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-12440575-B2
Publication Date
2025-10-14
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 subject matter is a complex comprising an anti-transferrin receptor antibody covalently linked through a lysine residue to at least one oligonucleotide that induces dystrophin exon 55 skipping. The antibody configurations comprise specified heavy- and light-chain sequences, including heavy chains with a variable region and human IgG CH1 domain lacking human IgG CH2 and CH3 domains, paired with light chains having human kappa constant regions.
The complex delivers molecular payloads into muscle cells through receptor-mediated internalization for treating dystrophinopathies, such as Duchenne muscular dystrophy. Described embodiments incorporate phosphorodiamidate morpholino oligomers, linker and spacer structures comprising a cleavable valine-citrulline sequence, and pharmaceutical formulations. Preclinical results indicate that anti-transferrin receptor conjugates improve muscle delivery, tissue accumulation, dystrophin exon skipping, and dystrophin expression compared with unconjugated oligonucleotides. Because the background section is omitted from the provided text, the problem being solved is not explicitly described in patent.
Claims Coverage
The claims information identifies two independent claims directed to complexes comprising an anti-transferrin receptor antibody covalently linked to at least one oligonucleotide that induces dystrophin exon 55 skipping, encompassing four principal inventive features.
Anti-transferrin receptor antibody complex with a truncated heavy chain
Claim 1 covers a complex comprising an anti-transferrin receptor antibody covalently linked at a lysine residue to at least one oligonucleotide that induces dystrophin exon 55 skipping. The heavy chain comprises a heavy-chain variable region, a human IgG CH1 domain, lacks human IgG CH2 and CH3 domains, and includes SEQ ID NO: 101, while the light chain comprises a light-chain variable region, a human kappa light-chain constant region, and SEQ ID NO: 90.
Anti-transferrin receptor antibody complex with specified variable and constant regions
Claim 16 covers a complex comprising an anti-transferrin receptor antibody covalently linked at a lysine residue to at least one oligonucleotide that induces dystrophin exon 55 skipping. The heavy chain comprises a heavy-chain variable region comprising SEQ ID NO: 76 and a heavy-chain constant-region portion consisting of SEQ ID NO: 96, paired with a light chain comprising SEQ ID NO: 90.
Oligonucleotide and cleavable linker refinements
Dependent claims define oligonucleotides having lengths of 15 to 35 nucleotides, phosphorodiamidate morpholino oligomer chemistry, specified sequence identifiers, and covalent attachment through a cleavable linker comprising a valine-citrulline sequence.
Administration to induce exon skipping in muscle cells
Dependent claims describe inducing dystrophin exon 55 skipping in a subject's muscle cells by administering a composition comprising the claimed complex.
The two independent claims cover distinct anti-transferrin receptor antibody architectures covalently linked at lysine residues to exon 55-skipping oligonucleotides, with dependent claims specifying linker structures, oligomer chemistries, and administration methods to induce exon skipping in muscle cells.
Stated Advantages
The description and drawing-sheet summary report enhanced oligonucleotide activity, showing that antibody-oligonucleotide conjugates increase dystrophin exon skipping and dystrophin protein expression in cells and tissues compared with unconjugated oligonucleotides.
Antisense oligonucleotide accumulation is increased across monkey tissues compared with unconjugated oligonucleotide, with measurable levels persisting for two to four weeks.
In mdx mice, conjugates increase exon 23 skipping, dystrophin expression, and tissue antisense oligonucleotide accumulation in muscle, including heart and diaphragm, compared with unconjugated antisense oligonucleotide.
In exon-52-deleted Duchenne muscular dystrophy patient cells, an anti-transferrin receptor Fab-ASO complex increases exon 53 skipping compared with naked PMO.
Documented Applications
Administering a composition comprising the claimed complex to induce dystrophin exon 55 skipping in a subject's muscle cells for the treatment of dystrophinopathies, including Duchenne muscular dystrophy.
Evaluating dystrophin levels, exon 23 skipping, and tissue oligonucleotide accumulation in mdx mouse muscle, heart, and diaphragm.
Evaluating dystrophin exon 51 and exon 53 skipping in Duchenne muscular dystrophy patient cells and model systems.
Evaluating antisense oligonucleotide tissue accumulation and persistence in cynomolgus monkeys.
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