Selective expansion of regulatory T cells by NKTR-358 in healthy volunteers and patients with systemic lupus erythematosus

Fanton, Christie; Furie, Richard; Chindalore, Vishala; Levin, Robert D.; Diab, Isam; Dixit, Neha; Haglund, Cat; Gibbons, Jacqueline A.; Hanan, Nathan; Dickerson, Daniel; Zalevsky, Jonathan; Kotzin, Brian L.

doi:10.1016/j.jtauto.2022.100152

Cited by 26 publications

(11 citation statements)

References 44 publications

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“…Meanwhile, several pharmaceutical companies have started to develop modified forms of IL-2, or so-called IL-2 muteins, which exhibit an extended half-life or a higher relative affinity for the trimeric IL-2R than for the dimeric IL-2R compared with native IL-2 promoting a higher selectivity for targeting the CD25 hi Treg population. The IL-2 mutein NKTR-358, a conjugate of polyethylene glycol (PEG) and native IL-2 with an extended half-life between 7 and 13 days and reduced affinity for the dimeric IL-2R, was tested recently within a randomized, placebo-controlled phase 1 study in 76 healthy volunteers and 36 SLE patients with mild-to-moderate disease activity using single or multiple ascending doses [46 ▪ ]. The primary objectives of this first-in-men study were safety and tolerability, secondary and exploratory objectives included pharmacokinetics, immunological responses, and clinical effects.…”

Section: Clinical Translation Of Low-dose Il-2 Therapy In Systemic Lu...mentioning

confidence: 99%

Low-dose interleukin-2 therapy: a promising targeted therapeutic approach for systemic lupus erythematosus

Akbarzadeh

Riemekasten

Humrich

2022

Current Opinion in Rheumatology

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Purpose of reviewLow-dose interleukin-2 (IL-2) therapy is increasingly recognized as a promising novel therapeutic concept in inflammatory and autoimmune diseases, in particular in systemic lupus erythematosus (SLE). As IL-2 is indispensable for the growth and survival of regulatory T cells (Treg), deficiency of this regulatory cytokine plays a significant role in immune dysregulation and breach of tolerance in SLE. Recovery of Treg activity by low-dose IL-2 therapy directly interferes with the immune pathology in SLE and thus can be considered a targeted treatment approach with a unique and physiological mode of action.Recent findingsIn this review, the pathophysiological rationales behind the concept of low-dose IL-2 therapy in SLE will be explained and major advances in translational research and the clinical development of low-dose IL-2 therapy focusing on the results from two recent, randomized and placebo-controlled phase 2 trials will be highlighted.SummarySeveral clinical studies including two recent randomized trials have proven the very good safety profile of low-dose IL-2 therapy and its capability to selectively recover and expand the Treg population in patients with active SLE. Given the emerging evidence for the clinical potential of low-dose IL-2 therapy in SLE, these studies strongly confirm the pathophysiological concept behind this targeted therapeutic approach in SLE and provide a robust basis for establishing further in-depth and confirmatory clinical trials testing the application of low-dose IL-2 in SLE and other autoimmune diseases.

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Section: Clinical Translation Of Low-dose Il-2 Therapy In Systemic Lu...mentioning

confidence: 99%

Low-dose interleukin-2 therapy: a promising targeted therapeutic approach for systemic lupus erythematosus

Akbarzadeh

Riemekasten

Humrich

2022

Current Opinion in Rheumatology

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“…Furthermore, given the feasibility to perform EICC from nasopharyngeal swabs and DBS, this approach lends itself to unsupervised home testing and possibly facilitate medical surveillance. The concept shown here may be transferred to other clinical applications, such as newborn screening for primary immunodeficiencies using DBS ( 31 ) or determination of immune cell infiltration in solid tumor tissues ( 32 ), where flow cytometry in particular is not suitable or reaches its limits, as well as to situations where patients suffer from chronic inflammatory pathologies like rheumatoid arthritis or systemic lupus erythematosus ( 33 , 34 ).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic immune monitoring for COVID-19 disease course prognosis

Samans

Chornet²,

Chornet³

et al. 2023

Front. Immunol.

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BackgroundThe course of COVID-19 is associated with severe dysbalance of the immune system, causing both leukocytosis and lymphopenia. Immune cell monitoring may be a powerful tool to prognosticate disease outcome. However, SARS-CoV-2 positive subjects are isolated upon initial diagnosis, thus barring standard immune monitoring using fresh blood. This dilemma may be solved by epigenetic immune cell counting.MethodsIn this study, we used epigenetic immune cell counting by qPCR as an alternative way of quantitative immune monitoring for venous blood, capillary blood dried on filter paper (dried blood spots, DBS) and nasopharyngeal swabs, potentially allowing a home-based monitoring approach.ResultsEpigenetic immune cell counting in venous blood showed equivalence with dried blood spots and with flow cytometrically determined cell counts of venous blood in healthy subjects. In venous blood, we detected relative lymphopenia, neutrophilia, and a decreased lymphocyte-to-neutrophil ratio for COVID-19 patients (n =103) when compared with healthy donors (n = 113). Along with reported sex-related differences in survival we observed dramatically lower regulatory T cell counts in male patients. In nasopharyngeal swabs, T and B cell counts were significantly lower in patients compared to healthy subjects, mirroring the lymphopenia in blood. Naïve B cell frequency was lower in severely ill patients than in patients with milder stages.ConclusionsOverall, the analysis of immune cell counts is a strong predictor of clinical disease course and the use of epigenetic immune cell counting by qPCR may provide a tool that can be used even for home-isolated patients.

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“…With the preclinical DTH results encouraging translation to human studies, we evaluated the effects of REZPEG in patients diagnosed with chronic plaque PsO in a multi-center, double-blind, placebo-controlled phase 1 randomized clinical trial. Previous phase 1 studies of REZPEG in healthy adult volunteers had demonstrated a dose range that is safe and selectively induces Tregs versus Tcons 29 . Accordingly, SC doses of 10 mg/kg and 24 mg/kg were selected for this study in PsO patients.…”

Section: Resultsmentioning

confidence: 99%

“…Cohort 2 enrollment was started in June 2020 with a dose of 24 mg/kg every two weeks, and after review of the data, it was decided that enrollment in Cohort 1 would not resume, limiting analyses due to fewer placebo patients enrolled than originally planned. These dosages are supported by phase 1 studies (single ascending dose; NCT04133116, and multiple ascending dose; NCT03556007) in healthy volunteers and patients with SLE 29 . REZPEG or placebo was administered SC every 2 weeks through 12 weeks for a total of 7 doses per patient.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of the regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in the treatment of inflammatory skin diseases including atopic dermatitis

Zalevsky,

Silverberg,

Rosmarin

et al. 2024

Preprint

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Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases but relatively little is known about the therapeutic potential of Treg restoration. Here we present the first clinical evidence for the Treg-selective interleukin-2 (IL-2) receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with atopic dermatitis (AD) or psoriasis. REZPEG was safe and well-tolerated, demonstrating consistent pharmacokinetics and clinical efficacy, meeting the primary, secondary and exploratory objectives in both trials. AD patients receiving the highest dose tested demonstrated an 83% improvement in Eczema Area and Severity Index (EASI) score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) responses were maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These clinical improvements were accompanied by sustained increases in CD25bright Tregs and induction of multiple immunoregulatory mechanisms. REZPEG presents a novel homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control. ClinicalTrials.gov identifiers: NCT04081350 and NCT04119557.

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Selective expansion of regulatory T cells by NKTR-358 in healthy volunteers and patients with systemic lupus erythematosus

Cited by 26 publications

References 44 publications

Low-dose interleukin-2 therapy: a promising targeted therapeutic approach for systemic lupus erythematosus

Low-dose interleukin-2 therapy: a promising targeted therapeutic approach for systemic lupus erythematosus

Epigenetic immune monitoring for COVID-19 disease course prognosis

Efficacy and safety of the regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in the treatment of inflammatory skin diseases including atopic dermatitis

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