Granted Patent B2

US 12,460,011 · App. 19/189,163 · Granted Nov 4, 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.

C07K16/2881A61K47/6807A61K47/6849A61K47/6889A61P21/00C12N15/113C07K2317/55C07K2317/92

Abstract

Claims (32)

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

wherein the anti-transferrin receptor antibody binds in the range of C89 to F760 of human transferrin receptor protein 1 (TfR1) having an amino acid sequence as set forth in SEQ ID NO: 1;

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 19-25 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 comprise a modified backbone comprising one or more phosphorothioate linkages,

wherein the complex is formable by a process comprising reacting a first electrophile of a linker precursor compound and a thiol group of a cysteine of the anti-transferrin receptor antibody.

2 . The complex of claim 1 , wherein the first electrophile of the linker precursor compound is a maleimide moiety.

3 . The complex of claim 2 , wherein the maleimide moiety is present in a (maleimidomethyl)cyclohexane-1-carboxylate group of the linker precursor compound.

4 . The complex of claim 2 , wherein the complex is formable by a process comprising reacting a second electrophile of the linker precursor compound with a nucleophile covalently attached to the oligonucleotide.

5 . The complex of claim 4 , wherein the nucleophile covalently attached to the oligonucleotide comprises an aminoalkyl group.

6 . The complex of claim 5 , wherein the aminoalkyl group is a NH 2 —C6 group.

7 . The complex of claim 6 , wherein the nucleophile covalently attached to the oligonucleotide is covalently attached to a terminal phosphate group of the oligonucleotide.

8 . The complex of claim 7 , wherein the region of complementarity is 16-21 nucleotides in length.

9 . The complex of claim 7 , 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.

10 . The complex of claim 9 , wherein the oligonucleotide is a double-stranded molecule comprising the antisense strand hybridized to a sense strand.

11 . The complex of claim 10 , wherein each nucleoside of the oligonucleotide is selected from the group consisting of: a 2′-O-methyl nucleoside and a 2′-fluoro nucleoside.

12 . The complex of claim 11 , wherein the anti-transferrin antibody is covalently linked to the oligonucleotide on the 3′ end of the sense strand.

13 . The complex of claim 11 , wherein the anti-transferrin antibody is covalently linked to the oligonucleotide on the 5′ end of the sense strand.

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

15 . The complex of claim 14 , wherein the one or more sugar or carbohydrate molecules comprise a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, a phospholipid unit, or combinations thereof.

16 . The complex of claim 15 , wherein the anti-transferrin receptor antibody is in the form of an IgG, ScFv, Fab fragment, Fab′ fragment, F(ab′)2 fragment, or Fv fragment.

17 . The complex of claim 15 , wherein the anti-transferrin receptor antibody is in the form of a full-length IgG comprising 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.

18 . The complex of claim 17 , the at least one amino acid substitution reduces Fc receptor binding of the anti-transferrin receptor antibody.

19 . The complex of claim 17 , 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 comprising the amino acid sequence of SEQ ID NO: 37.

20 . The complex of claim 18 , wherein the anti-transferrin receptor antibody comprises a CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and a CDRL3 of an antibody selected from the group consisting of: OKT9, M11, M23, M27, B84, 7A4, 8A2, 15D2, 10D11, 7B10, 15G11, 16G5, 13C3, 16G4, 16F6, 7G7, 4C2, 1B12, 13D4, OX26, DF1513, 1A1B2, 66IG10, JF0956, 29806, TFRC/1818, 1E6, 66Ig10, TFRC/1059, Q1/71, 13E4, TFRC/1149, BA120g, LUCA31, B3/25, 5E9C11, BK19.9, and T58/1.

21 . The complex of claim 18 , wherein the anti-transferrin receptor antibody comprises a CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and a CDRL3 of an antibody selected from the group consisting of: OKT9, 7A4, 8A2, 15D2, 10D11, 7B10, 15G11, 16G5, 13C3, 16G4, 16F6, 7G7, 4C2, 1B12, 13D4, OX26, 13E4, B3/25, and BK19.9.

22 . A method of delivering an oligonucleotide to a subject, the method comprising intravenously administering to the subject the complex of claim 21 .

23 . The method of claim 22 , wherein the subject has a muscular dystrophy.

24 . The method of claim 22 , wherein the subject has myotonic dystrophy type I.

25 . The method of claim 24 , wherein the oligonucleotide is delivered to a muscle cell of the subject.

26 . The method of claim 25 , wherein the muscle cell is a skeletal muscle cell, a cardiac muscle cell, or a smooth muscle cell.

27 . The method of claim 26 , wherein the subject is human.

28 . The method of claim 26 , wherein the subject is cynomolgus.

Assignments (2)

Continuity (35)

References Cited (400)

Cited By (3)

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