Muscle targeting complexes and formulations for treating myotonic dystrophy
Inventors
Hilderbrand, Scott • Weeden, Timothy • Najim, John • Zanotti, Stefano • Subramanian, Romesh R. • Qatanani, Mohammed T. • Desjardins, Cody A. • Tang, Kim • Quinn, Brendan
Assignees
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Publication Number
US-12697394-B2
Publication Date
2026-08-04
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., useful for targeting DMPK) covalently linked to an antibody (e.g., anti-TfR1 antibody).
Core Innovation
The complex comprises an anti-TfR1 Fab linked to a DMPK-targeting chemically modified oligonucleotide. The oligonucleotide includes LNA, 2′-deoxyribonucleoside, and 2′-O-methoxyethyl modified nucleosides with phosphorothioate internucleoside linkages. The Fab possesses defined heavy- and light-chain amino acid sequences, with oligonucleotide groups covalently linked to different Fab amino acid residues. Described formulations include aqueous, lyophilized, or frozen forms containing tris(hydroxymethyl)aminomethane and sucrose.
The conjugate demonstrates delivery to cardiac, diaphragm, and skeletal muscle, yielding DMPK knockdown, reduction of nuclear DMPK foci, and correction of disease-associated muscle splicing defects in DM1-model mice. It provides suppression of DMPK expression in DM1 patient and non-human-primate myotubes. Lyophilized conjugate formulations retain key characteristics during storage, supporting therapeutic applications for reducing DMPK expression and treating myotonic dystrophy.
Claims Coverage
The claims identify one independent claim directed to an oligonucleotide–Fab complex, reciting three inventive features.
Chemically modified DMPK-targeting oligonucleotide
The complex includes a chemically modified oligonucleotide directed to DMPK comprising specified nucleotide modifications and phosphorothioate internucleoside linkages.
Fab with defined chain sequences
The complex comprises an anti-TfR1 Fab possessing defined heavy-chain and light-chain amino acid sequences.
Covalent attachment to Fab amino acid residues
Each oligonucleotide is covalently linked to a different amino acid residue of the Fab.
The independent claim covers the specified modified oligonucleotide–Fab complex and its covalent linkage arrangement, while dependent claims encompass refinements to attachment features, salt forms, formulations, and methods directed to reducing DMPK expression or treating myotonic dystrophy.
Stated Advantages
The conjugate delivers the oligonucleotide to cardiac, diaphragm, and skeletal muscle, producing DMPK knockdown, reduction of nuclear DMPK foci, and correction of muscle splicing defects in DM1-model mice.
The conjugate produces DMPK knockdown and suppression of DMPK expression in DM1 patient and non-human-primate myotubes.
A Tris and sucrose formulation is favorable, and lyophilized conjugate formulations retain key characteristics and stability during storage.
Documented Applications
Therapeutic use and methods for reducing DMPK expression and treating myotonic dystrophy, including myotonic dystrophy type 1 and disease associated with a CTG trinucleotide repeat.
Formulations of the conjugate, including aqueous, lyophilized, frozen, Tris and sucrose, and intravenous formulations.
Evaluation of DMPK knockdown, nuclear DMPK foci reduction, and splicing defect correction in DM1-model mice, DM1 patient myotubes, and non-human-primate myotubes.
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