IP Library › Granted Patent US 12,491,257
Granted Patent B2
US 12,491,257 · App. 18/755,579 · Granted Dec 9, 2025

Compositions and methods of using PRKAG2-targeting antibody-oligonucleotide conjugates

Inventors: Maria Azzurra Missinato (San Diego, CA); Georgios Karamanlidis (Thousand Oaks, CA); Sami Abdulwahab Abdulkadir (San Diego, CA); Subbarao Nallagatla (San Diego, CA); Maryam Jordan (Escondido, CA)
Assignee: AVIDITY BIOSCIENCES, INC.
A61K47/6807A61K47/6849A61P9/00C07K16/2881C12N15/113C12N2310/11C12N2310/14C12N2310/313C12N2310/321
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Quick Facts
Patent No.
US 12,491,257
App. No.
18/755,579
Granted
Dec 9, 2025
Kind
B2
Abstract

Disclosed herein are polynucleic acid molecules, pharmaceutical compositions, and methods of use for PRKAG2 antibody oligonucleotide conjugates (AOC).

Claims (23)

1 . A polynucleotide conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to a polynucleotide that hybridizes to a target sequence of a human PRKAG2 mRNA and mediates downregulation of the human PRKAG2 mRNA in a cardiac muscle cell, wherein the polynucleotide is a double-stranded small interfering RNA (siRNA) comprising a guide strand and a passenger strand, wherein the guide strand comprises the nucleic acid sequence selected from SEQ ID NOs: 61 and 65.

2 . The polynucleotide conjugate of claim 1 , wherein the target sequence is a human PRKAG2 mRNA having a gain of function mutation.

3 . The polynucleotide conjugate of claim 1 , wherein the passenger strand comprises the nucleic acid sequence selected from SEQ ID NOs: 163 and 167.

4 . The polynucleotide conjugate of claim 1 , wherein the polynucleotide comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety.

5 . The polynucleotide conjugate of claim 4 , wherein the at least one 2′ modified nucleotide comprises:

2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl, 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), or 2′-O—N-methylacetamido (2′-O-NMA) modified nucleotide, a locked nucleic acid (LNA), an ethylene nucleic acid (ENA), or a combination thereof.

6 . The polynucleotide conjugate of claim 4 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.

7 . The polynucleotide conjugate of claim 1 , wherein the polynucleotide comprises a 5′-terminal vinylphosphonate modified nucleotide.

8 . The polynucleotide conjugate of claim 4 , wherein the passenger strand comprises the nucleic acid sequence selected from SEQ ID NOs: 223 and 224.

9 . The polynucleotide conjugate of claim 4 , wherein the guide strand comprises the nucleic acid sequence selected from SEQ ID NOs: 211 and 212.

10 . The polynucleotide conjugate of claim 4 , wherein the guide strand comprises the nucleic acid sequence of SEQ ID NO: 211 or 212 and the passenger strand comprises the nucleic acid sequence of SEQ ID NO: 223 or 224.

11 . The polynucleotide conjugate of claim 1 , wherein the polynucleotide conjugate has a polynucleotide to antibody ratio of from about 1 to about 4.

12 . The polynucleotide conjugate of claim 1 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a non-human antibody or antigen binding fragment thereof, a human antibody or antigen binding fragment thereof, a humanized antibody or antigen binding fragment thereof, a chimeric antibody or antigen binding fragment thereof, a monoclonal antibody or antigen binding fragment thereof, a monovalent Fab′, a divalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody or antigen binding fragment thereof.

13 . The polynucleotide conjugate of claim 1 , wherein polynucleotide conjugate comprises a linker connecting the anti-transferrin receptor antibody or antigen-binding fragment thereof to the polynucleotide.

14 . A polynucleotide molecule for modulating human PRKAG2 mRNA expression, wherein the polynucleotide molecule is a double-stranded siRNA comprising a guide strand and a passenger strand, wherein the guide strand comprises the nucleic acid sequence selected from SEQ ID NOs: 61 and 65.

15 . A method of treating cardiomyopathy in a subject in need thereof comprising administering to said subject a polynucleotide conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to a polynucleotide that hybridizes to a target sequence of a human PRKAG2 mRNA, thereby treating cardiomyopathy in said subject, and wherein the polynucleotide is a double-stranded siRNA comprising a guide strand and a passenger strand, wherein the guide strand comprises the nucleic acid sequence selected from SEQ ID NOs: 61 and 65.

16 . The method of claim 15 , wherein the cardiomyopathy is caused by at least one of: a glycogen storage disease, PRKAG2 syndrome or PRKAG2 cardiac syndrome.

17 . The method of claim 16 , wherein the PRKAG2 syndrome or the PRKAG2 cardiac syndrome is caused by a mutated human PRKAG2 mRNA that has a gain of function.

18 . A conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to an siRNA that decreases human PRKAG2 mRNA levels in a cardiac muscle cell, wherein the anti-transferrin receptor antibody or antigen-binding fragment thereof comprises the VH sequence of SEQ ID NO: 256, 257, 258, 259, or 260, and the VL sequence of SEQ ID NO: 261, 262, 263, 264, or 265, and wherein the guide strand sequence of the siRNA is selected from the group consisting of SEQ ID NOs: 61 and 65, and the passenger strand sequence of the siRNA is selected from the group consisting of SEQ ID NOs: 163 and 167.

19 . The conjugate of claim 18 , wherein the passenger strand or the guide strand of the siRNA comprises a 5′-terminal vinylphosphonate modified nucleotide.

20 . The conjugate of claim 18 , wherein the conjugate comprises a linker connecting the anti-transferrin receptor antibody or antigen-binding fragment thereof to the siRNA.

21 . The conjugate of claim 20 , wherein the linker comprises a maleimide group.

22 . The conjugate of claim 18 , wherein the siRNA comprises the guide strand sequence of SEQ ID NO:61 and the passenger strand sequence of SEQ ID NO:163.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 20, 2026
From: AVIDITY BIOSCIENCES, INC.
To: ATRIUM THERAPEUTICS, INC.
Reel/Frame 074143/0921 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 1, 2024
From: MISSINATO, MARIA AZZURRA; KARAMANLIDIS, GEORGIOS; ABDULKADIR, SAMI ABDULWAHAB; NALLAGATLA, SUBBARAO; JORDAN, MARYAM
To: AVIDITY BIOSCIENCES, INC.
Reel/Frame 068159/0508 →
Continuity (2)
Provisional Application 63510531 · Jun 27, 2023
Related Publication 20250108120A1 · Apr 3, 2025
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