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-12397062-B2
Publication Date
2025-08-26
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 complexes comprise an anti-transferrin receptor antibody covalently linked at a lysine residue to at least one oligonucleotide inducing dystrophin exon 44 skipping. Two antibody configurations are specified, including an antibody lacking human IgG CH2 and CH3 domains, and an antibody comprising defined heavy-chain and light-chain regions. The complexes encompass phosphorodiamidate morpholino oligomers and cleavable linkers comprising a valine-citrulline sequence.
Preclinical evaluations report enhanced dystrophin exon skipping and protein expression across DMD patient cells, mdx mouse muscle tissues, and cynomolgus monkey tissues. Reported assessments additionally describe increased oligonucleotide accumulation, functional performance improvements, and creatine kinase measures in mdx mouse studies. Because the background section is omitted from the supplied content, the problem being solved is not explicitly described in patent.
Claims Coverage
The relevant independent claims cover sequence-defined anti-transferrin receptor antibody-oligonucleotide complexes that induce dystrophin exon 44 skipping, defining two inventive features.
Antibody lacking human IgG CH2 and CH3 domains
The claim specifies an anti-transferrin receptor antibody covalently linked at a lysine residue to at least one oligonucleotide inducing dystrophin exon 44 skipping, wherein the heavy chain comprises a heavy chain variable region, a human IgG CH1 domain, SEQ ID NO: 101, and lacks human IgG CH2 and CH3 domains, and the light chain comprises a light chain variable region, a human kappa light chain constant region, and SEQ ID NO: 90.
Antibody with specified variable and constant region sequences
The claim specifies an anti-transferrin receptor antibody covalently linked at a lysine residue to at least one oligonucleotide inducing dystrophin exon 44 skipping, wherein the heavy-chain variable region comprises SEQ ID NO: 76, the heavy-chain constant-region portion consists of SEQ ID NO: 96, and the light chain comprises SEQ ID NO: 90.
The two independent claims define distinct anti-transferrin receptor antibody configurations covalently linked at a lysine residue to an oligonucleotide that induces dystrophin exon 44 skipping, with dependent claims further reciting oligonucleotide sequences, lengths, phosphorodiamidate morpholino chemistries, linker features, and methods of administration.
Stated Advantages
Anti-TfR Fab-ASO conjugates increase oligonucleotide accumulation in cynomolgus monkey tissues compared with unconjugated ASO.
The description reports enhanced exon skipping and dystrophin protein expression in DMD patient cells and mdx mouse muscle tissues.
The description reports improvements in functional performance and creatine kinase measures in mdx mouse studies.
The description reports increased exon skipping in cynomolgus monkey tissues.
Documented Applications
Inducing dystrophin exon 44 skipping in muscle cells of a subject by administering a composition comprising the claimed complex, including treatment of a subject with Duchenne muscular dystrophy.
Exon 23 skipping and dystrophin protein evaluation in mdx mouse muscle, and exon 53 skipping in DMD patient cells.
Platform evaluation of oligonucleotides promoting DMD exon skipping relating to exon skipping, dystrophin production, functional performance, and antibody binding.
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