Chiral nucleic acid adjuvant having antitumor effect and antitumor agent

• US 10,149,905 B2
• Filed: 01/14/2015
• Issued: 12/11/2018
• Est. Priority Date: 01/15/2014
• Status: Active Grant

• Current Assignee: Wave Life Sciences Japan, Inc.
• Original Assignee: Shin Nippon Biomedical Laboratories Limited, Wave Life Sciences Japan, Inc.
• Inventors: Gemba, Takefumi, Nagata, Ryoichi, Torikai, Yusuke
• Primary Examiner(s): Whiteman, Brian A
• Application Number:
  US15/111,798
• Publication Number:
  US 20160331836A1
• Time in Patent Office: 1,427 Days
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/572 cytotoxic response
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/117 Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
• CPC Class Codes: C12N 2310/17 Immunomodulatory nucleic acids
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/344 Position-specific modifications, e.g. on every purine, at the 3'-end
• CPC Class Codes: C12N 2320/31 Combination therapy

Abstract

Summary

Problem

The purpose of the present invention is to provide: a chiral nucleic acid adjuvant having anti-tumor activity; and an anti-tumor agent.

Solution

The present invention relates to an adjuvant for anti-tumor agent, wherein the adjuvant comprises oligonucleotides which comprise two to four CpG motif each represented by 5′-X₁CpGX₂-3′ and has a length of 14 to 32 nucleotides, wherein a nucleic acid at 3′ end side of at least two CpG motifs is connected by phosphorothioate linkage,

wherein each nucleic acid at 3′ end and 5′ end of the oligonucleotide is S type nucleic acid connected by phosphorothioate linkage, and wherein the oligonucleotide comprises at least one nucleic acid without phosphorothioate modification. The present invention relates to an anti-tumor agent containing its adjuvant.

Claims

1. An adjuvant comprising an oligonucleotide which comprises two to four CpG motifs each represented by 5′

-X₁CpGX₂-3′ and

has a length of 14 to 32 nucleotides,

wherein each CpG is a non-methylated CpG without a modified phosphate backbone;

wherein the X₁ is A;

wherein the X₂ is T;

wherein the 3′

end side of at least two CpG motifs are independently connected to a nucleic acid moiety comprising a phosphorothioate linkage,

wherein linkages at both the 3′

end and the 5′

end of the oligonucleotide are S type phosphorothioate linkages;

wherein the oligonucleotide comprises at least one linkage that is not a phosphorothioate linkage outside of the CpG motif; and

wherein the oligonucleotide comprises a 5′

-ACpGTT^SPT^SP-3′

motif, wherein each SP represents an S type phosphorothioate linkage.

2. An agent which comprises the adjuvant of claim 1.

4. A method for treating a tumor, comprising administering to a subject suffering therefrom an agent of claim 2.

3. A method for treating a tumor, comprising administering to a subject suffering therefrom an adjuvant comprising an oligonucleotide which comprises two to four CpG motifs each represented by 5′

-X₁CpGX₂-3′ and

has a length of 14 to 32 nucleotides,

wherein each CpG is a non-methylated CpG without a modified phosphate backbone;

wherein the X₁ is A;

wherein the X₂ is T;

wherein the 3′

end side of at least two CpG motifs are independently connected to a nucleic acid moiety comprising a phosphorothioate linkage,

wherein linkages at both the 3′

end and the 5′

end of the oligonucleotide are S type phosphorothioate linkages;

wherein the oligonucleotide comprises at least one linkage that is not a phosphorothioate linkage outside of the CpG motif; and

wherein the oligonucleotide comprises a 5′

-ACpGTT^SPT^SP-3′

motif, wherein each SP represents an S type phosphorothioate linkage.