Muscle targeting complexes and formulations for treating facioscapulohumeral muscular dystrophy
Inventors
Weeden, Timothy • Hsia, Nelson • Zanotti, Stefano • Beskrovnaya, Oxana • Qiu, Qifeng • Hilderbrand, Scott • Deckert, Jochen • Vornlocher, Hans-Peter • Hossbach, Markus • Hultsch, Kathrin • Yoder, Nicholas C. • Vieira, Benjamin
Assignees
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Publication Number
US-12752013-B2
Publication Date
2026-10-06
Expiration Date
Abstract
Aspects of the disclosure relate to complexes and other aspects relate to formulations (e.g., aqueous, lyophilized forms) comprising such complexes comprising an oligonucleotide (e.g., an RNAi oligonucleotide such as an siRNA, useful for targeting DUX4) covalently linked to an antibody (e.g., anti-TfR1 antibody).
Core Innovation
The disclosure describes muscle-targeting complexes comprising anti-TfR1 Fab fragments covalently linked to DUX4-targeting RNAi oligonucleotides. The oligonucleotides incorporate chemical modifications including 2′-O-methyl and 2′-fluoro nucleosides, phosphorothioate and phosphodiester linkages, and 5′-(E)-vinylphosphonate. One to five oligonucleotide groups are covalently attached to different amino acid residues of a Fab defined by specified heavy- and light-chain sequences.
The technology encompasses pharmaceutical compositions containing the conjugates, including aqueous, Tris, and sucrose formulations provided in lyophilized or frozen forms for intravenous administration. Evaluations describe complex stability during storage alongside reduced DUX4 transcriptome markers in FSHD patient-derived cells and mouse muscle. The complexes are configured to reduce DUX4 expression and treat facioscapulohumeral muscular dystrophy.
Claims Coverage
The claims define four independent claims, specifically claims 1, 8, 15, and 22, encompassing four inventive features that pair specified oligonucleotide structures with a Fab antibody fragment.
Double-stranded oligonucleotide linked to a Fab
Claim 1 covers a complex comprising a double-stranded oligonucleotide group of formula (Ic) covalently linked at attachment point A to a Fab with specified heavy- and light-chain sequences, wherein one to five oligonucleotide groups are linked to different amino acid residues of the Fab.
Specified RNAi oligonucleotide linked to a Fab
Claim 8 covers a complex comprising a specified RNAi oligonucleotide group of formula (Ia) with defined antisense and sense strand sequences and chemical modifications, covalently linked at attachment point A to a Fab with specified heavy- and light-chain sequences, with one to five instances linked to different amino acid residues of the Fab.
Modified oligonucleotide structure linked to a Fab
Claim 15 covers a complex comprising a specified modified oligonucleotide group of formula (Ib), including 2′-O-methyl and 2′-fluoro nucleosides, phosphorothioate and phosphodiester linkages, and 5′-(E)-vinylphosphonate, covalently linked to a Fab with specified heavy- and light-chain sequences at one to five amino acid residues.
Formula (Id) structure linked to a Fab
Claim 22 covers a complex comprising a specified structure of formula (Id), or a pharmaceutically acceptable salt thereof, covalently linked to a Fab with specified heavy- and light-chain sequences, specifying one to five instances linked to different amino acid residues of the Fab.
The independent claims cover four specified oligonucleotide–Fab complex structures sharing covalent attachment of one to five oligonucleotide groups to distinct amino acid residues of a defined Fab fragment.
Stated Advantages
The formulation is reported to retain stability and TfR1 binding.
The complexes are reported to reduce DUX4-marker expression in FSHD patient-derived cells and mouse muscle.
Documented Applications
The complexes are proposed for reducing DUX4 expression and treating facioscapulohumeral muscular dystrophy (FSHD).
The document reports evaluation of DUX4-marker knockdown in FSHD patient-derived cells, myotubes, and mouse muscle.
The composition is formulated for intravenous administration to a human subject.
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