CHIRAL NUCLEIC ACID ADJUVANT HAVING ANTITUMOR EFFECT AND ANTITUMOR AGENT

• US 20160331836A1
• Filed: 01/14/2015
• Published: 11/17/2016
• 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: Ukai, Yusuke, Gemba, Takefumi, Nagata, Ryoichi
• Granted Patent: US 10,149,905 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 for anti-tumor agent,

wherein the adjuvant comprises oligonucleotide which comprises two to four CpG motifs each represented by 5′

-X₁CpGX₂-3′ and

has a length of 14 to 32 nucleotides,

wherein the CpG is non-methylated CpG without modified phosphate backbones,

wherein the X₁ is A or T,

wherein the X₂ is A or T,

wherein nucleic acids connected by phosphorothioate (PS) linkage are connected at 3′

end side of the at least two CpG motifs,

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.

2. The adjuvant as claimed in claim 1,

wherein the X₁ is A,

wherein the X₂ is T, and

wherein the nucleic acid bound by phosphorothioate linkage is first phosphorothioated T bound by phosphorothioate linkage.

3. The adjuvant as claimed in claim 2,

wherein the oligonucleotide comprises a second phosphorothioated T at the 3′

end side of the first phosphorothioated T,

wherein a nucleic acid adjacent to 5′

end of the oligonucleotide is a S type nucleic acid bound by phosphorothioate linkage, and

wherein a nucleic acid adjacent to 3′

end of the oligonucleotide is a S type nucleic acid bound by phosphorothioate linkage.

4. The adjuvant as claimed in claim 1,

wherein the oligonucleotide has any of nucleotide sequences selected from nucleotide sequences represented by the sequence number 4, 6, 26, 33, 42, 43, 49-51, 56-58, 60-63, 74, 78-80, 82, 83, 85-96, 98, 99, 101-106, 108, 109 and 111-118.

5. The adjuvant as claimed in claim 1,

wherein the oligonucleotide is

an oligonucleotide represented by sequence number 56, 57, 82, 103 or 109, or

an oligonucleotide where one or more nucleic acids are substituted, deleted, added or inserted in the oligonucleotide represented by sequence number 56, 57, 82, 103 or 109, and has anti-tumor activity.

6. An anti-tumor agent which comprises the adjuvant as claimed in any of claims 1 to 5.

7. An anti-tumor agent,

wherein the agent comprises the adjuvant as claimed in any of claims 1 to 5, and the oligonucleotide as an effective ingredient.