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

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)