaluate their potential as clinical targets, and systematically summarize their roles in potential treatment strategies. Also, we propose modalities to integrate our increasing knowledge on Tregs phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Finally, we propose possible treatment strategies that can be used to develop Treg-targeted therapies.

show abstract

“…45,180,186 This has fostered increasing numbers of novel IL-2 constructs including fusokines, muteins and IL-2/receptor fusion proteins. 54,181,187,188 A recent study reported human IL-2 complexed to a human anti-IL2 mAb with in vivo enhancing activity. 189 The development of highly CD25 specific signaling reagents with increased persistence suggests in vivo delivery to selectively target Tregs versus Tconv may lead to more effective therapeutic application during disorders where effector cells are present.…”

Section: Future Perspectivesmentioning

confidence: 99%

The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

Copsel¹,

Wolf

Komanduri

et al. 2019

Haematologica

View full text Add to dashboard Cite

CD4 + FoxP3 + regulatory T cells (Tregs) are a non-redundant population critical for the maintenance of self-tolerance. Over the past decade, the use of these cells for therapeutic purposes in transplantation and autoimmune disease has emerged based on their capacity to inhibit immune activation. Basic science discoveries have led to identifying key receptors on Tregs that can regulate their proliferation and function. Notably, the understanding that IL-2 signaling is crucial for Treg homeostasis promoted the hypothesis that in vivo IL-2 treatment could provide a strategy to control the compartment. The use of low-dose IL-2 in vivo was shown to selectively expand Tregs versus other immune cells. Interestingly, a number of other Treg cell surface proteins, including CD28, CD45, IL-33R and TNFRSF members, have been identified which can also induce activation and proliferation of this population. Pre-clinical studies have exploited these observations to prevent and treat mice developing autoimmune diseases and graft- versus -host disease post-allogeneic hematopoietic stem cell transplantation. These findings support the development of translational strategies to expand Tregs in patients. Excitingly, the use of low-dose IL-2 for patients suffering from graft- versus -host disease and autoimmune disease has demonstrated increased Treg levels together with beneficial outcomes. To date, promising pre-clinical and clinical studies have directly targeted Tregs and clearly established the ability to increase their levels and augment their function in vivo . Here we review the evolving field of in vivo Treg manipulation and its application to allogeneic hematopoietic stem cell transplantation.

show abstract

Blocking IL-2 Signal In Vivo with an IL-2 Antagonist Reduces Tumor Growth through the Control of Regulatory T Cells

Cited by 42 publications

References 38 publications

Directed evolution of super-secreted variants from phage-displayed human Interleukin-2

Directed evolution of super-secreted variants from phage-displayed human Interleukin-2

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

Contact Info

Product

Resources

About

Blocking IL-2 Signal In Vivo with an IL-2 Antagonist Reduces Tumor Growth through the Control of Regulatory T Cells

Cited by 42 publications

References 38 publications

Directed evolution of super-secreted variants from phage-displayed human Interleukin-2

Directed evolution of super-secreted variants from phage-displayed human Interleukin-2

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

The promise of CD4+FoxP3+ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

Contact Info

Product

Resources

About

The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation