ArticleCancer immunology research2022
Discovery of a Conditionally Activated IL-2 that Promotes Antitumor Immunity and Induces Tumor Regression.
Article in Cancer immunology research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 2 of them syntheses that pooled it.
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40 citing papers in PubMed, 2 syntheses or guidelines pooled it, 56 citations in OpenAlex.
- A systematic review of interleukin-2-based immunotherapies in clinical trials for cancer and autoimmune diseases.EBioMedicine · 2023Pooled it
- Engineering cytokines for cancer immunotherapy: a systematic review.Frontiers in immunology · 2023Pooled it
- 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
- De novo design of protease-activatable cytokine prodrugs.bioRxiv : the preprint server for biology · 2026Article
- CD25 genetic ablation on lymphoid cell lines to obtain models of stimulation through the Interleukin-2 beta/gamma receptor.Scientific reports · 2026Article
- Bi-functional anti-LAG-3-IL-2c enhances immune checkpoint inhibitor and CAR T-cell therapy for cancer.iScience · 2026Article
- A modular platform for Sterically Masked Activated Cytokines (SMACks).Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- DF6215, an α-optimized IL-2-Fc fusion, expands immune effectors and drives robust preclinical anti-tumor activity.Cell reports. Medicine · 2026Article
- Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy.Oncoimmunology · 2025Review
- TIM3-blockade synergizes with IL2 in alleviating intra-tumoral CD8Nature communications · 2025Article
- Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion protein.Journal for immunotherapy of cancer · 2025Article
- Conditional Activation of Protein Therapeutics by Templated Removal of Peptide Nucleic Acid Masking Groups.Angewandte Chemie (International ed. in English) · 2025Article
- Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies.Journal for immunotherapy of cancer · 2025Article
- The Multifaceted Role of the IL-2 Cytokine Family in Melanoma: Mechanisms, Therapeutic Implications, and Immune Modulation.Journal of immunology research · 2025Review
- Immunocytokines in cancer immunotherapy: opportunities and challenges.Frontiers in oncology · 2025Review
- Cytokine Couture: Designer IL2 Molecules for the Treatment of Disease.ImmunoTargets and therapy · 2025Review
- Canine Adipose-Derived Mesenchymal Stromal Cells Reduce Cell Viability and Migration of Metastatic Canine Oral Melanoma Cell Lines In Vitro.Veterinary sciences · 2024Article
- A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Advancements and challenges in immunocytokines: A new arsenal against cancer.Acta pharmaceutica Sinica. B · 2024Review
- Tumor-Localized Interleukin-2 and Interleukin-12 Combine with Radiation Therapy to Safely Potentiate Regression of Advanced Malignant Melanoma in Pet Dogs.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
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12 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
IL-2 is a cytokine clinically approved for the treatment of melanoma and renal cell carcinoma. Unfortunately, its clinical utility is hindered by serious side effects driven by the systemic activity of the cytokine. Here, we describe the design and characterization of a conditionally activated IL-2 prodrug, WTX-124, that takes advantage of the dysregulated protease milieu of tumors. WTX-124 was engineered as a single molecule containing an inactivation domain and a half-life extension domain that are tethered to a fully active IL-2 by protease-cleavable linkers. We show that the inactivation domain prevented IL-2 from binding to its receptors in nontumor tissues, thereby minimizing the toxicity associated with systemic exposure to IL-2. The half-life extension element improves the pharmacokinetic profile of WTX-124 over free IL-2, allowing for greater exposure. WTX-124 was preferentially activated in tumor tissue by tumor-associated proteases, releasing active IL-2 in the tumor microenvironment. In vitro assays confirmed that the activity of WTX-124 was dependent on proteolytic activation, and in vivo WTX-124 treatment resulted in complete rejection of established tumors in a cleavage-dependent manner. Mechanistically, WTX-124 treatment triggered the activation of T cells and natural killer (NK) cells, and markedly shifted the immune activation profile of the tumor microenvironment, resulting in significant inhibition of tumor growth in syngeneic tumor models. Collectively, these data demonstrate that WTX-124 minimizes the toxicity of IL-2 treatment in the periphery while retaining the full pharmacology of IL-2 in the tumor microenvironment, supporting its further development as a cancer immunotherapy treatment. See related Spotlight by Silva, p. 544.
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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.