Toll-like receptor 2 agonists and vaccines and uses thereof

Abstract

The present invention relates to Toll-Like Receptor 2 (TLR2) agonists, in particular, to TLR2-activating lipoproteins, and more particularly to TLR2-activating lipopeptides derived from the bacteria Bordetella pertussis . The invention further extends to the use of said TLR2-activating lipoproteins as a therapeutic or as part of a vaccine composition in the treatment and prevention of infectious diseases, cancer or allergic diseases.

1 . A lipoprotein obtainable from  Bordetella pertussis  for enhancing a Th1 response, the lipoprotein having an N terminal signal peptide of less than 40 amino acids in length wherein the N terminal signal peptide comprises a lipobox comprising an amino acid sequence X1, X2, X3, X4, wherein X1 can be selected from Leucine, Valine and Isoleucine; X2 can be selected from Alanine, Serine, Threonine, Valine and Isoleucine; X3 can be selected from Glycine, Alanine, and Serine; and X4 is Cysteine, wherein X4 is capable of being acylated, or a fragment or derivative thereof wherein the lipoprotein or the fragment or derivative thereof is a Toll-like receptor 2 agonist. 
     
     
         2 . The lipoprotein as claimed in  claim 1 , wherein the lipoprotein comprises an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 or a derivative or fragment thereof. 
     
     
         3 . The lipoprotein as claimed in  claim 1 , wherein the lipoprotein is a lipopeptide comprising an amino acid sequence of SEQ ID NO:13 or SEQ ID NO:14. 
     
     
         4 . The lipoprotein of  claim 1  for use in medicine. 
     
     
         5 . The lipoprotein of  claim 1  for use in the treatment or prevention of a condition caused by a pathogen, cancer or an allergic disease. 
     
     
         6 . Use of a lipoprotein obtainable from  Bordetella pertussis  for enhancing a Th1 response, the lipoprotein having an N terminal signal peptide of less than 40 amino acids in length wherein the N terminal signal peptide comprises a lipobox comprising an amino acid sequence X1, X2, X3, X4, wherein X1 can be selected from Leucine, Valine and Isoleucine; X2 can be selected from Alanine, Serine, Threonine, Valine and Isoleucine; X3 can be selected from Glycine, Alanine, and Serine; and X4 is Cysteine, wherein X4 is capable of being acylated, or a fragment or derivative thereof wherein the lipoprotein or the fragment or derivative thereof is a Toll-like receptor 2 agonist in the preparation of a medicament for the prevention or treatment of a condition caused by a pathogen or tumourigenesis. 
     
     
         7 . The lipoprotein for use as claimed in  claim 5 , wherein the pathogen is a bacterium, a virus, a fungus or a parasite. 
     
     
         8 . The lipoprotein for use or the use as claimed in  claim 7 , wherein the bacterium is  B. pertussis.    
     
     
         9 . The use as claimed in  claim 6 , wherein the lipoprotein comprises an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 or a derivative or fragment thereof. 
     
     
         10 . The use as claimed in  claim 6 , wherein the lipoprotein is a lipopeptide comprising an amino acid sequence of SEQ ID NO:13 or SEQ ID NO:14. 
     
     
         11 . A method for the administration of at least one lipoprotein obtainable from  Bordetella pertussis  for enhancing a Th1 response, the lipoprotein having an N terminal signal peptide of less than 40 amino acids in length wherein the N terminal signal peptide comprises a lipobox comprising an amino acid sequence X1, X2, X3, X4, wherein X1 can be selected from Leucine, Valine and Isoleucine; X2 can be selected from Alanine, Serine, Threonine, Valine and Isoleucine; X3 can be selected from Glycine, Alanine, and Serine; and X4 is Cysteine, wherein X4 is capable of being acylated, or a fragment or derivative thereof wherein the lipoprotein or the fragment or derivative thereof is a Toll-like receptor 2 agonist as part of a vaccine composition. 
     
     
         12 . The method of  claim 11 , wherein the vaccine composition is for the treatment of or prophylaxis of a condition caused by a pathogen, cancer or an allergic disease. 
     
     
         13 . The method as claimed in  claim 11 , wherein the at least one lipoprotein is an adjuvant. 
     
     
         14 . The method as claimed in  claim 11 , wherein the at least one TLR2-activating lipoprotein is an antigen. 
     
     
         15 . The method of  claim 11 , wherein the vaccine composition comprises at least one antigen derived from an infectious disease or a tumour antigen. 
     
     
         16 . The method as claimed in  claim 11 , wherein the lipoprotein comprises an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 or a derivative or fragment thereof. 
     
     
         17 . The method as claimed in  claim 11 , wherein the lipoprotein is a lipopeptide comprising an amino acid sequence of SEQ ID NO:13 or SEQ ID NO:14. 
     
     
         18 . A composition to mediate an immune response in a subject comprising at least one lipoprotein obtainable from  Bordetella pertussis  for enhancing a Th1 response, the lipoprotein having an N terminal signal peptide of less than 40 amino acids in length wherein the N terminal signal peptide comprises a lipobox comprising an amino acid sequence X1, X2, X3, X4, wherein X1 can be selected from Leucine, Valine and Isoleucine; X2 can be selected from Alanine, Serine, Threonine, Valine and Isoleucine; X3 can be selected from Glycine, Alanine, and Serine; and X4 is Cysteine, wherein X4 is capable of being acylated, or a fragment or derivative thereof wherein the lipoprotein or the fragment or derivative thereof is a Toll-like receptor 2 agonist, optionally comprising an antigen from a pathogen, from a tumour cell or an allergen. 
     
     
         19 . The composition of  claim 18 , wherein the at least one lipoprotein is an immunogenic determinant. 
     
     
         20 . The composition of  claim 18 , wherein the at least one lipoprotein is an adjuvant. 
     
     
         21 . The composition of  claim 18 , wherein the composition is for use in mediating an immune response against a pathogen. 
     
     
         22 . The composition of  claim 18 , wherein the composition is an acellular  pertussis  vaccine composition. 
     
     
         23 . The composition as claimed in  claim 18 , wherein the lipoprotein comprises an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 or a derivative or fragment thereof. 
     
     
         24 . The composition as claimed in  claim 18 , wherein the lipoprotein is a lipopeptide comprising an amino acid sequence of SEQ ID NO:13 or SEQ ID NO:14. 
     
     
         25 . The composition of  claim 18  for use in medicine. 
     
     
         26 . Use of the composition of  claim 18  in the preparation of a medicament for the prevention or treatment of a condition caused by a pathogen or cancer or an allergic disease. 
     
     
         27 . The composition of  claim 18  for use in the treatment or prevention of a condition caused by a pathogen or tumourigenesis. 
     
     
         28 . Use of a composition of  claim 18  in a method of vaccinating a subject to induce immunity against a pathogen. 
     
     
         29 . The use as claimed in  claim 26  wherein the pathogen is an infectious agent. 
     
     
         30 . The use as claimed in  claim 29 , wherein the infectious agent is a bacterium, a virus, a fungus or a parasite. 
     
     
         31 . The use as claimed in  claim 30 , wherein the bacterium is  B. pertussis.    
     
     
         32 . A composition comprising at least one lipoprotein obtainable from  Bordetella pertussis  for enhancing a Th1 response, the lipoprotein having an N terminal signal peptide of less than 40 amino acids in length wherein the N terminal signal peptide comprises a lipobox comprising an amino acid sequence X1, X2, X3, X4, wherein X1 can be selected from Leucine, Valine and Isoleucine; X2 can be selected from Alanine, Serine, Threonine, Valine and Isoleucine; X3 can be selected from Glycine, Alanine, and Serine; and X4 is Cysteine, wherein X4 is capable of being acylated, or a fragment or derivative thereof wherein the lipoprotein or the fragment or derivative thereof is a Toll-like receptor 2 agonist for use as a booster to enhance the immune response generated in a host against a pathogen to which the subject has previously been exposed. 
     
     
         33 . The composition as claimed in  claim 32 , wherein the lipoprotein comprises an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 or a derivative or fragment thereof. 
     
     
         34 . The composition as claimed in  claim 32 , wherein the lipoprotein is a lipopeptide comprising an amino acid sequence of SEQ ID NO:13 or SEQ ID NO:14. 
     
     
         35 . The use as claimed in  claim 32  wherein the pathogen is an infectious agent. 
     
     
         36 . The use as claimed in  claim 35 , wherein the infectious agent is a bacterium, a virus, a fungus or a parasite. 
     
     
         37 . The use as claimed in  claim 36 , wherein the bacterium is  B. pertussis.    
     
     
         38 . A method of mediating an immune response in a subject against an infectious disease, said method comprising the steps of:
 providing a composition comprising at least one lipoprotein obtainable from  Bordetella pertussis  for enhancing a Th1 response, the lipoprotein having an N terminal signal peptide of less than 40 amino acids in length wherein the N terminal signal peptide comprises a lipobox comprising an amino acid sequence X1, X2, X3, X4, wherein X1 can be selected from Leucine, Valine and Isoleucine; X2 can be selected from Alanine, Serine, Threonine, Valine and Isoleucine; X3 can be selected from Glycine, Alanine, and Serine; and X4 is Cysteine, wherein X4 is capable of being acylated, or a fragment or derivative thereof wherein the lipoprotein or the fragment or derivative thereof is a Toll-like receptor 2 agonist; and   administering the composition to the subject in a therapeutically effective or prophylactically effective amount sufficient to elicit an immune response in the subject against the infectious disease.   
     
     
         39 . The method as claimed in  claim 38 , wherein the lipoprotein comprises an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 or a derivative or fragment thereof. 
     
     
         40 . The method as claimed in  claim 38 , wherein the lipoprotein is a lipopeptide comprising an amino acid sequence of SEQ ID NO:13 or SEQ ID NO:14. 
     
     
         41 . The method as claimed in  claim 38 , wherein the composition includes an antigen from a pathogen that causes the infectious disease. 
     
     
         42 . The method as claimed in  claim 38  wherein the pathogen is an infectious agent. 
     
     
         43 . The method as claimed in  claim 42 , wherein the infectious agent is a bacterium, a virus, a fungus or a parasite. 
     
     
         44 . The method as claimed in  claim 43 , wherein the bacterium is  B. pertussis.    
     
     
         45 . The method of  claim 38 , wherein the composition is a vaccine composition. 
     
     
         46 . A method of mediating an immune response in a subject with cancer, said method comprising the steps of:
 providing a composition comprising at least one lipoprotein obtainable from  Bordetella pertussis  for enhancing a Th1 response, the lipoprotein having an N terminal signal peptide of less than 40 amino acids in length wherein the N terminal signal peptide comprises a lipobox comprising an amino acid sequence X1, X2, X3, X4, wherein X1 can be selected from Leucine, Valine and Isoleucine; X2 can be selected from Alanine, Serine, Threonine, Valine and Isoleucine; X3 can be selected from Glycine, Alanine, and Serine; and X4 is Cysteine, wherein X4 is capable of being acylated, or a fragment or derivative thereof wherein the lipoprotein or the fragment or derivative thereof is a Toll-like receptor 2 agonist; and   administering the composition to the subject in a therapeutically effective or prophylactically effective amount.   
     
     
         47 . The method as claimed in  claim 46 , wherein the lipoprotein comprises an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 or a derivative or fragment thereof. 
     
     
         48 . The method as claimed in  claim 46 , wherein the lipoprotein is a lipopeptide comprising an amino acid sequence of SEQ ID NO:13 or SEQ ID NO:14. 
     
     
         49 . The method of  claim 46 , wherein the composition further comprises a tumour-specific antigen, tumour associated antigen tumour, a heat shock protein and antigenic peptide or a synthetic peptide antigen. 
     
     
         50 . The method of  claim 49 , wherein the antigen is killed whole tumor cells or extracts. 
     
     
         51 . The method as claimed in  claim 46 , wherein the cancer is hepatic cancer, lung cancer, in particular non-small cell lung cancer, prostate cancer, ovarian cancer, breast cancer, melanoma, basal cell carcinoma, or haematological malignancies. 
     
     
         52 . The method of  claim 46 , wherein the composition is a vaccine composition. 
     
     
         53 . A method of mediating an immune response in a subject with an allergic disease, said method comprising the steps of:
 providing a composition comprising at least one lipoprotein obtainable from  Bordetella pertussis  for enhancing a Th1 response, the lipoprotein having an N terminal signal peptide of less than 40 amino acids in length wherein the N terminal signal peptide comprises a lipobox comprising an amino acid sequence X1, X2, X3, X4, wherein X1 can be selected from Leucine, Valine and Isoleucine; X2 can be selected from Alanine, Serine, Threonine, Valine and Isoleucine; X3 can be selected from Glycine, Alanine, and Serine; and X4 is Cysteine, wherein X4 is capable of being acylated, or a fragment or derivative thereof wherein the lipoprotein or the fragment or derivative thereof is a Toll-like receptor 2 agonist; and   administering the composition to the subject in a therapeutically effective or prophylactically effective amount.   
     
     
         54 . The method as claimed in  claim 53 , wherein the allergic disease is asthma. 
     
     
         55 . The method of  claim 53 , wherein the composition is a vaccine composition. 
     
     
         56 . The method as claimed in  claim 53 , wherein the lipoprotein comprises an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 or a derivative or fragment thereof. 
     
     
         57 . The method as claimed in  claim 53 , wherein the lipoprotein is a lipopeptide comprising an amino acid sequence of SEQ ID NO:13 or SEQ ID NO:14.