Oligonucleotides for reduction of pd-l1 expression

Patent metadata

Field	Value
Publication number	US-2017283496-A1
Application number	US-201715458800-A
Country	US
Kind code	A1
Filing date	Mar 14, 2017
Priority date	Mar 14, 2016
Publication date	Oct 5, 2017
Grant date	—

Abstract

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.

First claim

1 . An antisense oligonucleotide conjugate comprising:
a. an oligonucleotide (Region A) comprising a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementarity to a PD-L1 target nucleic acid; and b. at least one asialoglycoprotein receptor targeting conjugate moiety (Region C) covalently attached to the oligonucleotide in a).

2 . The oligonucleotide conjugate of claim 1 , wherein the contiguous nucleotide sequence is complementary to a target nucleic acid selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2 and/or SEQ ID NO: 3.

3 . The oligonucleotide conjugate of claim 1 , wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid, wherein the subsequence is selected from the group consisting of position 371-3068, 5467-12107 and 15317-19511 on SEQ ID NO: 1

4 . The oligonucleotide conjugate of claim 1 , wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid, wherein the subsequence is selected from the group consisting of A221, A360, A180, A160 and A269.

5 . The oligonucleotide conjugate of claim 1 wherein the oligonucleotide comprises a sequence selected from SEQ ID NO: 466, 640, 342, 287 and 566.

6 . The oligonucleotide conjugate of claim 1 , wherein the contiguous nucleotide sequence comprises one or more modified nucleosides, such as one or more 2′ sugar modified nucleosides.

7 . The oligonucleotide conjugate of claim 6 , wherein the one or more 2′ sugar modified nucleoside is independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA and LNA nucleosides.

8 . The oligonucleotide conjugate of claim 6 , wherein the all the modified nucleosides are LNA nucleosides.

9 . The oligonucleotide conjugate of claim 7 , wherein the contiguous nucleotide sequence comprises at least one modified internucleoside linkage, such as at least one phosphorothioate internucleoside linkage.

10 . The oligonucleotide conjugate of claim 1 , wherein the oligonucleotide is a gapmer.

11 . The oligonucleotide conjugate of claim 10 , wherein the gapmer has formula 5′-D′-F-G-F′-3′ or 5′-F-G-F′-D″-3′, where region F and F′ independently comprise 1-7 modified nucleosides, G is a region between 6 and 16 nucleosides which are capable of recruiting RNaseH and region D′ or D″ is optional and comprise 0-5 phosphodiester linked nucleosides.

12 . The oligonucleotide conjugate of claim 1 , wherein the asialoglycoprotein receptor targeting conjugate moiety comprises at least one carbohydrate moiety selected from group consisting of galactose, galactosamine, N-formyl-galactosamine, N-acetylgalactosamine, N-propionyl-galactosamine, N-n-butanoyl-galactosamine and N-isobutanoylgalactosamine.

13 . The oligonucleotide conjugate of claim 1 , wherein the asialoglycoprotein receptor targeting conjugate moiety is mono-valent, di-valent, tri-valent or tetra-valent.

14 . The oligonucleotide conjugate of claim 1 , wherein the asialoglycoprotein receptor targeting conjugate moiety is a tri-valent N-acetylgalactosamine (GalNAc) moiety.

15 . The oligonucleotide conjugate of claim 1 , wherein the asialoglycoprotein receptor targeting conjugate moiety is the trivalent GalNAc moiety in FIG. 3 .

16 . The oligonucleotide conjugate of claim 1 , wherein the oligonucleotide conjugate is selected from CMP ID NO: 766_2, 767_2, 768_2, 769_2 and 770_2.

17 . An antisense oligonucleotide comprising an oligonucleotide or a contiguous nucleotide sequence according to claim 1 .

18 . A pharmaceutical composition comprising the oligonucleotide conjugate claim 1 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

19 . 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 an oligonucleotide conjugate of claim 1 in an effective amount to said cell.

20 . A method for treating a disease comprising administering a therapeutically or prophylactically effective amount of an oligonucleotide conjugate of claim 1 to a subject suffering from or susceptible to the disease.

21 . The method of claim 20 , wherein the disease is selected from viral liver infections such as HBV, HCV and HDV; parasite infections such as malaria, toxoplasmosis, leishmaniasis and trypanosomiasis; and liver cancer or metastases in the liver.

22 . A method for restoration of immune response against a virus or parasite comprising administering a therapeutically or prophylactically effective amount of an oligonucleotide conjugate of claim 1 to a subject infected with a virus or parasite.

23 . The method of claim 22 , 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.

Assignees

• Roche Innovation Ct Copenhagen As
• Hoffmann La Roche

Inventors

• Pedersen Lykke
• Javanbakht Hassan
• Jackerott Malene
• Ottosen Søren
• Luangsay Souphalone

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title