US 2026/0076989 A1 · OLIGONUCLEOTIDES, COMPOSITIONS AND METHODS THEREOF

Abstract

The present disclosure pertains to the recognition that immune responses mediated by CpG oligonucleotides can be affected by the stereochemistry of modified internucleotidic linkages such as phosphorothioates. In some embodiments, the present disclosure relates to chirally controlled CpG oligonucleotide compositions comprising CpG oligonucleotides comprising multiple modified internucleotidic linkages such as phosphorothioate linkages, wherein the oligonucleotides comprise one or more CpG region motifs having defined stereochemistry patterns of chiral internucleotidic linkages. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are capable of agonizing an immune response. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are antagonistic. Methods for making and using chirally controlled CpG oligonucleotide compositions are also described. In some embodiments, no immune modulation is desired, and the present disclosure provides methods of identifying chirally controlled oligonucleotide compositions which have decreased immune modulation.

Claims19

Dependent claims

-22. (canceled)

A composition comprising a plurality of compounds having the structure of:

or a salt thereof,
wherein:
Ac is an oligonucleotide chain;
a is 1-1000;
b is 1-1000;
each LLD is independently a covalent bond or an optionally substituted, C1-C80 saturated or partially unsaturated aliphatic group, wherein one or more methylene units are optionally and independently replaced by TLD or an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, —C≡C—, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2—, —SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—;
each RLD is independently an optionally substituted, C10-C80 saturated or partially unsaturated aliphatic group, wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, —C≡C—, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2—, —SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—;
TLD has the structure of:
W is O, S or Se;
each of X, Y and Z is independently —O—, —S—, —N(-L-R′)—, or L;
L is a covalent bond or an optionally substituted, linear or branched C1-C10 alkylene, wherein one or more methylene units of L are optionally and independently replaced by an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, —C≡C—, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2——SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—;
R1 is halogen, R, or an optionally substituted C1-C50 aliphatic wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, CEC, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2——SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—
each R′ is independently —R, —C(O)R, —CO2R, or —SO2R, or:
two R′ are taken together with their intervening atoms to form an optionally substituted aryl, carbocyclic, heterocyclic, or heteroaryl ring;
—Cy- is an optionally substituted bivalent ring selected from phenylene, carbocyclylene, arylene, heteroarylene, and heterocyclylene;
each R is independently hydrogen, or an optionally substituted group selected from C1-C6 aliphatic, carbocyclyl, aryl, heteroaryl, and heterocyclyl;
and
Ac comprises one or more chiral internucleotidic linkages, and each chiral internucleotidic linkage of Ac is independently chirally controlled.

15 more elements

A method for modulating hTLR9 agonist activity, comprising administering to a subject an oligonucleotide composition, wherein the composition comprises a plurality of compounds having the structure of:

or a salt thereof,
wherein:
Ac is an oligonucleotide chain;
a is 1-1000;
b is 1-1000;
each LLD is independently a covalent bond or an optionally substituted, C1-C80 saturated or partially unsaturated aliphatic group, wherein one or more methylene units are optionally and independently replaced by TLD or an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, —C≡C—, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2—, —SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—;
each RLD is independently an optionally substituted, C10-C80 saturated or partially unsaturated aliphatic group, wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, —C≡C—, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2—, —SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—;
TLD has the structure of:
W is O, S or Se;
each of X, Y and Z is independently —O—, —S—, —N(-L-R′)—, or L;
L is a covalent bond or an optionally substituted, linear or branched C1-C10 alkylene, wherein one or more methylene units of L are optionally and independently replaced by an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, —C≡C—, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2——SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—;
R1 is halogen, R, or an optionally substituted C1-C50 aliphatic wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, CEC, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2——SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—
each R′ is independently —R, —C(O)R, —CO2R, or —SO2R, or:
two R′ are taken together with their intervening atoms to form an optionally substituted aryl, carbocyclic, heterocyclic, or heteroaryl ring;
—Cy- is an optionally substituted bivalent ring selected from phenylene, carbocyclylene, arylene, heteroarylene, and heterocyclylene;
each R is independently hydrogen, or an optionally substituted group selected from C1-C6 aliphatic, carbocyclyl, aryl, heteroaryl, and heterocyclyl;
and
Ac comprises one or more chiral internucleotidic linkages, and each chiral internucleotidic linkage of Ac is independently chirally controlled.

15 more elements

A method for preparing a composition, comprising coupling a phosphoramidite, wherein the composition comprises a plurality of compounds having the structure of:

or a salt thereof,
wherein:
Ac is an oligonucleotide chain;
a is 1-1000;
b is 1-1000;
each LLD is independently a covalent bond or an optionally substituted, C1-C80 saturated or partially unsaturated aliphatic group, wherein one or more methylene units are optionally and independently replaced by TLD or an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, —C≡C—, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2—, —SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—;
each RLD is independently an optionally substituted, C10-C80 saturated or partially unsaturated aliphatic group, wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, —C≡C—, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2—, —SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—;
TLD has the structure of:
W is O, S or Se;
each of X, Y and Z is independently —O—, —S—, —N(-L-R′)—, or L;
L is a covalent bond or an optionally substituted, linear or branched C1-C10 alkylene, wherein one or more methylene units of L are optionally and independently replaced by an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, —C≡C—, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2——SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—;
R1 is halogen, R, or an optionally substituted C1-C50 aliphatic wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C1-C6 alkylene, C1-C6 alkenylene, CEC, a C1-C6 heteroaliphatic moiety, —C(R′)2—, —Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)2——SC(O)—, —C(O)S—, —OC(O)—, and —C(O)O—
each R′ is independently —R, —C(O)R, —CO2R, or —SO2R, or:
two R′ are taken together with their intervening atoms to form an optionally substituted aryl, carbocyclic, heterocyclic, or heteroaryl ring;
—Cy- is an optionally substituted bivalent ring selected from phenylene, carbocyclylene, arylene, heteroarylene, and heterocyclylene;
each R is independently hydrogen, or an optionally substituted group selected from C1-C6 aliphatic, carbocyclyl, aryl, heteroaryl, and heterocyclyl;
and
Ac comprises one or more chiral internucleotidic linkages, and each chiral internucleotidic linkage of Ac is independently chirally controlled.

15 more elements

Dependencies are inferred from the claim text.

Facts

Application

19/271,472Filed 16 Jul 2025

Priority

3 Jun 2016

Published

19 Mar 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

A61K 31/7125
Compounds having three or more nucleosides or nucleotides: nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other…
A61K 31/7088
Carbohydrates; Sugars; Derivatives thereof: compounds having three or more nucleosides or nucleotides
A61P 21/00
Drugs for disorders of the muscular or neuromuscular system
C07H 21/00
Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate

Family

Application62/345,709Us provisional application · filed 3 Jun 2016

Application62/405,816Us provisional application · filed 7 Oct 2016

Application17/177,111Division · filed 16 Feb 2021

Application19/271,472Division

Application16/305,937Continuation

Application17/177,111Continuation

US 11,013,757 B2Related patent

US 12,403,156 B2Related patent

US 2019/0209604 A1Published application

US 2022/0401467 A1Published application

US 2026/0076989 A1This patent

From the US filing history. Foreign family members aren’t listed.

Oligonucleotides, compositions and methods thereof

Life of this patent

Oligonucleotides, compositions and methods thereof

Life of this patent

Abstract

Claims19