Methods for treating cancer using an immunotoxin

Abstract

The present invention relates to methods for preventing or treating head and neck squamous cell cancer and bladder cancer using an immunotoxin comprising (a) a ligand that binds to a protein on the cancer cell attached to; (b) a toxin that is cytotoxic to the cancer cell. In a specific embodiment, the invention is directed to the prevention or treatment of head and neck squamous cell cancer or bladder cancer using VB4-845, which is a recombinant immunotoxin comprising a humanized, MOC31-derived, single-chain antibody fragment that is fused to a truncated form of Pseudomonas exotoxin A. Also encompassed by the invention are combination therapy methods, including the use of reduced dosages of chemotherapeutic agents, for the prevention or treatment of cancer. Also encompassed by the invention are formulations and methods for direct administration of the recombinant immunotoxin to the carcinoma, for the prevention or treatment of cancer.

1 . A method of treating or preventing head and neck squamous cell carcinoma or bladder cancer comprising administering an effective amount of an immunotoxin to an animal in need thereof, wherein said immunotoxin comprises: 
 (a) a ligand that binds to a protein on the cancer cell attached to;    (b) a toxin that is cytotoxic to the cancer cell.    
     
     
         2 . The method according to  claim 1  wherein the ligand binds to Ep-CAM on the cancer cell.  
     
     
         3 . The method according to  claim 1  wherein the ligand is an antibody or an antibody fragment.  
     
     
         4 . The method according to  claim 3  wherein the antibody or antibody fragment is murine, human or a chimeric antibody or antibody fragment.  
     
     
         5 . The method according to  claim 1  wherein the ligand is a humanized antibody or antibody fragment.  
     
     
         6 . The method according to  claim 5  wherein the humanized antibody or antibody fragment binds to an extracellular domain of human Ep-CAM and comprises complementarity determining region (CDR) sequences derived from a MOC-31 antibody.  
     
     
         7 . The method according to  claim 6  wherein the CDR sequences are shown in SEQ ID NOS: 4-9.  
     
     
         8 . The method according to  claim 3  wherein the antibody fragment is a Fab, Fab 1 , (Fab′) 2 , scFv or dsFv fragment.  
     
     
         9 . The method according to  claim 5  wherein the antibody or antibody fragment is derived from 4D5MOC-A.  
     
     
         10 . The method according to  claim 5  wherein the antibody or antibody fragment is derived from 4D5MOC-B.  
     
     
         11 . The method according to  claim 8  wherein the antibody fragment is a scFv fragment.  
     
     
         12 . The method according to  claim 3  wherein the antibody fragment has the sequence shown in SEQ ID NO: 3 or a variant thereof.  
     
     
         13 . The method according to  claim 3  wherein the antibody or fragment binds to human Ep-CAM with a dissociation constant (K D ) of less than 2.0×10 −8 .  
     
     
         14 . The method according to  claim 1  wherein the immunotoxin is VB4-845 or a variant thereof.  
     
     
         15 . The method according to  claim 1  wherein the immunotoxin is VB4-845.  
     
     
         16 . The method according to  claim 15  wherein the immunotoxin has the sequence shown in SEQ ID NO: 2.  
     
     
         17 . The method according to  claim 1  additionally comprising the administration of one or more further cancer therapeutics for simultaneous, separate or sequential treatment or prevention of head and neck squamous cell carcinoma or bladder cancer.  
     
     
         18 . The method according to  claim 1  wherein the immunotoxin is administered directly to the cancer site.  
     
     
         19 . The method according to  claim 18  wherein the direct administration is intratumoural, intravesicular or peritumoral.  
     
     
         20 . The method according to  claim 1  wherein the immunotoxin is administered at a dose from about 10 to about 3000 μg immunotoxin/tumor/day.  
     
     
         21 . The method according to  claim 1  wherein the immunotoxin is administered at a dose from about 20 to about 1240 μg immunotoxin/tumor/day for the treatment of HNSCC.  
     
     
         22 . The method according to  claim 20  wherein the immunotoxin is administered for a cycle consisting of a daily dose for 1 to 7 days.  
     
     
         23 . The method according to  claim 22  wherein the immunotoxin is administered for 1-6 cycles.  
     
     
         24 . The method according to  claim 1  wherein the immunotoxin is administered at a dose from about 100 to about 2000 μg immunotoxin/week for the treatment of bladder cancer.  
     
     
         25 . The method according to  claim 24  wherein the immunotoxin medicament is administered for a cycle consisting of one dose per week.  
     
     
         26 . The method according to  claim 25  wherein the immunotoxin is administered for 1-6 cycles.  
     
     
         27 . The method according to  claim 1  wherein the toxin is a ribosome-inactivating polypeptide.  
     
     
         28 . The method according to  claim 27  wherein the toxin is selected from the group consisting of gelonin, bouganin, saporin, ricin, ricin A chain, bryodin, diphtheria and restrictocin.  
     
     
         29 . The method according to  claim 27  wherein the toxin is  Pseudomonas  exotoxin A or a variant thereof.  
     
     
         30 . A kit for treating or preventing head and neck squamous cell carcinoma or bladder cancer comprising an effective amount of an immunotoxin comprising (a) a molecule that binds to a protein on the cancer cell attached to; (b) a toxin that is cytotoxic to the cancer cell and directions for the use thereof to treat the cancer.  
     
     
         31 .- 44 . (canceled)  
     
     
         45 . A kit for diagnosing head and neck squamous cell carcinoma or bladder cancer comprising a ligand that binds to a protein on the cancer cell and instructions for the use thereof to diagnose the cancer.  
     
     
         46 .- 56 . (canceled)  
     
     
         57 . A method for treating or preventing head and neck squamous cell carcinoma or bladder cancer comprising: 
 (1) testing a tumor sample from a patient for the expression of a protein suspected of being associated with the head and neck squamous cell carcinoma or bladder cancer; and    (2) if the protein is expressed at greater levels in the tumor sample as compared to a control, administering to the patient an effective amount of immunotoxin comprising: 
 (a) a ligand that binds to the protein on the cancer cell attached to;  
 (b) a toxin that is cytotoxic to the cancer cell.