Immunotherapy targeting intracellular pathogens

Abstract

The present invention relates to the use of immunogenic peptides comprising a T-cell epitope derived from an intracellular pathogen-associated antigen and a redox motif such as C-(X)2-[CST] or [CST]-(X)2-C in the prevention and/or treatment of infection with an intracellular pathogen and in the manufacture of medicaments therefore.

1 . A method of manufacturing a medicament comprising formulating a medicament comprising at least one isolated immunogenic peptide said medicament preventing or treating in a subject, infection with an intracellular pathogen, the immunogenic peptide comprising (i) a T-cell epitope derived from an intracellular pathogen-associated antigen of said intracellular pathogen and (ii) a C-(X)2-[CST] or [CST]-(X)2-C motif. 
     
     
         2 . The method of  claim 1 , said medicament inducing in a subject CD4+ regulatory T cells which are stimulating non-specific intracellular microbicidal mechanisms in cells of said subject infected with said intracellular pathogen. 
     
     
         3 . The method according to  claim 1 , wherein said intracellular pathogen-associated antigen is derived from a virus, a bacterium, a mycobacterium or a parasite. 
     
     
         4 . The method according to  claim 1 , wherein said C-(X)2-[CST] or [CST]-(X)2-C motif is adjacent to said T-cell epitope, or is separated from said T-cell epitope by a linker. 
     
     
         5 . The method according to  claim 4  wherein said linker consists of at most 7 amino acids. 
     
     
         6 . The method according to  claim 1 , wherein said C-(X)2-[CST] or [CST]-(X)2-C motif does not naturally occur within a region of 11 amino acids N- or C-terminally adjacent to the T-cell epitope in said intracellular pathogen-associated antigen. 
     
     
         7 . The method according to  claim 1 , wherein said immunogenic peptide further comprises an endosomal targeting sequence. 
     
     
         8 . The method according to  claim 1 , wherein said C-(X)2-[CST] or [CST]-(X)2-C motif is positioned N-terminally of the T-cell epitope. 
     
     
         9 . The method according to  claim 1 , wherein at least one X in said C-(X)2-[CST] or [CST]-(X)2-C motif is Gly, Ala, Ser or Thr. 
     
     
         10 . The method according to  claim 1 , wherein at least one X in said C-(X)2-[CST] or [CST]-(X)2-C motif is His or Pro. 
     
     
         11 . The method according to  claim 1 , wherein at least one C in said C-(X)2-[CST] or [CST]-(X)2-C motif is methylated. 
     
     
         12 . The method according to  claim 1 , wherein said immunogenic peptide is produced by chemical synthesis or by recombinant expression. 
     
     
         13 . A method for obtaining a population of intracellular pathogen-associated antigen-specific regulatory T cells with cytotoxic properties, the method comprising the steps of:
 providing peripheral blood cells;   contacting said cells in vitro with an immunogenic peptide comprising (i) a T-cell epitope derived from an intracellular pathogen-associated antigen and (ii) a C-(X)2-[CST] or [CST]-(X)2-C motif; and   expanding said cells in the presence of Interleukin 2 (IL-2).   
     
     
         14 . A method for obtaining a population of intracellular pathogen-associated antigen-specific regulatory T cells with cytotoxic properties, the method comprising the steps of:
 providing an immunogenic peptide comprising (i) a T-cell epitope derived from an intracellular pathogen-associated antigen and (ii) a C-(X)2-[CST] or [CST]-(X)2-C motif;   administering said immunogenic peptide to a subject; and   obtaining said population of intracellular pathogen-associated antigen-specific regulatory T cells from said subject.   
     
     
         15 . A population of intracellular pathogen-associated antigen-specific regulatory T cells with cytotoxic properties obtainable by the method according to  claim 13 . 
     
     
         16 . Use of A method of manufacturing a medicament comprising formulating a medicament comprising the population of intracellular pathogen-associated antigen-specific regulatory T cells according to  claim 15 , said medicament preventing or treating infection with said intracellular pathogen. 
     
     
         17 . An isolated immunogenic peptide comprising a T-cell epitope from an intracellular pathogen-associated antigen and, adjacent to said T-cell epitope or separated from said T-cell epitope by a linker, a C-(X)2-[CST] or [CST]-(X)2-C motif.