ArticleJournal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research2019
Development of an Interleukin-12 Fusion Protein That Is Activated by Cleavage with Matrix Metalloproteinase 9.
Article in Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 36 citations in OpenAlex.
- Targeting cytokine and chemokine signaling pathways for cancer therapy.Signal transduction and targeted therapy · 2024Review
- XTX301, a Tumor-Activated Interleukin-12 Has the Potential to Widen the Therapeutic Index of IL12 Treatment for Solid Tumors as Evidenced by Preclinical Studies.Molecular cancer therapeutics · 2024Article
- BRAIDing receptors for cell-specific targeting.eLife · 2024Article
- Intraperitoneal administration of a modified vaccinia virus Ankara confers single-chain interleukin-12 expression to the omentum and achieves immune-mediated efficacy against peritoneal carcinomatosis.Journal for immunotherapy of cancer · 2023Article
- A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy.Nature biotechnology · 2023Article
- Multicolor Light-Induced Immune Activation via Polymer Photocaged Cytokines.Biomacromolecules · 2023Article
- 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
- 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
- Exploiting protease activation for therapy.Drug discovery today · 2022Review
- Role of Serine Proteases at the Tumor-Stroma Interface.Frontiers in immunology · 2022Review
- Clinical translation of immunomodulatory therapeutics.Advanced drug delivery reviews · 2021Review
- Engineering Strategies for Immunomodulatory Cytokine Therapies - Challenges and Clinical Progress.Advanced therapeutics · 2021Article
- Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy.mAbsArticle
- Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Interleukin-12 (IL-12) is a pleiotropic cytokine that has profound effects on many aspects of cell-mediated responses and can enhance antitumor responses in experimental models. IL-12 has been tested clinically, however, side-effects have limited its use. We are developing an attenuated form of IL-12 whose biological activity could be restricted to sites of tumors by taking advantage of overexpressed tumor proteases that can activate the cytokine. We constructed a panel of fusion proteins (FPs) consisting of IL-12 joined to a specific inhibitor connected by a protease cleavage sequence (cs). We first identified a panel of single-chain Fragment variable (scFv) that bind to 3 independent epitopes on IL-12 and then incorporated them into separate IL-12 FPs containing either a matrix metalloproteinase (MMP) cs or a scrambled (scram) control cs. The intact IL-12 FPs showed attenuation in IL-12 activity compared to free IL-12 in 2 separate in vitro functional assays; proliferation of CTLL-2 and interferon-gamma (IFN-γ) induction by spleen cells. Furthermore, the FP containing the MMPcs showed an increase in biological activity of IL-12 in vitro when cleaved by MMP9. This FP strategy could be applied to other immunomodulators and potentially reduce unwanted side-effects observed with systemic delivery thus improving cytokine immunotherapy strategies.
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Registered trials
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