ß2GPI GENE EXPRESSION-SUPPRESSING NUCLEIC ACID CONJUGATE

Patent metadata

Field	Value
Publication number	US-2018193471-A1
Application number	US-201615740090-A
Country	US
Kind code	A1
Filing date	Jul 15, 2016
Priority date	Jul 16, 2015
Publication date	Jul 12, 2018
Grant date	—

Abstract

The present invention provides a nucleic acid conjugate comprising: a double-stranded nucleic acid consisting of a sense strand and an antisense strand and comprising a duplex region of at least 11 base pairs; and a ligand part, wherein an oligonucleotide with a strand length of 17 to 30 nucleotides in the antisense strand is complementary to a target β2GPI mRNA sequence, and the 3′ end or 5′ end of the sense strand has a ligand part represented by following formula (I), formula (II), formula (III), formula (IV) or formula (V).

First claim

1 - 30 . (canceled)

31 . A nucleic acid conjugate comprising: a double-stranded nucleic acid consisting of a sense strand and an antisense strand and comprising a duplex region of at least 11 base pairs; and
a ligand part, wherein an oligonucleotide strand with a strand length of 17 to 30 nucleotides in the antisense strand is complementary to a target β2GPI mRNA sequence selected from the group described in Tables 4-1 to 4-16, and the 3′ end or 5′ end of the sense strand has the ligand part represented by formula (I), formula (II), formula (III), formula (IV) or formula (V):

(wherein,
X is oligonucleotide-P(Z1)(Z2)-, where the oligonucleotide is the sense strand,
Q is absent or -T4-[Q4-P4]q4-,
R is the following structure

[Chemical Formula 2]

Z1 and Z2 are, independently of each other, O or S;
q1, q2, q3 and q4 are, independently of each other, an integer from 0 to 20;
P1, P2, P3 and P4 and T1, T2, T3 and T4 are, independently of each other, absent or —CO—, —NH—, —O—, —S—, —O—CO—, —NH—CO—, —CO—O— or CO—NH—, respectively, provided that when each of q1, q2, q3 and q4 is an integer from 2 to 20, each of P1, P2, P3 and P4 may be the same or different,
Q1, Q2, Q3 and Q4 are, independently of each other, absent or a substituted or unsubstituted C 1-14 alkylene, provided that when each of q1, q2, q3 and q4 is an integer from 2 to 20, each of Q1, Q2, Q3 and Q4 may be the same or different,
L1, L2 and L3 are, independently of each other, a sugar ligand.)

32 . The nucleic acid conjugate according to claim 31 , wherein one or more of L1, L2 and L3 are a sugar ligand represented by the following structure

(wherein, Ac represents acetyl group).

33 . The nucleic acid conjugate according to claim 31 , wherein L1, L2 and L3 are identical.

34 . The nucleic acid conjugate according to claim 31 , wherein
T1, T2 and T3 are identical, q1, q2 and q3 are identical, Q1, Q2 and Q3 are identical, and P1, P2 and P3 are identical.

35 . The nucleic acid conjugate according to claim 31 , wherein R is

(wherein, Ac represents acetyl group).

36 . The nucleic acid conjugate according to claim 31 , comprising a ligand part represented by any of formulae (I) to (V) at the 3′ end of the sense strand of the double-stranded nucleic acid.

37 . The nucleic acid conjugate according to claim 31 , comprising a ligand part represented by any of formulae (I) to (V) at the 5′ end of the sense strand of the double-stranded nucleic acid.

38 . The nucleic acid conjugate according to claim 31 , wherein
the duplex region comprises 11 to 27 base pairs, and the second nucleotide from the 5′ end of the antisense strand, which is complementary to the target β2GPI mRNA sequence selected from the group described in Tables 4-1 to 4-16, is complementary to the second ribonucleotide from the 3′ end of the target β2GPI mRNA sequence.

39 . The nucleic acid conjugate according to claim 31 , wherein the sense strand has a strand length of 21 to 25 nucleotides, and the antisense strand has a strand length of 21 to 25 nucleotides.

40 . The nucleic acid conjugate according to claim 31 , wherein the 3′ end of the sense strand and the 5′ end of the antisense strand form a blunt end.

41 . The nucleic acid conjugate according to claim 31 , wherein the double-stranded nucleic acid comprises a 2′-modified nucleotide.

42 . The nucleic acid conjugate according to claim 31 , wherein the antisense strand comprises a sequence selected from the group of antisense strands described in Tables 2-1 to 2-18, Tables 3-1 to 3-18 or Tables 4-1 to 4-16.

43 . The nucleic acid conjugate according to claim 31 , wherein the sense strand comprises a sequence selected from the group of sense strands described in Tables 2-1 to 2-18, Tables 3-1 to 3-18 or Tables 4-1 to 4-16.

44 . A nucleic acid conjugate-comprising composition, comprising the nucleic acid conjugate according to claim 31 .

45 . A method for suppressing expression of a β2GPI gene, comprising introducing a double-stranded nucleic acid into cells by using the composition according to claim 44 .

46 . The method according to claim 45 , wherein the cells are cells in the liver of a mammal.

47 . The method according to claim 45 , wherein the method of introduction into cells is a method of introduction into cells by intravenous administration or subcutaneous administration.

48 . A method for treating a β2GPI-associated disease, comprising administrating the composition according to claim 44 to a mammal.

49 . The method according to claim 48 , wherein the β2GPI-associated disease is an autoimmune disease or thrombosis.

50 . The method according to claim 48 , wherein the method of administration is intravenous administration or subcutaneous administration.

Assignees

• Kyowa Hakko Kirin Co Ltd

Inventors

• Nagatomo Kazutaka
• Masuda Kazuhiro
• Kanda Minako
• Yamada Yoji
• Iwai Hiroto
• Makino Asana
• Hosoe Shintaro
• Kuboyama Takeshi
• Uehara Keiji
• Suzuki Yasuhiro

Classifications

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C07H21/02

  with ribosyl as saccharide radical · CPC title

• A61K48/0075

  characterised by an aspect of the delivery route, e.g. oral, subcutaneous · CPC title

• A61K47/549 Primary

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title