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Publication Number
US-12478687-B2
Publication Date
2025-11-25
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 disclosure describes muscle-targeting complexes in which an anti-transferrin receptor antibody is covalently linked to a molecular payload for receptor-mediated delivery into muscle cells. The antibody features humanized variable-region frameworks, and the molecular payload comprises a phosphorodiamidate morpholino oligomer complementary to a dystrophin sequence for exon skipping. The complex is configured for administration to deliver the oligonucleotide to target cells and treat Duchenne muscular dystrophy.
The content describes muscle delivery as an intended use and reports HPRT proof-of-concept findings in cultured cells and mouse tissues. Testing of the DMD-targeting complex is presented as a proposed example rather than as a reported result. The background text is not provided, so the specific background problem is not explicitly described in the patent.
Claims Coverage
The claims identify two inventive features directed to methods using a complex comprising a humanized anti-transferrin receptor antibody covalently linked to a DMD-complementary phosphorodiamidate morpholino oligomer.
Delivery of a DMD-targeting oligonucleotide to a cell
A method of delivering an oligonucleotide to a cell in a subject by administering a complex comprising an anti-transferrin receptor antibody covalently linked to a 20-to-29-nucleotide phosphorodiamidate morpholino oligomer complementary to a dystrophin sequence, wherein the antibody comprises humanized framework regions.
Treatment of Duchenne muscular dystrophy
A method of treating Duchenne muscular dystrophy in a subject by administering a complex comprising an anti-transferrin receptor antibody covalently linked to a 20-to-29-nucleotide phosphorodiamidate morpholino oligomer complementary to a dystrophin sequence, with dependent claims specifying exon 44 or exon 45 skipping.
The independent claims cover cellular delivery of an oligonucleotide and treatment of Duchenne muscular dystrophy using an anti-transferrin receptor antibody covalently linked to a dystrophin-targeting phosphorodiamidate morpholino oligomer.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Delivery of an oligonucleotide to a cell in a subject using a complex comprising an anti-transferrin receptor antibody covalently linked to the oligonucleotide.
Treatment of Duchenne muscular dystrophy and other dystrophinopathies using the antibody–oligonucleotide complex, with dependent claims identifying exon 44 and exon 45 skipping.
HPRT proof-of-concept evaluation in cultured cells and mouse tissues, demonstrating reductions in HPRT in muscle tissues with no corresponding reduction in tested non-muscle tissues.
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