IP Library › Granted Patent US 12,280,122
Granted Patent B2
US 12,280,122 · App. 18/799,447 · Granted Apr 22, 2025

Muscle targeting complexes and uses thereof for treating myotonic dystrophy

Inventors: Romesh R. Subramanian (Framingham, MA); Mohammed T. Qatanani (Waltham, MA); Timothy Weeden (Waltham, MA); Cody A. Desjardins (Waltham, MA)
Assignee: Dyne Therapeutics, Inc.
A61K47/6807A61K47/60A61K47/6849A61P21/00C07K16/2881C12N15/1137C07K2317/55C07K2317/92C12N2310/11C12N2310/315C12N2310/322C12N2310/3513
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Quick Facts
Patent No.
US 12,280,122
App. No.
18/799,447
Granted
Apr 22, 2025
Kind
B2
Abstract

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload inhibits expression or activity of a DMPK allele comprising a disease-associated-repeat. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

Claims (27)

1. A composition comprising a plurality of complexes, each complex comprising an anti-transferrin receptor antibody covalently linked, via a protease-sensitive linker, to an oligonucleotide that targets a DMPK RNA, wherein each complex is configured for delivering the oligonucleotide into muscle cells,

wherein the oligonucleotide is 15, 16, 17, or 18 nucleotides in length and comprises a region of complementarity that is fully complementary, along a length of at least 14 contiguous nucleotides, to a coding region of a DMPK sequence as set forth in SEQ ID NO: 15,

wherein the oligonucleotide is configured to bring about degradation of the DMPK RNA via RNase H mediated degradation, wherein the oligonucleotide comprises a 5′-X-Y-Z-3′ formula, wherein X and Z are flanking regions comprising one or more 2′-modified nucleosides selected from the group consisting of: 2′-O-methyl, 2′-fluoro, 2′-O-methoxyethyl, and 2′,4′-bridged nucleosides, wherein Y is a gap region and each nucleoside in Y is a 2′-deoxyribonucleoside, and wherein the oligonucleotide comprises one or more phosphorothioate internucleoside linkages; and

wherein the anti-transferrin receptor antibody binds an extracellular domain of a transferrin receptor protein 1 (TfR1).

2. The composition of claim 1 , wherein the 5′ end of the oligonucleotide is covalently linked to a lysine in the anti-transferrin receptor antibody via the protease-sensitive linker.

3. The composition of claim 1 , wherein the protease-sensitive linker comprises a cleavage site of a lysosomal and/or endosomal protease.

4. The composition of claim 3 , wherein the lysosomal and/or endosomal protease is a cathepsin protease.

5. The composition of claim 1 , wherein the protease-sensitive linker comprises a valine-citrulline sequence.

6. The composition of claim 1 , wherein the protease sensitive linker comprises a triazole obtained by a cycloaddition reaction between an azide and an alkyne.

7. The composition of claim 6 , wherein prior to the cycloaddition reaction, the azide is located on the protease sensitive linker that is covalently linked to the 5′ end of the oligonucleotide and the alkyne is provided in a bicyclononyne moiety, and wherein the protease-sensitive linker further covalently links to the anti-transferrin receptor antibody.

8. The composition of claim 7 , wherein the protease-sensitive linker further comprises one or more polyethylene glycol units.

9. The composition of claim 1 , wherein each nucleotide in X and Z is a 2′-modified nucleoside.

10. The composition of claim 1 , wherein each internucleoside linkage in the oligonucleotide is a phosphorothioate linkage.

11. The composition of claim 1 , wherein the oligonucleotide is 16, 17 or 18 nucleotides in length.

12. The composition of claim 1 , wherein the region of complementarity is fully complementary, along a length of at least 16 contiguous nucleotides, to the coding region of the DMPK sequence.

13. The composition of claim 1 , wherein the anti-transferrin receptor antibody is in the form of a ScFv, Fab fragment, Fab′ fragment, F(ab′)2 fragment, or Fv fragment.

14. The composition of claim 13 , wherein the anti-transferrin receptor antibody is in the form of a Fab fragment.

15. The composition of claim 1 , wherein the DMPK RNA comprises 38 to 200 repeating CUG units.

16. The composition of claim 1 , wherein administration of the composition to a subject results in reduction of DMPK RNA level by at least 50% in muscle cells of the subject.

17. The composition of claim 1 , wherein administration of the composition to a subject rescues splicing defects in muscle cells of the subject.

18. The composition of claim 1 , wherein the muscle cells are skeletal muscle cells, cardiac muscle cells, or smooth muscle cells.

19. The composition of claim 17 , wherein the subject is human.

20. The composition of claim 17 , wherein the subject is cynomolgus.

21. The composition of claim 1 , further comprising a pharmaceutically acceptable carrier.

22. The composition of claim 1 , wherein the composition is formulated for intravenous administration.

23. The composition of claim 1 , wherein the complexes of the composition on average comprise 1 to 3 oligonucleotides.

24. The composition of claim 1 , wherein the DMPK RNA contains a disease-associated repeat sequence in the 3′-UTR that is associated with myotonic dystrophy type 1 (DM1).

Assignments (2)
SECURITY INTEREST Recorded Jun 27, 2025
From: DYNE THERAPEUTICS, INC.
To: HERCULES CAPITAL, INC., AS AGENT
Reel/Frame 071777/0300 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 16, 2024
From: SUBRAMANIAN, ROMESH R.; QATANANI, MOHAMMED T.; WEEDEN, TIMOTHY; DESJARDINS, CODY A.
To: DYNE THERAPEUTICS, INC.
Reel/Frame 068596/0967 →
Continuity (9)
Continuation 18416981 · Jan 19, 2024
Continuation 17205102 · Mar 18, 2021
Continuation 17264905
Provisional Application 62859672 · Jun 10, 2019
Provisional Application 62858888 · Jun 7, 2019
Provisional Application 62855761 · May 31, 2019
Provisional Application 62779161 · Dec 13, 2018
Provisional Application 62713914 · Aug 2, 2018
Related Publication 20240398967A1 · Dec 5, 2024
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