Modified proteins, designer toxins, and methods of making thereof
The present invention concerns methods of reducing the antigenicity of a proteinaceous compound while maintaining the compounds biological activity, as well as proteinaceous compositions with biological activity but reduced antigenicity. These methods and compositions have significant benefits to a subject in need of such compounds and compositions. Also included are modified toxin compounds that are truncated and/or possess reduce antigenicity. Such designer toxins have therapeutic, diagnostic, and preventative benefits, particularly as immunotoxins. Methods of treating cancer using these immunotoxins are provided.
1. An immunotoxin comprising a recombinant gelonin toxin and a ligand that specifically targets a receptor expressed on a target cell, wherein the recombinant gelonin toxin is modified relative to full-length, wild-type gelonin through the removal of one or more sequence regions that are antigenic in humans.
2. The immunotoxin of claim 1 , wherein the target cell is a cancer of the prostate, lung, brain, skin, liver, breast, lymphoid, stomach, testicular, ovarian, pancreatic, bone, bone marrow, head and neck, cervical, esophagus, eye, gall bladder, kidney, adrenal glands, heart, colon, or blood.
3. The immunotoxin of claim 2 , wherein the receptor is an antigen on the cancer cell.
4. The immunotoxin of claim 2 , wherein the cancer cell is a melanoma cell.
5. The immunotoxin of claim 1 , wherein the ligand is an antibody.
6. The immunotoxin of claim 5 , wherein the antibody is human or humanized.
7. The immunotoxin of claim 1 , wherein the antibody is a single chain antibody.
8. The immunotoxin of claim 1 , wherein the cell is in a patient.
9. The immunotoxin of claim 8 , wherein the immunotoxin is in a pharmaceutically acceptable composition.
10. The immunotoxin of claim 1 , wherein the ligand is a cytokine or growth factor.
11. The immunotoxin of claim 1 , wherein the ligand is a VEGF.
12. The immunotoxin of claim 1 , wherein the immunotoxin comprises an scFvMEL/rGel recombinant toxin fusion construct.
13. The immunotoxin of claim 1 , wherein the gelonin toxin is a humanized recombinant gelonin toxin.
14. The immunotoxin of claim 1 , wherein the immunotoxin comprises an amino acid region or regions that replaces one or more removed sequence regions that are antigenic in humans.
15. The immunotoxin of claim 14 , wherein the amino acid region or regions are identified in a protein database search for homologous regions.
16. The immunotoxin of claim 15 , wherein the database is a human protein database.