Combination of an immune checkpoint modulator and a complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for use in medicine

Abstract

The present invention provides a combination of an immune checkpoint modulator and a complex comprising a cell penetrating peptide, at least one antigen or antigenic epitope, and a TLR peptide agonist for use in medicine, in particular in the prevention and/or treatment of cancer. Moreover, the present invention also provides compositions, such as a pharmaceutical compositions and vaccines, which are useful in medicine, for example in the prevention and/or treatment of cancer.

1 . A combination of
 (i) an immune checkpoint modulator and   (ii) a complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein components a)-c) comprised by the complex are covalently linked. 
   
     
     
         2 . The combination according to  claim 1 , wherein the complex is a recombinant polypeptide or a recombinant protein. 
     
     
         3 . The combination according to  claim 1 , wherein the cell penetrating peptide comprised by the complex
 (i) has a length of the amino acid sequence of said peptide of 5 to 50 amino acids in total; and/or   (ii) has an amino acid sequence comprising a fragment of the minimal domain of ZEBRA, said minimal domain extending from residue 170 to residue 220 of the ZEBRA amino acid sequence according to SEQ ID NO: 3, wherein, optionally, 1-, 2, 3, 4, or 5 amino acids have been substituted, deleted, and/or added without abrogating said peptide's cell penetrating ability, or a variant thereof.   
     
     
         4 .- 6 . (canceled) 
     
     
         7 . The combination according to  claim 3 , wherein the cell penetrating peptide comprised by the complex has an amino acid sequence comprising or consisting of an amino acid sequence according to SEQ ID NO: 6 (CPP3/Z13), SEQ ID NO: 7 (CPP4/Z14), SEQ ID NO: 8 (CPP5/Z15), or SEQ ID NO: 11 (CPP8/Z18), or a sequence variants thereof without abrogating said peptide's cell penetrating ability. 
     
     
         8 . (canceled) 
     
     
         9 . The combination according to  claim 1 , wherein the at least one antigen or antigenic epitope comprised by the complex comprises or consists of at least one pathogen epitope and/or at least one tumor epitope. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The combination according to  claim 1 , wherein the complex comprises more than one antigen or antigenic epitope. 
     
     
         13 . (canceled) 
     
     
         14 . The combination according to  claim 1 , wherein the at least one TLR peptide agonist comprised by the complex is a TLR2, TLR4 and/or TLR5 peptide agonist. 
     
     
         15 .- 20 . (canceled) 
     
     
         21 . The combination according to  claim 1 , wherein the immune checkpoint modulator is an activator or an inhibitor of one or more immune checkpoint point molecule(s) selected from the group consisting of CD27, CD28, CD40, CD122, CD137, OX40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, CD40, CTLA-4, IDO, KIR, LAG3, PD-1, TIM-3, VISTA, CEACAM1, GARP, PS, CSF1R, CD94/NKG2A, TDO, GITR, TNFR and FasR/DcR3; or an activator or an inhibitor of one or more ligands thereof. 
     
     
         22 . (canceled) 
     
     
         23 . The combination according to  claim 21 , wherein the immune checkpoint modulator is an inhibitor of an inhibitory checkpoint molecule. 
     
     
         24 . The combination according to  claim 21 , wherein the immune checkpoint modulator is an activator of a stimulatory or costimulatory checkpoint molecule. 
     
     
         25 . The combination according to  claim 21 , wherein the immune checkpoint modulator is a modulator of CD40, CTLA-4, PD-L1, PD-L2, PD-1 and/or IDO. 
     
     
         26 . The combination according to  claim 21 , wherein more than one immune checkpoint modulator is used. 
     
     
         27 . (canceled) 
     
     
         28 . The combination according to  claim 21 , wherein the complex is a recombinant polypeptide or a recombinant protein wherein
 a) the cell penetrating peptide has an amino acid sequence comprising or consisting of an amino acid sequence according to SEQ ID NO: 6 (CPP3/Z13), SEQ ID NO: 7 (CPP4/Z14), SEQ ID NO: 8 (CPP5/Z15), or SEQ ID NO: 11 (CPP8/Z18), or sequence variants thereof without abrogating said peptide's cell penetrating ability;   b) the at least one antigen or antigenic epitope is a peptide, polypeptide or protein; and   c) the TLR peptide agonist is a TLR2 peptide agonist and/or a TLR4 peptide agonist.   
     
     
         29 .- 40 . (canceled) 
     
     
         41 . A kit comprising
 (i) an immune checkpoint modulator and   (ii) a complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein components a)-c) comprised by the complex are covalently linked and 
 a package insert or label having directions to treat cancer by using the combination. 
   
     
     
         42 .- 45 . (canceled) 
     
     
         46 . A composition comprising
 (i) an immune checkpoint modulator and   (ii) a complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein components a)-c) comprised by the complex are covalently linked. 
   
     
     
         47 .- 53 . (canceled) 
     
     
         54 . A kit comprising
 (i) a nucleic acid molecule comprising a polynucleotide encoding an immune checkpoint modulator, wherein the immune checkpoint modulator is a (poly)peptide or a protein; and   (ii) a nucleic acid molecule comprising a polynucleotide encoding a complex, the complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein the complex is a (poly)peptide or a protein; and a package insert or label having directions to express the immune checkpoint modulator and the complex and/or to treat cancer by using a combination of the immune checkpoint modulator and the complex. 
   
     
     
         55 .- 58 . (canceled) 
     
     
         59 . The kit according to  claim 54 , wherein the nucleic acid molecule is selected from the group consisting of a vector, an RNA molecule, and a DNA molecule. 
     
     
         60 . (canceled) 
     
     
         61 . A nucleic acid molecule comprising
 (i) a polynucleotide encoding an immune checkpoint modulator, wherein the immune checkpoint modulator is a (poly)peptide or a protein; and   (ii) a polynucleotide encoding a complex, the complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
   wherein the complex is a (poly)peptide or a protein.   
     
     
         62 .- 63 . (canceled) 
     
     
         64 . A composition comprising
 (i) a nucleic acid molecule comprising a polynucleotide encoding an immune checkpoint modulator, wherein the immune checkpoint modulator is a (poly)peptide or a protein; and   (ii) a nucleic acid molecule comprising a polynucleotide encoding a complex, the complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein the complex is a (poly)peptide or a protein. 
   
     
     
         65 .- 66 . (canceled) 
     
     
         67 . A method for preventing or treating cancer or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject:
 1) (i) an immune checkpoint modulator and
 (ii) a complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein components a)-c) comprised by the complex are covalently linked; 
 
   or   2) a composition comprising
 (i) an immune checkpoint modulator and 
 (ii) a complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein components a)-c) comprised by the complex are covalently linked: or 
 
   3) (i) a nucleic acid molecule comprising a polypeptide encoding an immune checkpoint modulator, wherein the immune checkpoint modulator is a (poly)peptide or a protein; and
 (ii) a nucleic acid molecule comprising a polypeptide encoding a complex, the complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein the complex is a (poly)peptide or a protein; 
 
   or   4) a composition comprising
 (i) a nucleic acid molecule comprising a polypeptide encoding an immune checkpoint modulator, wherein the immune checkpoint modulator is a (poly)peptide or a protein; and 
 (ii) a nucleic acid molecule comprising a polypeptide encoding a complex, the complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein the complex is a (poly)peptide or a protein; 
 
   or   5) a nucleic acid molecule comprising
 (i) a polypeptide encoding an immune checkpoint modulator, wherein the immune checkpoint modulator is a (poly)peptide or a protein; and 
 (ii) a polypeptide encoding a complex, the complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein the complex is a (poly)peptide or a protein. 
 
   
     
     
         68 . (canceled) 
     
     
         69 . A combination therapy for preventing and/or treating cancer, wherein the combination therapy comprises administration of
 1) (i) an immune checkpoint modulator and
 (ii) a complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein components a)-c) comprised by the complex are covalently linked; 
 
   or   2) a composition comprising
 (i) an immune checkpoint modulator and 
 (ii) a complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein components a)-c) comprised by the complex are covalently linked; 
 
   or   3) (i) a nucleic acid molecule comprising a polypeptide encoding an immune checkpoint modulator, wherein the immune checkpoint modulator is a (poly)peptide or a protein, and
 (ii) a nucleic acid molecule comprising a polypeptide encoding a complex, the complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein the complex is a (poly)peptide or a protein, 
 
   or   4) a composition comprising
 (i) a nucleic acid molecule comprising a polypeptide encoding an immune checkpoint modulator, wherein the immune checkpoint modulator is a (poly)peptide or a protein; and 
 (ii) a nucleic acid molecule comprising a polypeptide encoding a complex, the complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein the complex is a (poly)peptide or a protein; 
 
   or   5) a nucleic acid molecule comprising
 (i) a polypeptide encoding an immune checkpoint modulator, wherein the immune checkpoint modulator is a (poly)peptide or a protein; and 
 (ii) a polypeptide encoding a complex, the complex comprising:
 a) a cell penetrating peptide; 
 b) at least one antigen or antigenic epitope; and 
 c) at least one TLR peptide agonist, 
 wherein the complex is a (poly)peptide or a protein. 
 
   
     
     
         70 . The combination according to  claim 14 , wherein the at least one TLR peptide agonist comprised by the complex comprises or consists of any amino acid sequence according to SEQ ID NO: 15 or 47 or a sequence variant thereof.