Methods and Compositions for Treating Prostate Cancer Using DNA Vaccines

Abstract

A DNA vaccine for the treatment of prostate cancer, comprising a plasmid vector comprising a nucleotide sequence encoding prostatic acid phosphatase (PAP) operably linked to a transcription regulatory element, wherein upon administration to a mammal a cytotoxic immune reaction against cells expressing PAP is induced. In preferred embodiment, the PAP encoded is a xenoantigen highly homologous to the autoantigen PAP of the mammal. Also disclosed are methods for inducing prostatitis, or inducing immune reaction to PAP, or treating prostate cancer in a mammal, using the DNA vaccine and pharmaceutical compositions comprising the vaccine. Preferably, xenoantigen vaccination is followed by boosting with autoantigen PAP from the same animal species as the mammal being treated.

1 . A method for inducing an immune reaction to prostatic acid phosphatase (PAP) in a mammal in need thereof, comprising 
 administering to the mammal an effective amount of a recombinant DNA construct comprising a polynucleotide sequence encoding PAP operatively linked to a transcriptional regulatory element, whereby the mammal develops immune reaction against PAP.    
     
     
         2 . The method of  claim 1 , wherein the mammal has prostate cancer.  
     
     
         3 . The method of  claim 1 , wherein the polynucleotide sequence encodes a human PAP.  
     
     
         4 . The method according to  claim 1 , wherein the polynucleotide sequence encodes a rodent PAP.  
     
     
         5 . The method according to  claim 1 , wherein the recombinant DNA construct is administered to the mammal intramuscularly, intravascularly, intravenously, or intraarterially.  
     
     
         6 . The method of  claim 1 , wherein the mammal is human.  
     
     
         7 . The method according to  claim 1 , wherein destructive prostatitis is induced in the mammal.  
     
     
         8 . The method according to  claim 1  wherein cellular immune reaction against cells expressing PAP is induced.  
     
     
         9 . The method according to  claim 8 , wherein both humoral and cellular immune reactions against PAP are induced.  
     
     
         10 . A method for inducing immune reaction to prostatic acid phosphatase (PAP) in a mammal in need thereof, comprising 
 administering to the mammal an effective amount of a first recombinant DNA construct comprising a first polynucleotide sequence encoding a first PAP polypeptide operatively linked to a transcriptional regulatory element; and    administering to the mammal an effective amount of a second recombinant DNA construct comprising a second polynucleotide sequence encoding a second PAP polypeptide operatively linked to a transcriptional regulatory element;    wherein the first polynucleotide sequence and the second polynucleotide molecule originate from two different animal species,    whereby an immune reaction against PAP is induced in the mammal.    
     
     
         11 . A method according to  claim 10 , wherein the first polynucleotide sequence originates from an animal species other than the mammal, and the second polynucleotide sequence originates from the same animal species as the mammal.  
     
     
         12 . A method according to  claim 10 , wherein the mammal is a human, and the first polynucleotide sequence encoding PAP originates from a rodent.  
     
     
         13 . A method according to  claim 10 , wherein the second polynucleotide sequence originates from the same animal species as the mammal, and the first polynucleotide sequence encodes a PAP polypeptide that shares at least 85% homology to the first PAP polypeptide.  
     
     
         14 . A method according to  claim 13 , wherein the first polynucleotide sequence encodes a PAP polypeptide that shares at least 88% homology to the first PAP polypeptide.  
     
     
         15 . A method according to  claim 13 , wherein the first polynucleotide sequence encodes a PAP polypeptide that shares at least 90% homology to the first PAP polypeptide.  
     
     
         16 . A method according to  claim 13 , wherein the first polynucleotide sequence encodes a PAP polypeptide that shares at least 95% homology to the first PAP polypeptide.  
     
     
         17 . A method according to  claim 13 , wherein the first polynucleotide sequence encodes a PAP polypeptide that shares at least 98% homology to the first PAP polypeptide.  
     
     
         18 . The method of  claim 13 , wherein the mammal has prostate cancer.  
     
     
         19 . The method according to  claim 13 , wherein the first and the second recombinant DNA constructs are administered to the mammal intravascularly, intraarterially, intravenously, or intramuscularly.  
     
     
         20 . The method according to  claim 10 , wherein destructive prostatitis is induced in the mammal.  
     
     
         21 . The method according to  claim 13 , wherein cellular immune reaction against PAP is induced.  
     
     
         22 . The method according to  claim 21 , wherein both humoral and cellular immune reactions against PAP are induced.  
     
     
         23 . A DNA vaccine comprising a plasmid vector comprising a polynucleotide sequence encoding prostatic acid phosphatase operably linked to a transcription regulatory element, wherein upon administration of said vaccine to a mammal a cytotoxic immune reaction against cells expressing PAP is induced.  
     
     
         24 . The DNA vaccine according to  claim 23 , suitable for intradermal, intravascular, intramuscular or intraarterial administration to a human.  
     
     
         25 . The DNA vaccine according to  claim 23 , wherein the plasmid vector comprises a backbone of pNGVL3; a polynucleotide sequence encoding PAP operably inserted therein, and an ISS motif.  
     
     
         26 . The DNA vaccine according to  claim 23 , wherein the plasmid vector comprises: 
 a polynucleotide sequence encoding PAP operatively linked to a CMV promoter;    a CMV intron A operatively linked to the polynucleotide sequence encoding PAP for enhancing expression of the polynucleotide sequence; and    at least one copy of an immunostimulatory fragment comprising 5′-GTCGTT-3′.    
     
     
         27 . The DNA vaccine according to  claim 26 , wherein the plasmid vector comprises at least two copies of an immunostimulatory fragment comprising 5′-GTCGTT-3′.  
     
     
         28 . The DNA vaccine according to  claim 23 , wherein the plasmid vector does not express in eukaryotic cells any gene other than the polynucleotide sequence encoding PAP.  
     
     
         29 . The DNA vaccine according to  claim 23 , wherein the plasmid vector is pTVG4.  
     
     
         30 . A pharmaceutical composition comprising the DNA vaccine of  claim 23 , and a pharmaceutically acceptable carrier.  
     
     
         31 . A pharmaceutical composition comprising the DNA vaccine of  claim 30 , further comprising a suitable amount of GM-CSF.  
     
     
         32 . A pharmaceutical composition comprising the DNA vaccine of  claim 26 , and a pharmaceutically acceptable carrier.