# US 2024/0197901 A1 · Muscle targeting complexes and uses thereof for treating myotonic dystrophy

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- Number: US 2024/0197901 A1
- Document ID: US20240197901A1
- Status: Published application
- Kind: A1
- Application number: 18/416,981
- Filed: 2024-01-19
- Published: 2024-06-20
- Earliest claimed: 2018-08-02
- Assignees: Dyne Therapeutics, Inc.
- Applicants: Dyne Therapeutics, Inc.
- Inventors: Romesh R. Subramanian; Mohammed T. Qatanani; Timothy Weeden; Cody A. Desjardins
- Web page: https://patentgrep.com/patent/US20240197901A1

## CPC

- A61K 47/6807: {the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- C07K 16/2881: {against CD71}
- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/55: Fab or Fab'
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/77: Internalization into the cell
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- C12N 2310/322: 2'-R Modification
- C12N 2310/3513: Protein; Peptide
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## 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

### Claim at position 1

1-79. (canceled)

### Claim 80

A complex comprising an anti-transferrin receptor antibody covalently linked, via a protease-sensitive linker, to an oligonucleotide that targets a DMPK RNA, wherein the 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).

### Claim 81 (depends on 80)

The complex of claim 80, wherein the 5′ end of the oligonucleotide is covalently linked to a lysine in the anti-transferrin receptor antibody via the protease-sensitive linker.

### Claim 82 (depends on 80)

The complex of claim 80, wherein the protease-sensitive linker comprises a cleavage site of a lysosomal and/or endosomal protease.

### Claim 83 (depends on 82)

The complex of claim 82, wherein the lysosomal and/or endosomal protease is a cathepsin protease.

### Claim 84 (depends on 80)

The complex of claim 80, wherein the protease-sensitive linker comprises a valine-citrulline sequence.

### Claim 85 (depends on 80)

The complex of claim 80, wherein the protease sensitive linker comprises a triazole obtained by a cycloaddition reaction between an azide and an alkyne.

### Claim 86 (depends on 85)

The complex of claim 85, 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.

### Claim 87 (depends on 86)

The complex of claim 86, wherein the protease-sensitive linker further comprises one or more polyethylene glycol units.

### Claim 88 (depends on 80)

The complex of claim 80, wherein each nucleotide in X and Z is a 2′-modified nucleoside.

### Claim 89 (depends on 80)

The complex of claim 80, wherein each internucleoside linkage in the oligonucleotide is a phosphorothioate linkage.

### Claim 90 (depends on 80)

The complex of claim 80, wherein the oligonucleotide is 16, 17 or 18 nucleotides in length.

### Claim 91 (depends on 80)

The complex of claim 80, 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.

### Claim 92 (depends on 80)

The complex of claim 80, wherein the anti-transferrin receptor antibody is in the form of a ScFv, Fab fragment, Fab′ fragment, F(ab′)2 fragment, or Fv fragment.

### Claim 93 (depends on 92)

The complex of claim 92, wherein the anti-transferrin receptor antibody is in the form of a Fab fragment.

### Claim 94 (depends on 80)

The complex of claim 80, wherein the DMPK RNA comprises 38 to 200 repeating CUG units.

### Claim 95 (depends on 80)

The complex of claim 80, wherein administration of the complex to a subject results in reduction of DMPK RNA level by at least 50% in muscle cells of the subject.

### Claim 96 (depends on 80)

The complex of claim 80, wherein administration of the complex to a subject rescues splicing defects in muscle cells of the subject.

### Claim 97 (depends on 80)

The complex of claim 80, wherein the muscle cells are skeletal muscle cells, cardiac muscle cells, or smooth muscle cells.

### Claim 98 (depends on 96)

The complex of claim 96, wherein the subject is human.

### Claim 99 (depends on 96)

The complex of claim 96, wherein the subject is cynomolgus.

### Claim 100 (depends on 80)

The complex of claim 80, wherein the DMPK RNA contains a disease-associated repeat sequence in the 3′-UTR that is associated with myotonic dystrophy type 1 (DM1).