Format

Send to

Choose Destination
See comment in PubMed Commons below
Expert Opin Drug Deliv. 2014 Jan;11(1):5-16. doi: 10.1517/17425247.2013.839655. Epub 2013 Sep 27.

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

Author information

1
William Harvey Research Institute Barts and The London Medical School, Bone and Joint Research Unit , Charterhouse Square, London WC1M 6BQ , UK +44 207 882 2352; +44 207 882 6121; y.chernajovsky@qmul.ac.uk.

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.

PMID:
24073618
DOI:
10.1517/17425247.2013.839655
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Taylor & Francis
    Loading ...
    Support Center