Muscle targeting complexes and uses thereof for treating dystrophinopathies
Inventors
Subramanian, Romesh R. • Qatanani, Mohammed T. • Weeden, Timothy • Desjardins, Cody A. • Quinn, Brendan • Najim, John
Assignees
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Publication Number
US-12403203-B2
Publication Date
2025-09-02
Expiration Date
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 promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in a mRNA expressed from a mutant DMD allele.
Core Innovation
The disclosed composition comprises complexes of an anti-transferrin receptor antibody in Fab form covalently linked to oligonucleotides that induce dystrophin exon 55 skipping. The Fab comprises specified heavy- and light-chain amino acid sequences [procedural detail omitted for safety], an average loading of one to three oligonucleotides per antibody, and a defined spacer-containing linker structure. The disclosure further describes phosphorodiamidate morpholino oligomers, pharmaceutical formulations, and methods for treating Duchenne muscular dystrophy.
The conjugate structures include a Val-Cit linker, reactive click-chemistry moieties, and an optional L1 spacer, linking through antibody lysine or cysteine residues at oligonucleotide ends or internally. The disclosure characterizes these complexes for cellular uptake, serum stability, exon skipping, and dystrophin restoration via receptor-mediated uptake into muscle cells. Preclinical evaluations report muscle delivery, increased dystrophin expression, and functional improvements compared with naked oligonucleotides in cell and animal models.
Claims Coverage
The provided claims identify one independent claim directed to an anti-transferrin receptor Fab-oligonucleotide composition, encompassing four inventive features.
Anti-transferrin receptor Fab
The composition comprises complexes containing an anti-transferrin receptor antibody in Fab form comprising specified heavy- and light-chain amino acid sequences [procedural detail omitted for safety].
Covalent oligonucleotide linkage and loading
The Fab is covalently linked to at least one oligonucleotide, with each antibody in the complexes linked on average to one to three oligonucleotides.
Exon 55-skipping oligonucleotide
The covalently linked oligonucleotide induces dystrophin exon 55 skipping.
Specified linker structure
The complexes comprise a defined linker structure wherein n equals 3 and m equals 4, and an L1 spacer selected from stated chemical groups or combinations thereof.
The independent claim covers an anti-transferrin receptor Fab composition covalently linked to exon 55-skipping oligonucleotides, defined by specific antibody chain sequences, average loading, and a designated spacer-containing linker structure.
Stated Advantages
Anti-transferrin receptor conjugates provide muscle delivery, increased dystrophin expression, and functional improvements with increased exon-skipping activity compared with naked oligonucleotides in cell and animal models.
Receptor-mediated uptake provides a delivery mechanism for oligonucleotide payloads into muscle cells to promote dystrophin exon skipping and dystrophin restoration.
Compared with naked ASO, the reported anti-TfR antibody-oligonucleotide conjugate increases exon 23 skipping, dystrophin protein, and muscle ASO accumulation in quadriceps, heart, and diaphragm in mdx mice.
In DMD patient cells, anti-TfR Fab conjugation improves exon 53 skipping compared with naked PMO, including at lower tested doses.
Documented Applications
Pharmaceutical formulations containing anti-transferrin receptor Fab-oligonucleotide conjugates for the treatment of Duchenne muscular dystrophy.
Methods of inducing dystrophin exon 55 skipping in a subject's muscle cells by administering the composition, including in a subject with Duchenne muscular dystrophy.
Muscle delivery of DMD-targeting oligonucleotide payloads, including exon-skipping applications described for dystrophin exons 23 and 53 and gene-editing applications.
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