Castration resistant prostate cancer
The present invention relates to a polyplex for use in the treatment of castration resistant prostate cancer (CRPC) comprising a double stranded RNA (dsRNA) and a polymeric conjugate, wherein said polymeric conjugate consists of a linear polyethyleneimine (LPEl), one or more polyethylene glycol (PEG) moieties, one or more linkers and one or more targeting moieties, wherein said LPEl is covalently bound to one or more PEG moieties and each of said one or more PEG moieties is conjugated via one of the one or more linkers to one of the one or more targeting moieties, wherein each of said one or more targeting moieties is capable of binding to a cancer antigen, and wherein said cancer antigen is prostate surface membrane antigen (PSMA). Further, the invention relates to a pharmaceutical composition for use in the treatment of CRPC.
1. A method of treating castration resistant prostate cancer (CRPC) comprising administering to a patient in need thereof, an effective amount of a polyplex comprising a double stranded RNA (dsRNA) and a polymeric conjugate,
wherein said polymeric conjugate consists of a linear polyethyleneimine (LPEI), one or more polyethylene glycol (PEG) moieties, one or more linkers and one or more targeting moieties, wherein said LPEI is covalently bound to one or more PEG moieties and each of said one or more PEG moieties is conjugated via one of said one or more linkers to one of said one or more targeting moieties,
wherein each of said one or more targeting moieties is capable of binding to a cancer antigen, and wherein said cancer antigen is prostate surface membrane antigen (PSMA).
2. The method according to claim 1 , wherein said dsRNA is polyinosinic-polycytidylic acid double stranded RNA (polylC).
3. The method according to claim 1 , wherein said LPEI is covalently bound to one PEG moiety (LPEI-PEG 1:1) or to three PEG moieties (LPEI-PEG 1:3).
4. The method according to claim 1 , wherein said linker is a peptide moiety and wherein said peptide moiety consists of 3 to 7 amino acid residues.
5. The method according to claim 4 , wherein said peptide moiety comprises the amino acid residue —(NH—(CH 2 ) 7 —CO)—.
6. The method according to claim 5 , wherein said peptide moiety is:
(SEQ ID NO: 1)
-(NH-(CH 2 ) 7 -CO)-Phe-Gly-Trp-Trp-Gly-Cys- or
(SEQ ID NO: 2)
-(NH-(CH 2 ) 7 -CO)-Phe-Phe-(NH-CH 2 -CH(NH 2 )-CO)-
Asp-Cys-.
7. The method according to claim 1 , wherein said polymeric conjugate is selected from formula (a), (b), (c) or (d):
(a) T-(NH—(CH 2 ) 7 —CO)-Phe-Phe-(NH—CH 2 —CH(NH 2 )—CO)-Asp-Cys-PEG-LPEI (SEQ ID NO:17);
(b) T-(NH—(CH 2 ) 7 —CO)-Phe-Gly-Trp-Trp-Gly-Cys-PEG-LPEI (SEQ ID NO:18);
(c) [T-(NH—(CH 2 ) 7 —CO)-Phe-Phe-(NH—CH 2 —CH(NH 2 )—CO)-Asp-Cys-PEG]3-LPEI (SEQ ID NO:31); or
(d) [T-(NH—(CH 2 ) 7 —CO)-Phe-Gly-Trp-Trp-Gly-Cys-PEG]3-LPEI (SEQ ID NO: 32);
and wherein said T represents said targeting moiety.
8. The method according to claim 1 , wherein said polymeric conjugate is selected from the group consisting of formula (i), (ii), (iii) and (iv):
wherein R1 is
wherein R2 is
wherein R1 is
wherein R2 is
wherein said T represents said targeting moiety;
and wherein n is 40-45.
9. The method according to claim 1 , wherein said targeting moiety is HOOC(CH 2 ) 2 —CH(COOH)—NH—CO—NH—CH(COOH)—(CH 2 ) 2 —CO— (DUPA moiety).
10. The method according to claim 1 , wherein CRPC is non-metastatic CRPC or metastatic CRPC.
11. The method according to claim 1 , wherein said CRPC is androgen receptor (AR) independent CRPC.
12. The method according to claim 11 , wherein said androgen receptor (AR) independent CRPC is neuroendocrine prostate cancer.
13. The method according to claim 1 , wherein said polyplex is used in combination with immune cells.
14. The method according to claim 13 , wherein said immune cells are selected from the group consisting of tumor-infiltrating T-cells (T-TILs), tumor specific engineered T-cells and peripheral blood mononuclear cells (PBMCs).
15. A method of treating castration resistant prostate cancer (CRPC) comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition, wherein said pharmaceutical composition comprises a pharmaceutically acceptable carrier and a polyplex comprising a double stranded RNA (dsRNA) and a polymeric conjugate, wherein said polymeric conjugate consists of a linear polyethyleneimine (LPEI), one or more polyethylene glycol (PEG) moieties, one or more linkers and one or more targeting moieties,
wherein said LPEI is covalently bound to one or more PEG moieties and each of said one or more PEG moieties is conjugated via one of said one or more linkers to one of said one or more targeting moieties,
wherein each of said one or more targeting moieties is capable of binding to a cancer antigen, and
wherein said cancer antigen is prostate surface membrane antigen (PSMA).
16. The method according to claim 1 , wherein CRPC is metastatic CRPC.
17. The method according to claim 1 , wherein said CRPC is androgen receptor (AR) dependent.
18. The method according to claim 5 , wherein said peptide moiety is
—(NH—(CH 2 ) 7 —CO)-Phe-Gly-Trp-Trp-Gly-Cys- (SEQ ID NO: 1).
19. The method according to claim 1 , wherein said polymeric conjugate is formula
(b) T-(NH—(CH 2 ) 7 —CO)-Phe-Gly-Trp-Trp-Gly-Cys-PEG-LPEI (SEQ ID NO:18),
wherein said T represents said targeting moiety.
20. The method according to claim 1 , wherein said polymeric conjugate is of formula (ii):
wherein R2 is