# US 2017/0283496 A1 · Oligonucleotides for reduction of pd-l1 expression

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- Number: US 2017/0283496 A1
- Document ID: US20170283496A1
- Status: Published application
- Kind: A1
- Application number: 15/458,800
- Filed: 2017-03-14
- Published: 2017-10-05
- Earliest claimed: 2016-03-14
- Applicants: Roche Innovation Center Copenhagen A/S; F. Hoffmann-La Roche AG
- Inventors: Lykke Pedersen; Hassan Javanbakht; Malene Jackerott; Søren Ottosen; Souphalone Luangsay
- Web page: https://patentgrep.com/patent/US20170283496A1

## CPC

- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- A61K 38/1709: {from mammals}
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/20: for DNA viruses
- A61P 33/00: Antiparasitic agents
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 15/1138: {against receptors or cell surface proteins}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2039/505: {comprising antibodies}
- A61K 2039/55516: {Proteins; Peptides}
- A61K 2039/572: {cytotoxic response}
- C07K 2317/70: characterized by effect upon binding to a cell or to an antigen
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2310/351: Conjugate
- G01N 2800/26: Infectious diseases, e.g. generalised sepsis
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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.

## Claims

### 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).

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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.

### Claim 7 (depends on 6)

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.

### Claim 8 (depends on 6)

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

### Claim 9 (depends on 7)

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.

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 10)

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.

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

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.

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 1)

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

### Claim 19 (depends on 1)

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.

### Claim 20 (depends on 1)

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.

### Claim 21 (depends on 20)

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.

### Claim 22 (depends on 1)

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.

### Claim 23 (depends on 22)

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.