ArticleImmunology2011
Development of an attenuated interleukin-2 fusion protein that can be activated by tumour-expressed proteases.
Article in Immunology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
35 citing papers in PubMed, 53 citations in OpenAlex.
- Protein engineering to overcome limitations of key cytokines in cancer immunotherapy: current approaches and future perspectives.Immuno-oncology technology · 2025Review
- Orthogonalized human protease control of secreted signals.Nature chemical biology · 2025Article
- Redirecting immune signaling with cytokine adaptors.Nature communications · 2025Article
- Cytokines in cancer.Cancer cell · 2025Review
- Orthogonalized human protease control of secreted signals.bioRxiv : the preprint server for biology · 2024Article
- Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview.Pharmaceutics · 2024Review
- BRAIDing receptors for cell-specific targeting.eLife · 2024Article
- Pharmacokinetics, pharmacodynamics, and toxicity of a PD-1-targeted IL-15 in cynomolgus monkeys.PloS one · 2024Article
- Innate Immunity in Cancer Biology and Therapy.International journal of molecular sciences · 2023Review
- A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy.Nature biotechnology · 2023Article
- Strategies for Conditional Regulation of Proteins.JACS Au · 2023Review
- A Protease Activatable Interleukin-2 Fusion Protein Engenders Antitumor Immune Responses by Interferon Gamma-Dependent and Interferon Gamma-Independent Mechanisms.Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research · 2022Article
- Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker.Nature biomedical engineering · 2022Article
- Exploiting protease activation for therapy.Drug discovery today · 2022Review
- Massively parallel, computationally guided design of a proenzyme.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- A tumor-specific pro-IL-12 activates preexisting cytotoxic T cells to control established tumors.Science immunology · 2022Article
- Role of Serine Proteases at the Tumor-Stroma Interface.Frontiers in immunology · 2022Review
- Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity.Cell research · 2021Article
- A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy.Nature communications · 2021Article
- Next-generation cytokines for cancer immunotherapy.Antibody therapeutics · 2021Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The ability to alter the cytokine microenvironment has the potential to shape immune responses in many physiological settings, including the immunotherapy of tumours. We set out to develop a general approach in which cytokines could be functionally attenuated until activated. We report the development and initial characterization of fusion proteins in which human or mouse interleukin-2 (IL-2), a potent growth factor for immune cells, is joined to a specific IL-2 inhibitory binding component separated by a protease site. The rationale is that upon cleavage by a protease the cytokine is free to dissociate from the inhibitory component and becomes biologically more available. We describe the successful development of two attenuation strategies using specific binding: the first uses the mouse IL-2 receptor alpha chain as the inhibitory binding component whereas the second employs a human antibody fragment (scFv) reactive with human IL-2. We demonstrated that the fusion proteins containing a prostate-specific antigen or a matrix metalloproteinase (MMP) protease cleavage site are markedly attenuated in the intact fusion protein but had enhanced bioactivity of IL-2 in vitro when cleaved. Further, we showed that a fusion protein composed of the IL-2/IL-2 receptor alpha chain with an MMP cleavage site reduced tumour growth in vivo in a peritoneal mouse tumour model. This general strategy should be applicable to other proteases and immune modulators allowing site-specific activation of immunomodulators while reducing unwanted side-effects.
Indexed as
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What OpenQuestion holds
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.