ArticlePloS one2017
Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
83 citing papers in PubMed, 144 citations in OpenAlex.
- Pembrolizumab plus high-dose IL-2 in advanced clear cell renal cell carcinoma: six-year survival outcomes and molecular signatures from a phase 2 trial.Nature communications · 2026Trial
- PEGylated IL2 and tumor-targeted radiotherapy augment CD8Theranostics · 2026Trial
- Effective TIL Therapy for Patients with Checkpoint-Resistant Melanoma without Lymphodepleting Regimens Requires IFNα.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2023Trial
- TransCon IL-2 β/γ: a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer.Journal for immunotherapy of cancer · 2022Trial
- Bempegaldesleukin plus nivolumab in first-line renal cell carcinoma: results from the PIVOT-02 study.Journal for immunotherapy of cancer · 2022Trial
- Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2021Trial
- Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.Nature communications · 2020Trial
- Trial
- Cytokine fusion proteins for solid tumor therapy: mechanistic insights and clinical advances.Journal of hematology & oncology · 2026Review
- Messenger RNA delivery of a dual CD25/CD122 affinity-tuned IL-2 variant prolongs exposure and potentiates antitumor T cell immunity.Science advances · 2026Article
- Traceless linkers used for reversible protein-polymer conjugations.Chemical science · 2026Review
- Cytokine Engineering in CAR-T Cell Therapy: Next-Generation Strategies.Immune network · 2025Review
- Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy.Oncoimmunology · 2025Review
- Correlation of radiotherapy, targeted therapy, and immunotherapy with hepatocellular carcinoma recurrence.World journal of gastrointestinal oncology · 2025Review
- Recent Advances in Immunotherapy for Melanoma: Perspectives on the Development of Novel Treatments: A Mini Review.Cancers · 2025Review
- Present and future of cancer nano-immunotherapy: opportunities, obstacles and challenges.Molecular cancer · 2025Review
- Review
- SHR-1916: A Novel PEGylated Interleukin-2 Analogue with Altered Cellular Selectivity and Improved Pharmacokinetic Profiles for Cancer Immunotherapy.Drug design, development and therapy · 2025Article
- Cytokine Couture: Designer IL2 Molecules for the Treatment of Disease.ImmunoTargets and therapy · 2025Review
23 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.