Modified oligonucleotides and methods of use

Patent metadata

Field	Value
Publication number	US-12077757-B2
Application number	US-202017063080-A
Country	US
Kind code	B2
Filing date	Oct 5, 2020
Priority date	Sep 14, 2016
Publication date	Sep 3, 2024
Grant date	Sep 3, 2024

Abstract

Modified oligonucleotides comprising modifications at the 2′ and/or 3′ position(s) along with methods of making and use, e.g., against HBV are disclosed.

First claim

The invention claimed is:

1. A chimeric antisense oligonucleotide represented by Formula (A):
5′-X-Y-Z3′  (A),

wherein
X-Y-Z is a chimeric oligonucleotide comprising a sequence of 18 to 22 nucleosides, optionally conjugated at the 5′ and/or 3′ end to a ligand targeting group;
X is a domain comprising a sequence of modified nucleosides that is 3 to 10 nucleosides in length;
Z is a domain comprising a sequence of modified nucleosides that is 3 to 10 nucleosides in length; and
Y is a domain comprising a sequence of 2 to 10 2′-deoxy-nucleosides linked through thiophosphate intersubunit linkages,
each modified nucleoside in the X domain and each modified nucleoside in the Z domain are nucleosides of Formula (1)

wherein
R is H or a positively charged counter ion,
B is a nucleobase independently selected from the group consisting of adenine, guanine, thymine, cytosine, uracil, 5-methylcytosine, 2,6-diaminopurine, and 5-methyluracil,
R 1 is —CR′ 3 , —CR′ 2 OCR′ 3 , —(CR′ 2 ) 3 OCR′ 3 , —(CR′ 2 ) 1-2 CR′ 3 , —(CR′ 2 ) 2 OCR′ 3 , or —Et, and
R′ is independently in each instance H or F, and
wherein the oligonucleotide comprises a nucleobase sequence that is complementary or hybridizes to a target RNA.

2. The oligonucleotide of claim 1 ,
wherein R is H,
R is —(CR′ 2 ) 2 OCR′ 3 , and
each R′ is H.

3. The oligonucleotide of claim 1 , wherein the X domain and the Z domain each comprise a sequence of modified nucleosides that is 4-6 nucleosides in length.

4. The oligonucleotide of claim 1 , wherein R 1 is —Et.

5. The oligonucleotide of claim 1 , wherein R 1 is —(CH 2 ) 2 OCH 3 .

6. The oligonucleotide of claim 1 , wherein the Y domain comprises 10 2′-deoxy-nucleosides.

7. The oligonucleotide of claim 6 , wherein the X domain and the Z domain each comprise a sequence of modified nucleosides that is 5 nucleosides in length.

8. The oligonucleotide of claim 1 , wherein the ligand targeting group comprises a GalNAc moiety.

9. The oligonucleotide of claim 1 , wherein each B is independently selected from the group consisting of adenine, guanine, thymine, cytosine, uracil, 5-methylcytosine, 2,6-diaminopurine, and 5-methyluracil.

10. The oligonucleotide of claim 1 , wherein each 2′-deoxy-nucleoside of the Y domain has a nucleobase independently selected from the group consisting of adenine, guanine, thymine, cytosine, uracil, 5-methylcytosine, 2,6-diaminopurine, and 5-methyluracil.

11. The oligonucleotide of claim 1 , wherein the target RNA is viral RNA.

12. The oligonucleotide of claim 1 , wherein the oligonucleotide comprises a nucleobase sequence that is complementary or hybridizes to the target RNA at a higher affinity than an unmodified oligonucleotide of the same sequence.

13. The oligonucleotide of claim 1 , wherein the oligonucleotide complexed with the target RNA under physiological conditions has a melting temperature of >37° C.

14. A pharmaceutical composition comprising the oligonucleotide of claim 1 and a pharmaceutically acceptable excipient.

15. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is formulated for parenteral delivery.

Assignees

• Janssen Biopharma Inc
• Janssen Pharmaceutica Nv

Inventors

• Gryaznov Sergei
• Beigelman Leonid
• Stoycheva Antitsa Dimitrova
• Montero Saul Martinez
• Hong Jin
• Pandey Rajendra K
• Rajwanshi Vivek Kumar
• Pandarinathan Lakshmipathi
• Jin Yi
• Baral Bharat

Classifications

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• A61K31/712

  Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose · CPC title

• C12N2310/3525

  MOE, methoxyethoxy · CPC title

• C12N2310/3145

  with the nitrogen in 3' or 5'-position · CPC title

• C12N2310/351

  Conjugate · CPC title