Latency can be conferred to a variety of cytokines by fusion with latency-associated peptide from TGF-β. (January 2014)

• Record Type: Journal Article
• Authors: Mullen, Lisa; Rigby, Anne; Sclanders, Michelle; Adams, Gill; Mittal, Gayatri; Colston, Julia; Fatah, Rewas; Subang, Cristina; Foster, Julie; Francis-West, Philippa; Köster, Mario; Hauser, Hansjörg; Layward, Lorna; Vessillier, Sandrine; Annenkov, Alex; Al-Izki, Sarah; Pryce, Gareth; Bolton, Chris; Baker, David; Gould, David J; Chernajovsky, Yuti
• Is Part Of: Expert opinion on drug delivery. Volume 11:Number 1(2014:Jan.)
• Page Start: 5
• Page End: 16
• Publication Date: 2014-01
• Subjects: Drug delivery devices -- Periodicals; Drug delivery systems -- Periodicals; 615.605
• DOI: 10.1517/17425247.2013.839655
• Languages: English
• ISSNs: 1742-5247

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p> <bold> <italic>Objectives: </italic> </bold>Targeting cytokines to sites of disease has clear advantages because it increases their therapeutic index. We designed fusion proteins of the latent-associated peptide (LAP) derived from TGF-β with various cytokines via a matrix metalloproteinase (MMP) cleavage site. This design confers latency, increased half-life and targeting to sites of inflammation. The aim of this study is to determine whether this approach can be applied to cytokines of different molecular structures and sizes.</p> <p> <bold> <italic>Methods: </italic> </bold>Mature cytokines cloned downstream of LAP and a MMP cleavage site were expressed in 293T cells and assessed for latency and biological activity by Western blotting and bioassay.</p> <p> <bold> <italic>Results: </italic> </bold>We demonstrate here that fusion proteins of TGF-β, erythropoietin, IL-1ra, IL-10, IL-4, BMP-7, IGF1 and IL-17 were rendered latent by fusion to LAP, requiring cleavage to become active in respective bioassays. As further proof of principle, we also show that delivery of engineered TGF-β can inhibit experimental autoimmune encephalomyelitis and that this approach can be used to efficiently deliver cytokines to the brain and spinal cord in mice with this disease.</p> <p> <bold> <italic>Conclusions:</italic> </bold> The latent cytokine approach can be successfully applied to a range of molecules, including cytokines of different molecular structure and mass, growth factors and a cytokine antagonist.</p> </abstract>