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

Lisa Mullen, Anne Rigby, Michelle Sclanders, Gill Adams, Gayatri Mittal, Julia Colston, Rewas Fatah, Cristina Subang, Julie Foster, Philippa Francis-West, Mario Koester, Hansjoerg Hauser, Lorna Layward, Sandrine Vessillier, Alex Annenkov, Sarah Al-Izki, Gareth Pryce, Chris Bolton, David Baker, David J. GouldYuti Chernajovsky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


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-beta 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-beta, 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-beta 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.

Original languageEnglish
Pages (from-to)5-16
Number of pages12
JournalExpert Opinion On Drug Delivery
Issue number1
Publication statusPublished - Jan 2014


  • bioassay
  • cytokines
  • latency-associated peptide
  • protein design
  • targeted delivery


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