Modified toxins
The present application relates to compositions of modified toxins exhibiting cytotoxicity and/or reduced immunogenicity. Also provided are polypeptide toxophores from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope. Another aspect relates to a fusion protein which comprises a modified diphtheria toxin and a non-diphtheria toxin fragment that is a cell binding portion. Another aspect relates to the use of a modified diphtheria toxin for the treatment of a malignant disease or a non-malignant disease. A modified diphtheria toxin or fusion protein may be administered with one or more other agents.
1. A modified diphtheria toxin that comprises an amino acid sequence set forth as SEQ ID NO: 513.
2. The modified diphtheria toxin of claim 1 , that further comprises at least one cell binding ligand from a non-diphtheria toxin polypeptide.
3. The modified diphtheria toxin of claim 2 , wherein the at least one cell-binding ligand is an antibody or antigen-binding fragment thereof, a cytokine, a polypeptide, a hormone, a growth factor, or insulin.
4. The modified diphtheria toxin of claim 3 , wherein the at least one cell-binding ligand is a cytokine, and the cytokine is IL-2 or IL-3.
5. The modified diphtheria toxin of claim 3 , wherein the at least one cell-binding ligand is an antibody that is monoclonal, polyclonal, humanized, genetically engineered or grafted.
6. The modified diphtheria toxin of claim 3 , wherein the at least one cell-binding ligand is an antigen-binding fragment of an antibody that is a Fab, a Fab 2 , a F(ab′) 2 , a ScFv, a (ScFv) 2 , a single chain binding polypeptide, a V H or a V L .
7. A pharmaceutical composition that comprises the modified diphtheria toxin of claim 1 and a pharmaceutically acceptable excipient or carrier.
8. A pharmaceutical composition that comprises the modified diphtheria toxin of claim 2 and a pharmaceutically acceptable excipient or carrier.