Muscle-targeting complexes and uses thereof
Inventors
Subramanian, Romesh R. • Qatanani, Mohammed T. • Weeden, Timothy • Rhodes, Jason P. • Desjardins, Cody A. • Quinn, Brendan • Najim, John
Assignees
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Publication Number
US-12742007-B2
Publication Date
2026-09-22
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 inhibits activity of a disease allele associated with muscle disease. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.
Core Innovation
The claims describe a complex comprising an anti-transferrin receptor (TfR) antibody covalently linked to a molecular payload configured to modulate expression or activity of a muscle disease gene. The antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 76 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 75, with disclosed forms including humanized antibodies, Fab fragments, and full-chain variants. A composition claim further covers these complexes wherein each antibody is on average covalently linked to 1 to 3 molecular payloads.
The payloads encompass oligonucleotides, such as antisense, RNAi, or morpholino oligonucleotides, as well as peptides or proteins connected through cleavable or non-cleavable linkers. Disclosed experimental systems demonstrate payload delivery and target-gene modulation across DMPK, DMD, ACTA1, and DUX4 muscle disease models, including DMPK mRNA knockdown, splicing correction, and dystrophin restoration. Because the background section is omitted, the problem being solved is not explicitly described in patent.
Claims Coverage
The provided claims identify two independent claims covering an antibody-payload complex and a composition of such complexes, directed to two primary inventive features.
Anti-TfR antibody covalently linked to a molecular payload
A claim covers a complex comprising an anti-transferrin receptor (TfR) antibody covalently linked to a molecular payload configured to modulate expression or activity of a muscle disease gene, wherein the antibody comprises a heavy chain variable region comprising SEQ ID NO: 76 and a light chain variable region comprising SEQ ID NO: 75.
Composition with defined average payload loading
A claim covers a composition comprising complexes in which an anti-TfR antibody comprising the heavy chain variable region of SEQ ID NO: 76 and the light chain variable region of SEQ ID NO: 75 is covalently linked to at least one molecular payload configured to modulate expression or activity of a muscle disease gene, wherein each anti-TfR antibody is on average covalently linked to 1 to 3 molecular payloads.
The independent claims cover the specified anti-TfR antibody covalently linked to a muscle-disease-gene modulating payload and compositions of these complexes having an average loading of 1 to 3 payloads per antibody.
Stated Advantages
The conjugates reduce DMPK expression in mouse and cynomolgus monkey muscle, showing dose-dependent knockdown with effects persisting up to 12 weeks in mice, while causing little change in most non-muscle tissues.
Conjugate treatment alters muscle-gene splicing, reduces nuclear mutant DMPK and myotonia-related measures, and provides functional improvements in disease models.
Conjugates promote dystrophin exon skipping, such as exon 51 and exon 53, and increase dystrophin protein expression, outperforming unconjugated oligonucleotides at matched concentrations.
The conjugates achieve enhanced DUX4 biomarker and target-transcript suppression compared with unconjugated oligonucleotides or non-targeting antibody controls.
A single dose of DTX-C-012 was reported as tolerated.
Documented Applications
Modulating expression or activity of a muscle disease gene in a subject's muscle cells by administering a composition comprising the claimed complex.
Treating Duchenne muscular dystrophy, including applications targeting dystrophin via exon skipping (such as exon 23, exon 51, and exon 53) and restoring dystrophin protein across skeletal muscles and heart in patient cells and dystrophin-deficient mouse models.
Treating myotonic dystrophy type 1, targeting DMPK to produce mRNA knockdown, splicing correction, and reduction of myotonia.
Targeting DUX4 to suppress DUX4-target transcript levels across muscle tissues and cell models in facioscapulohumeral muscular dystrophy contexts.
Target-gene modulation across ACTA1 muscle disease models as well as human and nonhuman-primate myotubes.
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