Compositions and Methods for Treating Skeletal Muscle Disease

Patent metadata

Field	Value
Publication number	US-2024216530-A1
Application number	US-202218548823-A
Country	US
Kind code	A1
Filing date	Mar 3, 2022
Priority date	Mar 3, 2021
Publication date	Jul 4, 2024
Grant date	—

Abstract

Compositions and methods are provided for treating myopathies by administering a complex formed between a therapeutic mRNA polynucleotide and a 3E10 antibody or variant thereof, or antigen-binding fragment thereof. In some instances, the complexes are stabilized through a molar ratio of 3E10 antibody or variant thereof, or antigen-binding fragment thereof to therapeutic polynucleotide of at least about 2:1.

First claim

What is claimed is:

1 . A method for treating a genetic skeletal muscle disease in a subject in need thereof, the method comprising:
parenterally administering a therapeutically effective amount of a composition comprising a complex formed between (i) a 3E10 antibody or antigen-binding fragment thereof, and (ii) a therapeutic mRNA polynucleotide encoding a skeletal muscle protein; wherein the 3E10 antibody or antigen-binding fragment thereof comprises: (a) a light chain variable region (VL) complementarity determining region (CDR) 1 comprising the amino acid sequence of 3E10-VL-CDRm (SEQ ID NO:60), (b) a VL CDR2 comprising the amino acid sequence of 3E10-VL-CDR2m (SEQ ID NO:62), (c) a VL CDR3 comprising the amino acid sequence of 3E10-VL-CDR3m (SEQ ID NO:63), (d) a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of 3E10-VH-CDR1m (SEQ ID NO:58), (e) a VH CDR2 comprising the amino acid sequence of 3E10-VH-CDR2m (SEQ ID NO:59), and (f) a VH CDR3 comprising the amino acid sequence of 3E10-VH-CDR3m (SEQ ID NO:60).

2 . The method of claim 1 , wherein the therapeutic mRNA polynucleotide encodes a skeletal muscle polypeptide for which the subject has a loss-of-function mutation.

3 . The method of claim 1 , wherein the 3E10 antibody or antigen-binding fragment thereof comprises:
(a) a light chain variable region (VL) complementarity determining region (CDR) 1 comprising the amino acid sequence of 3E10-VL-CDR1 (SEQ ID NO:9), (b) a VL CDR2 comprising the amino acid sequence of 3E10-VL-CDR2 (SEQ ID NO:10), (c) a VL CDR3 comprising the amino acid sequence of 3E10-VL-CDR3 (SEQ ID NO:11), (d) a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of 3E10-VH-CDR1a (SEQ ID NO:16), (e) a VH CDR2 comprising the amino acid sequence of 3E10-VH-CDR2 (SEQ ID NO:4), and (f) a VH CDR3 comprising the amino acid sequence of 3E10-VH-CDR3 (SEQ ID NO:5).

4 . The method of claim 1 , wherein the genetic skeletal muscle disease is a non-dystrophic genetic myopathy.

5 . The method of claim 1 , wherein the genetic skeletal muscle disease is a dystrophic genetic myopathy.

6 . The method of claim 1 , wherein the parenteral administration is intramuscular administration, intravenous administration, or subcutaneous administration.

7 . The method of claim 1 , wherein the composition comprises a molar ratio of (i) 3E10 antibody or variant thereof, or antigen-binding fragment thereof to (ii) therapeutic polynucleotide of at least 2:1.

8 . The method of claim 7 , wherein the composition comprises a molar ratio of (i) 3E10 antibody or antigen-binding fragment thereof to (ii) therapeutic polynucleotide of at least 5:1.

9 . The method of claim 7 , wherein the composition comprises a molar ratio of (i) 3E10 antibody or antigen-binding fragment thereof to (ii) therapeutic polynucleotide of at least 20:1.

10 . The method of claim 7 , wherein the composition comprises a molar ratio of (i) 3E10 antibody or antigen-binding fragment thereof to (ii) therapeutic polynucleotide of at least 50:1.

11 - 15 . (canceled)

16 . The method of claim 1 , wherein the composition comprises a molar ratio of (i) 3E10 antibody or antigen-binding fragment thereof to (ii) therapeutic polynucleotide of from 2:1 to 50:1, wherein the therapeutic polynucleotide is no more than 2000 nucleotides in length.

17 . The method of claim 1 , wherein the composition comprises a molar ratio of (i) 3E10 antibody or antigen-binding fragment thereof to (ii) therapeutic polynucleotide of from 2:1 to 30:1, wherein the therapeutic polynucleotide is no more than 1000 nucleotides in length.

18 . (canceled)

19 . The method of claim 1 , wherein the subject carries at least one variant form of a gene encoding the skeletal-muscle protein.

20 . The method of claim 1 , wherein the skeletal-muscle polypeptide is selected from the group consisting of nebulin (NEB), skeletal muscle alpha-actin (ACTA), alpha-tropomyosin-3 (TPM3), beta-tropomyosin-2 (TPM2), troponin T1 (TNNT1), cofilin-2 (CFL2), Kelch-repeat-and-BTB-domain-containing-13 (KBTBD13), Kelch-like-family member-40 (KLHL40), Kelch-like protein 4 (KLHL4), Kelch-like-family member 41 (KLHL41), leiomodin-3 (LMOD3), myopalladin (MYPN), ryanodine receptor (RYR1), selenoprotein N (SEPN1), myotubularin (MTM1), dynamin-2 (DNM2), amphiphysin-2 (BIN1), titin (TTN), striated muscle preferentially expressed protein kinase (SPEG), slow-skeletal/beta-cardiac myosin heavy chain (MYH7) cytochrome b, cytochrome c oxidase, thymidine kinase (TK2), polymerase gamma 1 (POLG1), lysosomal enzyme acid alpha-glucosidase (GAA), glycogen-debranching enzyme (AGL), myophosphorylase (PYGM), carnitine transporter OCTN2 (SLC22A5), electron-transfer flavoprotein (ETF), ETF-dehydrogenase (ETFH), adipose triglyceride lipase (PNPLA2), skeletal muscle chloride channel (CIC1), alpha-subunit of the skeletal muscle sodium channel (SCN4A), myotonin-protein kinase (DMPK), zinc finger 9 (ZNF9), dystrophin (DMD), myotilin (MYOT), lamin A/C (LMNA), caveolin 3 (CAV3), DnaJ Heat Shock Protein Family (Hsp40) Member B6 (DNAJB6), desmin (DES), transportin 3, Heterogeneous nuclear ribonucleoprotein D-like (HNRPDL), calpain 3, dysferlin (DYSF), gamma-sarcoglycan (SGCG), alpha-sarcoglycan (SGCA), beta-sarcoglycan (SGCB), delta-sarcoglycan (SGCD), telethonin (TCAP), E3 ubiquitin-protein ligase TRIM32 (TRIM32), Fukutin-related protein (FKRP), Protein O-mannosyl-transferase 1 (POMT1), anoctamin 5 (ANO5), fukutin, Protein O-mannosyl-transferase 2 (POMT2), O-linked-mannose beta-1,2-N acetylglucosaminyltransferase (POMTnG1), dystroglycan (DAG1), plectin (PLEC1), LGMD2R, Trafficking protein particle complex subunit 11 (TRAPPC11), Mannose-1-phosphate guanyltransferase beta (GMPPB), D-ribitol-5-phosphate cytidylyltransferase (ISPD), alpha-glucosidase, LIM and senescent cell antigen-like-containing domain protein 2 (LIMS2), isoprenoid synthase domain containing (ISPD), Popeye-domain containing 1 (POPDC1), lamina-associated polypeptide 1B (TOR1AIP1), Oglucosyltransferase 1 (POGLUT1), Laminin subunit alpha-2 (LAMA2), collagen alpha-1(VI) chain (COL6A1), collagen alpha-2(VI) chain (COL6A2), collagen alpha-3(VI) chain (COL6A3), double homeobox 4 (DUX4), and emerin (EMD).

21 . The method of claim 1 , wherein the 3E10 antibody or antigen-binding fragment thereof comprises a VL comprising an amino acid sequence that is at least 85% identical to 3E10-VL (SEQ ID NO:8).

22 . (canceled)

23 . The method of claim 1 , wherein the 3E10 antibody or antigen-binding fragment thereof comprises a VH comprising an amino acid sequence that is at least 85% identical to 3E10-VH (SEQ ID NO:2).

24 . (canceled)

25 . The method of claim 1 , wherein the 3E10 antibody or antigen-binding fragment thereof comprises:
a heavy chain comprising, from N- to C-terminal, VH-CH1-hinge-CH2-CH3, and a light chain comprising, from N- to C-terminal, VL-CL.

26 . The method of claim 25 , wherein the hinge-CH2-CH3 is an Fc domain selected from the group consisting of the Fc domain from human IgG1, IgG2, IgG3 and IgG4.

27 .- 61 . (canceled)

62 . A pharmaceutical composition comprising a complex formed between (i) a 3E10 antibody or antigen-binding fragment thereof, and (ii) a therapeutic mRNA polynucleotide, wherein the pharmaceutical composition comprises a molar ratio of (a) 3E10 antibody or antigen-binding fragment thereof to (b) therapeutic polynucleotide of at least 2:1; and
wherein the 3E10

Assignees

• Univ Yale
• Gennao Bio Inc

Inventors

• Quijano Elias
• Glazer Peter
• Turner Bruce C
• Squinto Stephen

Classifications

• C07K16/44 Primary

  against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids} · CPC title

• A61K38/1719

  Muscle proteins, e.g. myosin or actin · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61K47/6807

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

• A61K2039/545

  characterised by the dose, timing or administration schedule · CPC title