Method for treatment of cancer and infectious diseases and compositions useful in same

Abstract

Administration of expressible polynucleotides encoding eukaryotic heat shock proteins to mammalian cells leads to the stimulation of an immune response to antigens present in those cells. This makes it possible to stimulate an immune response to target antigens, including target tumor antigens or antigens associated with an infectious disease, without having to isolate a unique antigen or antigen-associated heat shock protein for each target antigen by administering to a mammalian subject or to a group of mammalian cells containing the antigen, an expressible polynucleotide encoding a heat shock protein. The expressed heat shock protein may have the same structure as native heat shock proteins, or may have a modified form adapted to control the trafficking of the expressed heat shock protein within the cells.

1 . A method for stimulating a therapeutic immune response in a subject in need of such treatment, comprising the step of introducing to the subject, or to a target group of cells from the subject, an expressible polynucleotide encoding a eukaryotic heat shock protein.  
     
     
         2 . A method for stimulating a prophylactic immune response against recurrence of a disease from which a subject is suffering, comprising administering to the subject, or to a target group of cells from the subject harboring an antigen associated with the disease, an expressible polynucleotide encoding a eukaryotic heat shock protein.  
     
     
         3 . The method according to  claim 1  or  2 , wherein the eukaryotic heat shock protein is an XDEL-negative heat shock protein.  
     
     
         4 . The method according to  claim 1  or  2 , wherein the eukaryotic heat shock protein is a heat shock protein from which the carboxy-terminal XDEL retention sequence has been deleted.  
     
     
         5 . The method according to  claim 1  or  2 , wherein the eukaryotic heat shock protein is a heat shock protein in which the carboxy-terminal XDEL retention sequence has been masked.  
     
     
         6 . The method according to  claim 1  or  2 , wherein the expressible polynucleotide encodes a eukaryotic heat shock protein having a carboxy-terminal retention sequence of the sequence XDEL.  
     
     
         7 . The method according to  claim 6 , wherein the eukaryotic heat shock protein is BiP.  
     
     
         9 . The method according to any of  claims 1  to  8 , wherein the cells are cancer cells.  
     
     
         10 . The method according to any of  claims 1  to  8 , wherein the cells are neoplastic cells.  
     
     
         11 . The method according to  claim 10 , wherein the neoplastic cells are selected from among sarcoma cells, lymphoma cells, leukemia cells, carcinoma cells and melanoma cells.  
     
     
         12 . The method according to any of  claims 1  to  8 , wherein the cells are infected with a virus.  
     
     
         13 . The method according to any of  claims 1  to  8 , wherein the cells are infected with a parasite.  
     
     
         14 . The method according to any of  claims 1  to  8 , wherein the cells are infected with a mycoplasma.  
     
     
         15 . The method according to any of  claims 1  to  8 , wherein the cells are infected with a bacterium.  
     
     
         16 . The method according to any of  claims 1  to  8 , wherein the cells are infected with a fungus or yeast.  
     
     
         17 . The method according to any of  claim 1  to  16 , wherein the expressible polynucleotide is introduced into a target group of cells ex vivo, and the target group of cells are thereafter administered to the subject.  
     
     
         18 . The method according to  claim 17 , wherein the composition is administered by transfection in a liposome.  
     
     
         19 . The method according to any of  claim 1  to  18 , wherein the subject is a human.  
     
     
         20 . A recombinant vector comprising 
 (a) a promoter system effective to promote expression of the vector in mammalian cells; and    (b) a region encoding a cytosolic heat shock protein (i) an amino terminal signal sequence effective to promote uptake of the expressed cytosolic heat shock protein by the endoplasmic reticulum and (ii) a carboxy-terminal retention sequence effective to promote retention of the heat shock protein in the endoplasmic reticulum.    
     
     
         21 . The recombinant vector of  claim 20 , wherein the signal sequence comprises a positively charged N-terminal region, a hydrophobic core region and a third region of greater polarity than the hydrophobic region.  
     
     
         22 . The recombinant vector according to  claim 20  or  21 , wherein the cytosolic heat shock protein is hsp70.  
     
     
         23 . A method for stimulating an immune response to an antigen present in a target group of mammalian cells, comprising administering to the target group of cells an expressible polynucleotide, wherein expression of the polynucleotide is effective to increase the amount of antigen-associated heat shock protein present in the cells.  
     
     
         24 . The method according to  claim 23 , wherein the expressible polynucleotide encodes a eukaryotic heat shock protein.  
     
     
         25 . The method according to  claim 23  or  24 , wherein the expressible polynucleotide encodes a peptide having a retention sequence recognized by the erd-2 receptors.  
     
     
         26 . The method according to  claim 25 , wherein the retention sequence is XDEL.