Antibacterial therapy with bacteriophage physico-chemically altered to delay inactivation by the host defense system

Abstract

The present invention is directed to bacteriophage therapy, using methods which enable the bacteriophage to delay inactivation by any and all parts of the host defense system (HDS) against foreign objects. The HDS normally reduces the number of bacteriophage in an animal, which decreases the efficiency of the bacteriophage in killing the host bacteria present during an infection. Disclosed is a method of producing bacteriophage modified for anti-HDS purposes by physico-chemical alteration of the bacteriophage surface proteins, so that the altered bacteriophage remain active in the body for longer periods of time than the unmodified bacteriophage.

We claim:  
     
         1 . A method for treating an infectious disease caused by a bacteria, in an animal, comprising: 
 administering to an animal in need of such treatment, a lytic or non-lytic physico-chemically altered bacteriophage that is specific for said bacteria, in a dosage effective to substantially eliminate the bacteria, wherein said physico-chemically altered bacteriophage has a delayed inactivation by an animal's host defense system (HDS).    
     
     
         2 . The method according to    claim 1   , wherein said bacteria is a drug resistant bacteria.  
     
     
         3 . The method according to    claim 1   , wherein said animal is not a mammal.  
     
     
         4 . The method according to    claim 1   , wherein said animal is a mammal.  
     
     
         5 . The method according to    claim 4   , wherein said mammal is a human.  
     
     
         6 . The method according to    claim 1   , wherein said physico-chemically altered bacteriophage is PEGylated.  
     
     
         7 . The method according to    claim 1   , wherein said physico-chemically altered bacteriophage has at least a 15% longer half-life than a corresponding wild-type phage.  
     
     
         8 . The method according to    claim 1   , wherein the bacteria is selected from the group consisting of Mycobacteria, Staphylococci, Vibrio, Enterobacter, Enterococci, Escherichia, Haemophilus, Neisseria, Pseudomonas, Shigella, Serratia, Salmonella and Streptococci, and the bacteriophage can effectively lyse the bacteria.  
     
     
         9 . The method according to    claim 8   , wherein the bacteria is selected from the group consisting of  M. tuberculosis, M. avium-intracellulare  and  M. bovis.    
     
     
         10 . The method according to    claim 1   , wherein the bacteriophage is administered by way of an aerosol to an animal's lungs.  
     
     
         11 . The method according to    claim 1   , wherein the bacteriophage is administered at a dosage of about 10 6  to about 10 13  pfu/kg/day.  
     
     
         12 . The method according to    claim 11   , wherein the bacteriophage is administered at a dosage of about 10 12  pfu/kg/day.  
     
     
         13 . The method according to    claim 1   , wherein said bacteriophage is genetically modified to evade the HDS.  
     
     
         14 . A physico-chemically altered bacteriophage which is able to delay inactivation by an animal's host defense system.  
     
     
         15 . The bacteriophage according to    claim 14   , wherein said bacteriophage has at least a 15% longer half-life than a corresponding wild-type phage.  
     
     
         16 . The bacteriophage according to    claim 14   , wherein said phage is specific for bacterial families selected from the group consisting of Escherichia, Klebsiella, Shigella, Salmonella, Serratia, Yersinia, Enterobacter, Enterococci, Haemophilus, Mycobacteria, Neisseria, Pseudomonas, Staphylococci, Streptococci and Vibrio.  
     
     
         17 . The bacteriophage according to    claim 14   , wherein said bacteriophage is PEGylated.  
     
     
         18 . A method of obtaining a physico-chemically altered bacteriophage that is able to delay inactivation by an animal's host defense system against foreign bodies, comprising the steps of: 
 (a) protecting tail proteins on a bacteriophage, and    (b) then binding a polymer to any unprotected proteins on said bacteriophage.    
     
     
         19 . The method according to    claim 18   , wherein said polymer is polyethylene glycol (PEG).  
     
     
         20 . A method for treating an infectious disease caused by a bacteria, comprising administering to an animal in need of such treatment an antibiotic and/or a chemotherapeutic agent, in combination with a physico-chemically altered bacteriophage specific for said bacteria, in a dosage effective to substantially eliminate the bacteria, wherein said physico-chemically altered bacteriophage is able to delay inactivation by the animal's host defense system.  
     
     
         21 . The method according to    claim 20   , wherein said physico-chemically altered bacteriophage is PEGylated.  
     
     
         22 . A pharmaceutical composition comprising a physico-chemically altered bacteriophage which is able to delay inactivation by an animal's host defense system, in combination with a pharmaceutically acceptable carrier.  
     
     
         23 . The pharmaceutical composition according to    claim 22   , wherein said physico-chemically altered bacteriophage is PEGylated.  
     
     
         24 . The pharmaceutical composition according to    claim 22   , wherein said composition is an aerosol formulation for administration to an animal's lungs.  
     
     
         25 . The pharmaceutical composition according to    claim 22   , wherein said bacteriophage is in lyophilized form.