Oligonucleotides for reduction of PD-L1 expression
The present invention relates to antisense oligonucleotides that are capable of reducing expression of PD-L1 in a target cell. The oligonucleotides hybridize to PD-L1 mRNA. The present invention further relates to conjugates of the oligonucleotide and pharmaceutical compositions and methods for treatment of viral liver infections such as HBV, HCV and HDV; parasite infections such as malaria, toxoplasmosis, leishmaniasis and trypanosomiasis or liver cancer or metastases in the liver using the oligonucleotide.
1. An antisense oligonucleotide conjugate of the formula GN2-C6 o c o a o CCtatttaacatcAGAC (SEQ ID NO: 768), wherein C6 represents an amino alkyl group with 6 carbons, capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, subscript o represents a phosphodiester nucleoside linkage, and unless otherwise indicated, all internucleoside linkages are phosphorothioate internucleoside linkages, and wherein GN2 represents the following trivalent GalNAc cluster:
and further wherein the wavy line of the trivalent GalNAc cluster illustrates the site of conjugation of the trivalent GalNAc cluster to the C6 amino alkyl group.
2. A pharmaceutical composition comprising the antisense oligonucleotide conjugate of claim 1 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.
3. The pharmaceutical composition according to claim 2 wherein the pharmaceutically acceptable diluent is sterile phosphate buffered saline.
4. The pharmaceutical composition according to claim 2 wherein the pharmaceutically acceptable salt is sodium.
5. The pharmaceutical composition according to claim 2 wherein the pharmaceutically acceptable salt is potassium.
6. An in vivo or in vitro method for modulating PD-L1 expression in a target cell which is expressing PD-L1, said method comprising administering the antisense oligonucleotide conjugate of claim 1 in an effective amount to said cell.
7. A method for restoration of immune response against a virus, said method comprising administering a therapeutically or prophylactically effective amount of the antisense oligonucleotide conjugate of claim 1 to a subject infected with a virus.
8. The method according to claim 7 , wherein the virus is HBV.
9. The method according to claim 7 , wherein the restoration of the immune response is an increase in the liver of CD8+ T cells specific to one or more HBV antigens when compared to a control.
10. A method for restoration of immune response against a parasite, the method comprising administering a therapeutically or prophylactically effective amount of the antisense oligonucleotide conjugate of claim 1 to a subject infected with a parasite.
11. A method for treating HBV infection comprising administering a therapeutically effective amount of the antisense oligonucleotide conjugate of claim 1 to a subject suffering from HBV infection.
12. A pharmaceutically acceptable salt of an antisense oligonucleotide conjugate of the formula GN2-C6 o c o a o CCtatttaacatcAGAC (SEQ ID NO: 768), wherein C6 represents an amino alkyl group with 6 carbons, capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, subscript o represents a phosphodiester nucleoside linkage and unless otherwise indicated internucleoside linkages are phosphorothioate internucleoside linkages, and wherein GN2 represents the following trivalent GalNAc cluster:
and further wherein the wavy line of the trivalent GalNAc cluster illustrates the site of conjugation of the trivalent GalNAc cluster to the C6 amino alkyl group.
13. The pharmaceutically acceptable salt of the antisense oligonucleotide conjugate of claim 12 , which is a sodium salt.
14. The pharmaceutically acceptable salt of the antisense oligonucleotide conjugate of claim 12 , which is a potassium salt.