Granted Patent B1

US 12,370,264 · App. 19/066,035 · Granted Jul 29, 2025

Inventors: Romesh R. Subramanian (Framingham, MA); Mohammed T. Qatanani (Waltham, MA); Timothy Weeden (Waltham, MA); Cody A. Desjardins (Waltham, MA)

Assignee: Dyne Therapeutics, Inc.

A61K47/6849A61P21/00C07K16/2881C12N15/113C07K2317/24C07K2317/524C07K2317/526C07K2317/565C07K2317/567C07K2317/71C12N2310/11C12N2310/315C12N2310/321C12N2310/322C12N2320/32

Abstract

Claims (35)

1. A complex comprising an anti-transferrin receptor antibody covalently linked to a 5′ end or a 3′ end of an oligonucleotide,

wherein the anti-transferrin receptor antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

the VH comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), and a heavy chain complementarity determining region 3 (CDR-H3) of a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 639, and comprises humanized framework regions,

the VL comprises a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), and a light chain complementarity determining region 3 (CDR-L3) of a light chain variable region comprising the amino acid sequence of SEQ ID NO: 640, and comprises humanized framework regions,

wherein the oligonucleotide comprises one or more modifications and comprises an antisense strand comprising a region of complementarity of at least 15 nucleotides in length to the nucleotide sequence as set forth in SEQ ID NO: 15, wherein the oligonucleotide is in the range of 15-30 nucleotides in length;

wherein the one or more modifications comprise a 2′-modified nucleoside selected from the group consisting of: a 2′-O-methyl nucleoside, a 2′-fluoro nucleoside, and combinations thereof, and/or comprise a modified backbone comprising one or more phosphorothioate linkages.

2. The complex of claim 1 , wherein the antisense strand is 15-23 nucleotides in length.

3. The complex of claim 1 , wherein the region of complementarity is at least 18 nucleotides in length.

4. The complex of claim 1 , wherein the region of complementarity is at least 19 nucleotides in length.

5. The complex of claim 1 , wherein the oligonucleotide is a double-stranded molecule comprising the antisense strand hybridized to a sense strand.

6. The complex of claim 5 , wherein the antisense strand comprises a region of complementarity of at least 15 nucleotides in length to the target sequence of an oligonucleotide as set forth in any one of SEQ ID NOs: 979-985.

7. The complex of claim 6 , wherein each nucleoside of the oligonucleotide is selected from a 2′-O-methyl nucleoside and a 2′-fluoro nucleoside.

8. The complex of claim 7 , wherein the oligonucleotide comprises a modified backbone comprising one or more phosphorothioate linkages.

9. The complex of claim 1 , wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 are according to the Chothia numbering system.

10. The complex of claim 9 , wherein the anti-transferrin receptor antibody is in the form of a full-length IgG comprising a human IgG1 heavy chain constant region, or a functional variant thereof, and a human kappa light chain constant region.

11. The complex of claim 9 , wherein the anti-transferrin receptor antibody comprises a human kappa light chain constant region and a human IgG1 heavy chain constant region comprising at least one amino acid substitution relative to a wild-type human IgG1 heavy chain constant region.

12. The complex of claim 10 , wherein the full-length IgG comprises a heavy chain constant region comprising at least one amino acid substitution that alters the effector function of the anti-transferrin receptor antibody.

13. The complex of claim 12 , wherein the alteration of the effector function comprises reduced Fc receptor binding.

14. The complex of claim 12 , wherein the full-length IgG comprises two or more amino acid substitutions in a CH2 domain and two or more amino acid substitutions in a CH3 domain, relative to a full-length IgG comprising an IgG1 constant region having an amino acid sequence of SEQ ID NO: 37.

15. The complex of claim 10 , wherein one or more amino acid residues in the N-terminal region of a CH2 domain of the antibody are altered.

16. The complex of claim 11 , wherein the anti-transferrin receptor antibody further comprises one or more sugar or carbohydrate molecules.

17. The complex of claim 16 , wherein the one or more sugar or carbohydrate molecules comprise a fucose unit.

18. The complex of claim 12 , wherein the complex is formable by a process comprising reacting a first electrophile of a linker precursor compound and a nucleophile of the anti-transferrin receptor antibody.

19. The complex of claim 18 , wherein the nucleophile of the anti-transferrin receptor antibody is a thiol group of a cysteine of the anti-transferrin receptor antibody.

20. The complex of claim 18 , wherein the first electrophile of the linker precursor compound is a maleimide moiety, and wherein the nucleophile is a thiol-group of a cysteine residue of the anti-transferrin receptor antibody.

21. The complex of claim 20 , wherein the maleimide moiety is present in a (maleimidomethyl)cyclohexane-1-carboxylate group of the linker precursor compound.

22. The complex of claim 20 , wherein the complex is formable by a process comprising reacting a second electrophile of the linker precursor compound and a nucleophile covalently attached to the oligonucleotide.

23. The complex of claim 22 , wherein the nucleophile covalently attached to the oligonucleotide comprises an aminoalkyl group.

24. The complex of claim 23 , wherein the aminoalkyl group is a NH2-C6 group.

25. The complex of claim 24 , wherein the nucleophile covalently attached to the oligonucleotide is covalently attached to a terminal phosphate group of the oligonucleotide.

26. A method of delivering an oligonucleotide to a subject, the method comprising intravenously administering to the subject the complex of claim 1 .

27. The method of claim 26 , wherein the subject has myotonic dystrophy type I.

28. The method of claim 27 , wherein the oligonucleotide is delivered to a muscle cell of the subject.

29. The method of claim 28 , wherein the muscle cell is a skeletal muscle cell, a cardiac muscle cell, or a smooth muscle cell.

30. The method of claim 27 , wherein the subject is human.

Assignments (2)

Continuity (34)

References Cited (400)

Cited By (6)

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