JPWO2020098968A5

JPWO2020098968A5 -

Info

Publication number: JPWO2020098968A5
Application number: JP2021525070A
Authority: JP
Publication date: 2022-11-18

Claims

An L-nucleic acid molecule capable of binding to human CXCL8, said L-nucleic acid molecule comprising a central stretch of nucleotides, said central stretch of nucleotides comprising the nucleotide sequence 5′-GGAAGUACGUGGAAAGCCRA(X _U )RAGUGUGUCCCG-3 'An L-nucleic acid molecule comprising [SEQ ID NO: 27], wherein X _U is U or absent.

2. The L-nucleic acid molecule of claim 1 , wherein said L-nucleic acid molecule comprises a first terminal stretch of nucleotides, said central stretch of nucleotides and a second terminal stretch of nucleotides in the 5'->3' direction. There is
said first terminal stretch of nucleotides comprises 3-6 nucleotides;
said second terminal stretch of nucleotides comprises 3-6 nucleotides;
Preferably,
said first terminal stretch of nucleotides comprising 5-6 nucleotides;
said second terminal stretch of nucleotides comprises 5-6 nucleotides;
More preferably
said first terminal stretch of nucleotides comprising 5 nucleotides;
The L-nucleic acid molecule, wherein said second terminal stretch of nucleotides comprises 5 nucleotides.

said first terminal stretch of nucleotides comprises the nucleotide sequence 5′Z ₁ Z ₂ Z ₃ Z ₄ Z ₅ C 3′ and said second terminal stretch of nucleotides comprises the nucleotide sequence 5′GZ ₆ Z ₇ Z ₈ Z ₉ Z 3. The L nucleic acid molecule of claim 2 , comprising ₁₀ 3',
here,
Z ₁ is G or absent, Z ₂ is S or absent, Z ₃ is K or absent, Z ₄ is S, Z ₅ is D , Z ₆ is H, Z ₇ is S, Z ₈ is M or absent, Z ₉ is S or absent, Z ₁₀ is C or present without;
Preferably,
a) Z ₁ is G, Z ₂ is S, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is S and Z ₁₀ is C, or
b) Z ₁ is absent, Z ₂ is S, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is S and Z ₁₀ is absent, or
c) Z ₁ is absent, Z ₂ is absent, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is absent, Z ₁₀ is absent, or
d) Z ₁ is absent, Z ₂ is absent, Z ₃ is absent, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is absent, Z ₉ is absent, Z ₁₀ is absent, or
e) Z ₁ is absent, Z ₂ is S, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is S and Z ₁₀ is C, or
f) Z ₁ is absent, Z ₂ is absent, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is S and Z ₁₀ is C, or
g) Z ₁ is absent, Z ₂ is absent, Z ₃ is absent, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is S and Z ₁₀ is C, or
h) Z ₁ is G, Z ₂ is S, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is S and Z ₁₀ is absent, or
i) Z ₁ is G, Z ₂ is S, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is absent, Z ₁₀ is absent, or
j) Z ₁ is G, Z ₂ is S, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is absent, Z ₉ is absent, Z ₁₀ is absent, or
k) Z ₁ is absent, Z ₂ is S, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is absent, Z ₁₀ is absent, or
l) Z ₁ is absent, Z ₂ is S, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is absent, Z ₉ is absent, Z ₁₀ is absent, or
m) Z ₁ is absent, Z ₂ is absent, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is S and Z ₁₀ is absent, or
n) Z ₁ is absent, Z ₂ is absent, Z ₃ is absent, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is S and Z ₁₀ is absent, or
o) Z ₁ is absent, Z ₂ is absent, Z ₃ is K, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is absent, Z ₉ is absent, Z ₁₀ is absent, or
p) Z ₁ is absent, Z ₂ is absent, Z ₃ is absent, Z ₄ is S, Z ₅ is D, Z ₆ is H, Z ₇ is S , Z ₈ is M, Z ₉ is absent and Z ₁₀ is absent, L nucleic acid molecule.

The L-nucleic acid molecule according to any one of claims 1 to 3 , wherein said L-nucleic acid molecule consists of ribonucleotides.

said L-nucleic acid molecule comprises a nucleotide sequence selected from the group of SEQ ID NOS: 14-26, 39-44, or said L-nucleic acid molecule is selected from the group of SEQ ID NOS: 14-26, 39-44 or said L-nucleic acid molecule is selected from the group of SEQ ID NOs: 14-26, 39-44 5. The L-nucleic acid molecule according to any one of claims 1 to 4 , comprising an L-nucleic acid molecule that is homologous to said L-nucleic acid molecule comprising a nucleotide sequence that is at least 75% homologous to .

The L-nucleic acid molecule contains a modifying group, and preferably the excretion rate of the L-nucleic acid molecule containing the modifying group from an organism is decreased compared to the excretion rate of the L-nucleic acid not containing the modifying group. or/and the L-nucleic acid molecule containing the modifying group has an increased retention time in the organism compared to the retention time in the organism of the L-nucleic acid molecule not containing the modifying group. Item 6. The L-nucleic acid molecule according to any one of Items 1 to 5 .

Said modifying group is selected from the group comprising biodegradable and non-biodegradable modifications, preferably said modifying group is polyethylene glycol, linear polyethylene glycol, branched polyethylene glycol, hydroxyethyl starch, peptide, protein , polysaccharides, sterols, polyoxypropylenes, polyoxyamidates, and poly( 2 -hydroxyethyl)-L-glutamines.

the L-nucleic acid molecule comprises a modifying group;
the modifying group is for immobilization of the L-nucleic acid molecule, or the modifying group allows detection of the L-nucleic acid molecule;
The L-nucleic acid molecule according to any one of claims 1-5 .

An L-nucleic acid molecule according to any one of claims 1 to 8 for use in a method for the treatment and/or prevention of diseases.

An L-nucleic acid molecule according to any one of claims 1 to 8 for use in a method for detecting CXCL8.

An L-nucleic acid molecule according to any one of claims 1 to 8 for producing a detection means or biosensor.

A pharmaceutical composition comprising an L-nucleic acid molecule as defined in any one of claims 1 to 11 and optionally a further component, said further component comprising a pharmaceutically acceptable excipient A pharmaceutical composition selected from an agent, a pharmaceutically acceptable carrier, and a pharmaceutically active agent.

Use of the L-nucleic acid molecule according to any one of claims 1-11 for the manufacture of a medicament.

Use of an L-nucleic acid molecule according to any one of claims 1 to 11 for the manufacture of diagnostic agents, diagnostic tools or biosensors.

Use of an L-nucleic acid molecule according to any one of claims 1 to 11 for detecting CXCL8, preferably human CXCL8.

A kit for detecting CXCL8, said kit comprising an L-nucleic acid molecule according to any one of claims 1 to 11 and at least an instruction manual or a reaction container.

A method for detecting CXCL8 using said L-nucleic acid as defined in any one of claims 1 to 11 in a sample, said method comprising
a) providing a sample containing an unknown concentration of CXCL8;
b) contacting said sample or a dilution thereof with a diagnostic agent, diagnostic means or biosensor, as defined in claim 14;
c) measuring the signal using a diagnostic agent, diagnostic means or biosensor, as defined in claim 14;
d) optionally comparing said signal to a reference;
e) optionally, said concentration of CXCL8 in a sample having an unknown CXCL8 concentration is determined by comparing to a signal obtained from said at least one sample having a known CXCL8 concentration, preferably a known CXCL8 The method, wherein said at least one sample having a concentration is according to steps b) to c).

A complex comprising an L-nucleic acid molecule according to any one of claims 1 to 11 and CXCL8, preferably a crystalline complex.

A method for screening for antagonists of CXCL8-mediated activity comprising:
- providing a candidate antagonist of said activity mediated by CXCL8;
- providing an L-nucleic acid molecule as defined in any one of claims 1-11;
- providing a test system that provides a signal in the presence of an antagonist of said activity mediated by CXCL8;
- determining whether the candidate antagonist of said activity mediated by CXCL8 is an antagonist of said activity mediated by CXCL8.

A method for detecting L-nucleic acids as defined in any one of claims 1 to 11 in a sample, comprising:
a) providing a capture probe and a detection probe, said capture probe being at least in part the first portion of the L-nucleic acid molecule as defined in any one of claims 1 to 11 and the detection probe; said detection probe is at least partially complementary to a second portion of said L-nucleic acid molecule as defined in any one of claims 1 to 11 ; or The capture probe is at least partially complementary to the second portion of the L-nucleic acid molecule as defined in any one of claims 1-11 , and the detection probe is the at least partially complementary to a first portion of said L-nucleic acid molecule as defined in any one of
b) a sample containing the L-nucleic acid molecule according to any one of claims 1 to 11 or a sample presumed to contain an L-nucleic acid molecule as defined in claims 1 to 11 , wherein said adding capture probes and said detection probes separately or in combination;
c) said capture probe and said detection probe react simultaneously or sequentially in any order with said L-nucleic acid molecule as defined in any one or part of claims 1 to 11 ; a step of enabling;
d) optionally detecting whether said capture probe hybridizes to said L-nucleic acid molecule as defined in any one of claims 1 to 11 provided in step a);
e) detecting said complex formed in step c) consisting of said L-nucleic acid molecule and said capture probe and said detection probe as defined in any one of claims 1 to 11 ; A method, including