A Novel Complex Comprising A Cell Penetrating Peptide, A Cargo And A TLR Peptide Agonist For Treatment Of Glioblastoma

Abstract

The present invention provides a novel complex for use in the prevention and/or treatment of glioma, in particular glioblastoma, 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 components a)-c) are covalently linked. In particular, compositions for use in the prevention and/or treatment of glioma, in particular glioblastoma, such as a pharmaceutical compositions and vaccines are provided.

1 . A method for preventing and/or treating glioma, in particular gliobastoma, or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject 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 the components a)-c) are covalently linked.   
     
     
         2 . The method according to  claim 1 , wherein the complex is a recombinant polypeptide or a recombinant protein. 
     
     
         3 . The method according to  claim 1 , wherein the cell penetrating peptide
 (i) has a length of the amino acid sequence of said peptide of 5 to 50 amino acids in total, preferably of 10 to 45 amino acids in total, more preferably of 15 to 45 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.   
     
     
         4 .- 6 . (canceled) 
     
     
         7 . The method according to  claim 1 , wherein 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 (CPPS/Z15), or SEQ ID NO: 11 (CPPB/Z18), or sequence variants thereof without abrogating said peptide's cell penetrating ability, in particular sequence variants thereof sharing at least 70% sequence identity, preferably at least 80% sequence identity and more preferably at least 90% sequence identity without abrogating said peptide's cell penetrating ability. 
     
     
         8 . (canceled) 
     
     
         9 . The method according to  claim 1 , wherein the at least one antigen or antigenic epitope comprises or consists of at least one tumor epitope, preferably of at least one glioma epitope. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The method according to  claim 1 , wherein the complex comprises more than one antigen or antigenic epitope, in particular 2, 3, 4, 5, 6, 7, 8, 9, 10 or more antigens or antigenic epitopes. 
     
     
         13 . (canceled) 
     
     
         14 . The method according to  claim 9 , wherein the at least one tumor epitope is an epitope of an antigen selected from the group consisting of CMV, EGFRvIII, EphA2, gp100, Her2/neu, IL-13Rα2, survivin, hTert, TRP-2, MAGE-A1, MAGE-A3, YKL-40, brevican, neuroligin 4 and PTPRz1. 
     
     
         15 . (canceled) 
     
     
         16 . The method according to  claim 14 , wherein the complex comprises
 a) one or more epitopes of EGFRvIII or functional sequence variants thereof;   b) one or more epitopes of EphA2 or functional sequence variants thereof;   c) one or more epitopes of Her2/neu or functional sequence variants thereof;   d) one or more epitopes of IL-13Rα2 or functional sequence variants thereof;   e) one or more epitopes of survivin or functional sequence variants thereof;   f) one or more epitopes of TRP-2 or functional sequence variants thereof;   g) one or more epitopes of brevican or functional sequence variants thereof;   h) one or more epitopes of neuroligin 4 or functional sequence variants thereof; and/or   i) one or more epitopes of PTPRz1 or functional sequence variants thereof.   
     
     
         17 . The method according to  claim 16 , wherein the complex comprises
 a) a fragment of EGFRvIII comprising one or more epitopes or a functional sequence variant thereof;   b) a fragment of EphA2 comprising one or more epitopes or a functional sequence variant thereof;   c) a fragment of Her2/neu comprising one or more epitopes or a functional sequence variant thereof;   d) a fragment of IL-13Rα2 comprising one or more epitopes or a functional sequence variant thereof;   e) a fragment of survivin comprising one or more epitopes or a functional sequence variant thereof;   f) a fragment of TRP-2 comprising one or more epitopes or a functional sequence variant thereof;   g) a fragment of neuroligin 4 comprising one or more epitopes or a functional sequence variant thereof;   h) a fragment of brevican comprising one or more epitopes or a functional sequence variant thereof; and/or   i) a fragment of PTPRz1 comprising one or more epitopes or a functional sequence variant thereof.   
     
     
         18 .- 49 . (canceled) 
     
     
         50 . The method according to  claim 9 , wherein the at least one tumor epitope is an epitope of a neoantigen, preferably an epitope of a glioma-specific neoantigen. 
     
     
         51 . The method according to  claim 1 , wherein the at least one TLR peptide agonist is a TLR2, TLR4 and/or TLRS peptide agonist, preferably a TLR2 peptide agonist and/or a TLR4 peptide agonist. 
     
     
         52 . The method according to  claim 51 , wherein the at least one TLR peptide agonist comprises or consists of an amino acid sequence according to SEQ ID NO: 15 or a sequence variant thereof, in particular a sequence variant thereof sharing at least 70% sequence identity, preferably at least 80% sequence identity and more preferably at least 90% sequence identity without abrogating said peptide's TLR agonist ability. 
     
     
         53 .- 55 . (canceled) 
     
     
         56 . The method according to  claim 2 , wherein the components a) to c) are positioned in N-terminal→C-terminal direction of the main chain of said complex in the order:
 (α) component a)-component b)-component c); or 
 (β) component c)-component a)-component b), 
 wherein the components may be linked by a further component, in particular by a linker or a spacer. 
 
     
     
         57 . A method for preventing and/or treating glioma, in particular gliobastoma, or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject a nucleic acid encoding the complex as defined in  claim 1 , wherein the complex is a polypeptide or a protein. 
     
     
         58 . A method for preventing and/or treating glioma, in particular glioblastoma, or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject a vector comprising the nucleic acid as defined in  claim 57 . 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . A method for preventing and/or treating glioma, in particular glioblastoma, or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject a cell loaded with the complex as defined in  claim 1 . 
     
     
         62 . The method according to  claim 61 , wherein said cell is an antigen presenting cell, preferably a dendritic cell. 
     
     
         63 . (canceled) 
     
     
         64 . A method for preventing and/or treating glioma, in particular glioblastoma, or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject a vaccine comprising at least one of:
 (i) a complex as defined in  claim 1 ;   (ii) a nucleic acid encoding the complex as defined in (i);   (iii) a vector comprising the nucleic acid as defined in (ii);   (iv) a host cell comprising the vector as defined in (iii); or   (v) a cell loaded with the complex as defined in (i).   
     
     
         65 . A method for preventing and/or treating glioma, in particular glioblastoma, or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising at least one complex as defined in  claim 1  and a pharmaceutically acceptable carrier 
     
     
         66 . (canceled) 
     
     
         67 . (canceled) 
     
     
         68 . A method for preventing and/or treating glioma, in particular glioblastoma, or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject a combination of
 (i) a complex as defined in  claim 1 ; and   (ii) a chemotherapeutic agent, a targeted drug and/or an immunotherapeutic agent, such as an immune checkpoint modulator.   
     
     
         69 .- 79 . (canceled)