Activation of Recombinant Diphtheria Toxin Fusion Proteins by Specific Proteases Highly Expressed on the Surface of Tumor Cells
AssigneeThe Government of the United States of America, as rep. by the Secretary of Health and Human Service
InventorsStephen H. Leppla, Jennifer Avallone, Thomas Bugge, Shi-Hui Liu, Manuel Osorio
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Abstract
The present invention provides compositions and methods for inhibiting abnormal cell growth. In particular, the invention provides nucleic acids encoding Diphtheria toxin fusion proteins comprising residues 1-388 of Diphtheria toxin, wherein the native furin cleavage site has been substituted for a matrix metalloproteinase or plasminogen activator cleavage site, and a heterologous polypeptide and the polypeptides encoded by such nucleic acids. In addition, the invention provides methods of treating cancer by administering such polypeptides.
Claims49
A nucleic acid encoding a Diphtheria toxin fusion protein comprising
- (1) residues 1-388 of Diphtheria toxin, wherein the native furin cleavage site has been substituted for a cleavage site for a matrix metalloproteinase or a plasminogen activator;
- and
- (2) a heterologous polypeptide, wherein the heterologous polypeptide specifically binds to a protein overexpressed on the surface of a cell.
A nucleic acid encoding a Diphtheria toxin fusion protein comprising
- (1) residues 1-388 of Diphtheria toxin, wherein the native furin cleavage site has been substituted for a cleavage site for a urokinase a plasminogen activator;
- and
- (2) GM-CSF.
A method of treating cancer, the method comprising administering to a subject a Diphtheria toxin fusion protein comprising
- (1) residues 1-388 of Diphtheria toxin, wherein the native furin cleavage site has been substituted for a cleavage site for a matrix metalloproteinase or a plasminogen activator;
- and
- (2) a heterologous polypeptide, wherein the heterologous polypeptide specifically binds to a protein overexpressed on the surface of a cell.
A method of targeting a compound to a cell overexpressing a cytokine receptor or a growth factor receptor, the method comprising the steps of:
- administering to the cell Diphtheria toxin fusion protein comprising
- (1) residues 1-388 of Diphtheria toxin, wherein the native furin cleavage site has been substituted for a cleavage site for a matrix metalloproteinase or a plasminogen activator and wherein the Diphtheria toxin is cleaved by a matrix metalloproteinase or a plasminogen activator;
- and
- (2) a heterologous polypeptide, wherein the heterologous polypeptide specifically binds to a cytokine receptor or a growth factor receptor.
An isolated nucleic acid comprising the sequence set forth in any one of SEQ ID NOS:
- 2-18.
Dependencies are inferred from the claim text.