IP Library › Granted Patent US 12,409,230
Granted Patent B2
US 12,409,230 · App. 18/759,724 · Granted Sep 9, 2025

Compositions comprising PLN-targeting anti-transferrin receptor antibody-polynucleotides and methods of use thereof to treat cardiomyopathy

Inventors: Cecilia Hurtado (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.
A61K47/549A61K47/6849A61P9/00C12N15/113C12N2310/14C12N2310/315C12N2310/321C12N2310/3231C12N2310/3513
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Quick Facts
Patent No.
US 12,409,230
App. No.
18/759,724
Granted
Sep 9, 2025
Kind
B2
Abstract

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

Claims (28)

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 PLN mRNA and mediates downregulation of the PLN mRNA in a cardiac muscle cell, wherein the polynucleotide hybridizes to a nucleic acid sequence at positions 195-213, 242-379, 449-546, 780-811, 967-1002, 1072-1099, 1119-1138, and 1234-1253 of the PLN mRNA (NM 002667.5).

2. The polynucleotide conjugate of claim 1 , wherein the target sequence of the PLN mRNA is a genetic PLN variant having a genetic mutation selected from Arg14del (R14del), Arg9Cys (R9C), and Arg25Cys (R25C).

3. The polynucleotide conjugate of claim 1 , wherein the polynucleotide is an antisense oligonucleotide (ASO) or a double-stranded small interfering RNA (siRNA) comprising a guide strand and a passenger strand.

4. The polynucleotide conjugate of claim 3 , wherein the ASO comprises a nucleic acid sequence selected from SEQ ID NOs: 265-276.

5. The polynucleotide conjugate of claim 3 , wherein the ASO comprises a nucleic acid sequence having at least 14, 15, 16, 17, or 18 consecutive nucleotides from a sequence selected from SEQ ID NOs: 265-276.

6. The polynucleotide conjugate of claim 3 , wherein the passenger strand comprises a nucleic acid sequence selected from SEQ ID NOs: 144, 152, 155, 158-160, 162-166, 168-170, 172-177, 181, 187-188, 191-192, 196, 198, 200, 203, 206, 210-216, 225-228, 230, 232, 235-238, 241, 245-247, 254-255, 315, and 317.

7. The polynucleotide conjugate of claim 3 , wherein the guide strand comprises a nucleic acid sequence selected from SEQ ID NOs: 12, 20, 23, 26-28, 30-34, 36-38, 40-45, 49, 55-56, 59-60, 64, 66, 68, 71, 74, 78-84, 93-96, 98, 100, 103-106, 109, 113-115, 122-123, 301, and 303.

8. The polynucleotide conjugate of claim 3 , wherein the passenger strand comprises a nucleic acid sequence having at least 16, 17, 18, 19, 20, or 21 consecutive nucleotides from a sequence selected from SEQ ID NOs: 144, 152, 155, 158-160, 162-166, 168-170, 172-177, 181, 187-188, 191-192, 196, 198, 200, 203, 206, 210-216, 225-228, 230, 232, 235-238, 241, 245-247, 254-255, 315, and 317.

9. The polynucleotide conjugate of claim 3 , wherein the guide strand comprises a nucleic acid sequence having at least 16, 17, 18, 19, 20, or 21 consecutive nucleotides from a sequence selected from SEQ ID NOs: 12, 20, 23, 26-28, 30-34, 36-38, 40-45, 49, 55-56, 59-60, 64, 66, 68, 71, 74, 78-84, 93-96, 98, 100, 103-106, 109, 113-115, 122-123, 301, and 303.

10. 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.

11. The polynucleotide conjugate of claim 10 , 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), 2′-O—N-methylacetamido (2′-O-NMA) modified nucleotide, locked nucleic acid (LNA), or ethylene nucleic acid (ENA), or a combination thereof.

12. The polynucleotide conjugate of claim 10 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.

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

14. 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.

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

16. 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.

17. A polynucleotide molecule for modulating PLN mRNA expression, wherein the polynucleotide molecule is a single stranded ASO comprising a nucleic acid sequence selected from SEQ ID NOs: 265-276, or the polynucleotide molecule is a double stranded siRNA comprising a guide strand and a passenger strand, wherein the guide strand comprises a nucleic acid sequence selected from SEQ ID NOs: 12, 20, 23, 26-28, 30-34, 36-38, 40-45, 49, 55-56, 59-60, 64, 66, 68, 71, 74, 78-84, 93-96, 98, 100, 103-106, 109, 113-115, 122-123, 301, and 303.

18. A conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to an siRNA or an ASO that decreases PLN mRNA levels in a cardiac muscle cell, wherein the anti-transferrin receptor antibody or antigen-binding fragment thereof comprises a VH sequence of SEQ ID NO: 376, 377, 378, 379, or 380, and a VL sequence of SEQ ID NOs: 381, 382, 383, 384, or 385, and wherein the ASO comprises a nucleic acid sequence selected from SEQ ID NOs: 265-276, and wherein a guide strand sequence of the siRNA comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 12, 20, 23, 26-28, 30-34, 36-38, 40-45, 49, 55-56, 59-60, 64, 66, 68, 71, 74, 78-84, 93-96, 98, 100, 103-106, 109, 113-115, 122-123, 301, and 303 and a passenger strand sequence of the siRNA comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 144, 152, 155, 158-160, 162-166, 168-170, 172-177, 181, 187-188, 191-192, 196, 198, 200, 203, 206, 210-216, 225-228, 230, 232, 235-238, 241, 245-247, 254-255, 315, and 317.

19. The conjugate of claim 18 , wherein the passenger stand 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 is selected from the group consisting of the guide strand sequence of SEQ ID NO: 31 and the passenger strand sequence of SEQ ID NO: 163; the guide strand sequence of SEQ ID NO: 36 and the passenger strand sequence of SEQ ID NO: 168; the guide strand sequence of SEQ ID NO: 37 and the passenger sequence of SEQ ID NO: 169; the guide strand sequence of SEQ ID NO: 49 and the passenger strand sequence of SEQ ID NO: 181; the guide strand sequence of SEQ ID NO: 59 and the passenger strand sequence of SEQ ID NO: 191; the guide strand sequence of SEQ ID NO: 74 and the passenger strand sequence of SEQ ID NO: 206; the guide strand sequence of SEQ ID NO: 96 and the passenger strand sequence of SEQ ID NO: 228; the guide strand sequence of SEQ ID NO: 301 and the passenger strand sequence of SEQ ID NO: 315; and the guide strand sequence of SEQ ID NO: 303 and the passenger strand sequence of SEQ ID NO: 317.

23. A method of treating a cardiomyopathy associated with PLN 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 PLN mRNA, thereby treating the cardiomyopathy in said subject, wherein the polynucleotide hybridizes to a nucleic acid sequence at positions 195-213, 242-379, 449-546, 780-811, 967-1002, 1072-1099, 1119-1138 and 1234-1253 of the PLN mRNA (NM_002667.5).

24. The method of claim 23 , wherein the cardiomyopathy associated with PLN is a genetic cardiomyopathy associated with a genetic PLN variant comprising a genetic mutation selected from Arg14del (R14del), Arg9Cys (R9C), and Arg25Cys (R25C).

25. The method of claim 23 , wherein the cardiomyopathy associated with PLN is a dilated cardiomyopathy or a hypertrophic cardiomyopathy.

26. The method of claim 25 , wherein the dilated cardiomyopathy is a genetic dilated cardiomyopathy associated with TTN, LMNA, RI3M20, SCN5A, MYH7, TNNT2, and TPMI mutations.

27. The method of claim 25 , wherein the hypertrophic cardiomyopathy is associated with MYH7, MYBPC3, TNNT2, TNNC, and TPM1 mutations.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 20, 2026
From: AVIDITY BIOSCIENCES, INC.
To: ATRIUM THERAPEUTICS, INC.
Reel/Frame 074143/0954 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 1, 2024
From: HURTADO, CECILIA; KARAMANLIDIS, GEORGIOS; ABDULKADIR, SAMI ABDULWAHAB; NALLAGATLA, SUBBARAO; JORDAN, MARYAM
To: AVIDITY BIOSCIENCES, INC.
Reel/Frame 068159/0564 →
Continuity (2)
Provisional Application 63511450 · Jun 30, 2023
Related Publication 20250032622A1 · Jan 30, 2025
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