Latent fusion protein
The present invention provides a method for providing latency to a pharmaceutically active agent. The method has application in overcoming the toxic effect of systemic administration of potent biological agents. The method comprises associating a fusion protein comprising a latency associated peptide and a proteolytic cleavage site with a pharmaceutically active agent. The fusion protein also has application in providing site specific activation to a latent pharmaceutically active agent.
1. A heterologous fusion protein comprising (a) a biologically active protein, fused via (b) a proteolytic cleavage site to (c) a latency associated peptide (LAP) which comprises a precursor domain of TGFβ.
2. The heterologous fusion protein of claim 1 , wherein said biologically active protein comprises a growth factor, a differentiation factor, a cytokine, a chemokine, a trophic factor, a cytokine inhibitor, a cytokine receptor, a free-radical scavenging enzyme, a tissue inhibitor of a metalloproteinase, or an inhibitor of a serine protease.
3. The heterologous fusion protein of claim 1 , wherein said biologically active protein is an interferon.
4. The heterologous fusion protein of claim 1 , wherein said biologically active protein is an interleukin.
5. The heterologous fusion protein of claim 1 , wherein said LAP comprises the precursor domain TGFβ-1, 2, 3, 4 or 5.
6. The heterologous fusion protein of claim 1 , wherein said proteolytic cleavage site is a matrix metalloproteinase (MMP) cleavage site.
7. The heterologous fusion protein of claim 2 , wherein said proteolytic cleavage site is a matrix metalloproteinase (MMP) cleavage site.
8. A pharmaceutical composition comprising the heterologous fusion protein of claim 1 and a pharmaceutically acceptable carrier.
9. A method for the treatment of cancer in a mammal comprising administering to said mammal the heterologous fusion protein of claim 1 , wherein said heterologous fusion protein is suitable for cancer treatment.
10. The method of claim 9 , wherein said heterologous fusion protein is administered to said mammal by administration of a pharmaceutical composition comprising said heterologous fusion protein and a pharmaceutically acceptable carrier.