title: Latent cytokines for targeted therapy of inflammatory disorders.
abstract: BACKGROUND
  The use of cytokines as therapeutic agents is important, given their potent biological effects. However, this very potency, coupled with the pleiotropic nature and short half-life of these molecules, has limited their therapeutic use. Strategies to increase the half-life and to decrease toxicity are necessary to allow effective treatment with these molecules.
  
  
  METHODS
  A number of strategies are used to overcome the natural limitations of cytokines, including PEGylation, encapsulation in liposomes, fusion to targeting peptides or antibodies and latent cytokines. Latent cytokines are engineered using the latency-associated peptide of transforming growth factor-β to produce therapeutic cytokines/peptides that are released only at the site of disease by cleavage with disease-induced matrix metalloproteinases. The principles underlying the latent cytokine technology are described and are compared to other methods of cytokine delivery. The potential of this technology for developing novel therapeutic strategies for the treatment of diseases with an inflammatory-mediated component is discussed.
  
  
  CONCLUSIONS
  Methods of therapeutic cytokine delivery are addressed. The latent cytokine technology holds significant advantages over other methods of drug delivery by providing simultaneously increased half-life and localised drug delivery without systemic effects. Cytokines that failed clinical trials should be reassessed using this delivery system.
authors.affiliation: Queen Mary University of London, William Harvey Research Institute, Bone and Joint Research Unit, Barts and The London Medical School , Charterhouse Square , London EC1M 6BQ, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Mullen
authors.forename: Gill
authors.initials: G
authors.lastname: Adams
authors.forename: Lorna
authors.initials: L
authors.lastname: Layward
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vessillier
authors.forename: Alex
authors.initials: A
authors.lastname: Annenkov
authors.forename: Gayatri
authors.initials: G
authors.lastname: Mittal
authors.forename: Anne
authors.initials: A
authors.lastname: Rigby
authors.forename: Michelle
authors.initials: M
authors.lastname: Sclanders
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: David
authors.initials: D
authors.lastname: Gould
authors.forename: Yuti
authors.initials: Y
authors.lastname: Chernajovsky
mesh_terms: D000818:Animals; D016207:Cytokines / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D011498:Protein Precursors / Q000008:administration & dosage* / Q000737:chemistry; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D016207:Cytokines; D010455:Peptides; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; C472416:latency-associated propeptide, TGF-beta