Latency can be conferred to a variety of cytokines by fusion with latency-associated peptide from TGF-β

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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 and Chernajovsky, Yuti (2014) Latency can be conferred to a variety of cytokines by fusion with latency-associated peptide from TGF-β. Expert Opinion on Drug Delivery, 11 (1). pp. 5-16. ISSN 1742-5247

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Abstract

OBJECTIVES:

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.
METHODS:

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.
RESULTS:

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.
CONCLUSIONS:

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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: R Medicine
Depositing User: Gemma Hamilton
Date Deposited: 16 Nov 2018 14:27
Last Modified: 16 Nov 2018 14:27
URI: http://sro.sussex.ac.uk/id/eprint/80267

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