Compositions and methods of treating facioscapulohumeral muscular dystrophy

Patent metadata

Field	Value
Publication number	US-11999955-B2
Application number	US-202218052898-A
Country	US
Kind code	B2
Filing date	Nov 4, 2022
Priority date	Mar 19, 2020
Publication date	Jun 4, 2024
Grant date	Jun 4, 2024

Abstract

Disclosed herein are polynucleic acid molecules, pharmaceutical compositions, and methods for treating Facioscapulohumeral muscular dystrophy.

First claim

The invention claimed is:

1. A polynucleotide-antibody conjugate comprising an anti-transferrin receptor antibody or antigen binding fragment thereof conjugated to a polynucleotide, wherein the polynucleotide is from 19 to 30 nucleotides in length, wherein the polynucleotide comprises a nucleic acid sequence selected from a group consisting of SEQ ID NOs: 72, 76, 126, 131, 132, 134, 135, 136, 212, 216, 266, 271, 272, 274, 275, and 276 and wherein the polynucleotide mediates RNA interference against DUX4 mRNA and downregulation of DUX4 biomarker mRNA level.

2. The polynucleotide-antibody conjugate of claim 1 , wherein the polynucleotide is a single stranded polynucleotide.

3. The polynucleotide-antibody conjugate of claim 2 , wherein the single stranded polynucleotide is an antisense oligonucleotide (ASO) or a phosphorodiamidate morpholino oligomers (PMO).

4. The polynucleotide-antibody conjugate of claim 1 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof binds to a transferrin receptor on a cell surface of a muscle cell.

5. The polynucleotide-antibody 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.

6. The polynucleotide-antibody conjugate of claim 1 , wherein the polynucleotide hybridizes to at least 8 contiguous bases of the target sequence of a human DUX4 mRNA.

7. The polynucleotide-antibody conjugate of claim 1 , wherein the polynucleotide is from 19 to 25 nucleotides in length.

8. The polynucleotide-antibody conjugate of claim 1 , wherein the polynucleotide-antibody conjugate comprises a linker connecting the anti-transferrin receptor antibody or antigen binding fragment thereof to the polynucleotide.

9. The polynucleotide-antibody conjugate of claim 5 , 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′-ODMAOE), 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), ethylene nucleic acid (ENA), or a combination thereof.

10. The polynucleotide-antibody conjugate of claim 5 , wherein the at least one modified internucleotide linkage comprises a phosphorodithioate linkage.

11. The polynucleotide-antibody conjugate of claim 5 , wherein the polynucleotide comprises three or more 2′ modified nucleotides selected from 2-O-methyl modified nucleotide and 2′-deoxy-2′-fluoro modified nucleotide.

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

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

14. The polynucleotide-antibody conjugate of claim 1 , wherein the polynucleotide-antibody conjugate is formulated for parenteral administration.

15. The polynucleotide-antibody conjugate of claim 1 , wherein the downregulation of DUX4 biomarker mRNA level is evaluated by expression level of one or more DUX4 biomarker genes selected from a group consisting of MBD3L2, TRIM43, PRAMEF1, ZSCAN4, KHDC1L, and LEUTX.

16. The polynucleotide-antibody conjugate of claim 1 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is conjugated to the 5′ end of the polynucleotide.

Assignees

• Avidity Biosciences Inc

Inventors

• Malecova Barbora
• Burke Rob
• Sala Cano David
• Darimont Beatrice Diana

Classifications

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• A61K31/7125

  Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters · CPC title

• A61K47/6807 Primary

  the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61K47/6889

  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 · CPC title