Use of lytic toxins and toxin conjugates

Abstract

Agents are provided which are capable of inhibiting the cell division cycle in a target cell of interest. The agents comprise first and second components, wherein the first component is a targeting moiety which is capable of directing the second component to the target cell of interest. The second component is capable of inhibiting the cell division cycle in the target cell of interest. The agents are preferably provided in the form of conjugates, and the second component is preferably a cytolethal distending toxin. Methods for the preparation of the agents, and the use thereof for treating proliferative cell disorders and intracellular pathogens are also provided.

1 . An agent comprising first and second components, the first component comprising a targeting moiety (TM) and the second component comprising a cytolethal distending toxin (CDT), wherein the TM binds the second component to a target cell. 
     
     
         2 . An agent according to  claim 1 , wherein the CDT inhibits the cell division cycle in the target cell of interest. 
     
     
         3 . An agent according to  claim 1 , wherein the CDT blocks mitosis in the target cell of interest. 
     
     
         4 . An agent according to  claim 1 , wherein the CDT causes death to the target cell by a lytic mechanism. 
     
     
         5 . An agent according to  claim 1 , wherein the first and second components are coupled together via a direct covalent linkage or via a spacer molecule, thereby forming a conjugate. 
     
     
         6 . An agent according to  claim 5 , wherein the TM is an antibody or a fragment thereof, thereby forming an immunotoxin or immunoconjugate. 
     
     
         7 . An agent according to  claim 1 , wherein the CDT comprises cdtB or a fragment thereof having DNase activity. 
     
     
         8 . An agent according to  claim 1 , wherein the CDT comprises cdtB. 
     
     
         9 . An agent according to  claim 7 , wherein the CDT further comprises cdtA or a fragment thereof. 
     
     
         10 . An agent according to  claim 7 , wherein the CDT further comprises cdtC or a fragment thereof. 
     
     
         11 . A recombinant method for preparing an agent according to  claim 1 , comprising expression of one or more nucleic acid constructs encoding the first and second components. 
     
     
         12 . A method of preparing an agent according to  claim 5  comprising coupling together the first and second components, wherein the first and second components have been optionally prepared recombinantly. 
     
     
         13 . A method for the treatment of proliferative cell disorder, comprising administering an agent according to  claim 1 . 
     
     
         14 . A method according to  claim 13 , wherein the proliferative cell disorder is selected from the group consisting of Epstein Barr virus induced Burkitts lymphoma, Hodgkins lymphoma, and post-transplantation lymphoproliferative disease. 
     
     
         15 . A method for the treatment of an infection caused by an intracellular pathogen, comprising administering an agent according to  claim 1 . 
     
     
         16 . An agent according to  claim 1 , wherein the CDT comprises SEQ ID 2 and/or SEQ ID 4. 
     
     
         17 . A method according to  claim 11 , wherein the nucleic acid construct encoding the second component comprises SEQ ID 1 and/or SEQ ID 3.