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-12629426-B2
Publication Date
2026-05-19
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 invention is a complex comprising an anti-transferrin receptor antibody covalently linked to an oligonucleotide that induces dystrophin exon skipping. The antibody comprises specified heavy-chain and light-chain variable regions [procedural detail omitted for safety]. Disclosed embodiments further describe antibody formats, oligonucleotide targets and chemical features, and cleavable linkers comprising a valine-citrulline sequence or non-cleavable linkers to enable receptor-mediated delivery of molecular payloads into muscle cells.
Reported evaluations demonstrate muscle-targeted oligonucleotide delivery to tissues, with sustained accumulation in quadriceps, diaphragm, and heart compared with unconjugated oligonucleotide controls. In experimental animal models and patient cells, the conjugates induce dystrophin exon skipping, increase dystrophin expression and restoration, and improve functional measures.
Claims Coverage
The claims define one independent claim encompassing four inventive features, covering all elements of the claim directed to an anti-transferrin receptor antibody covalently linked to an oligonucleotide.
Anti-transferrin receptor antibody linked to a DMD exon-skipping oligonucleotide
The independent claim recites a complex comprising an anti-transferrin receptor antibody covalently linked to an oligonucleotide that induces dystrophin (DMD) exon skipping, wherein the antibody comprises specified heavy-chain and light-chain variable regions [procedural detail omitted for safety].
Oligonucleotide targets and sequence features
Dependent claims specify DMD exon targets and oligonucleotide sequence features [procedural detail omitted for safety], with one or more uracil bases optionally replaced by thymine bases, and an oligonucleotide length of 15–35 nucleotides.
Cleavable valine-citrulline linker
A dependent claim specifies that the antibody is covalently linked to the oligonucleotide through a cleavable linker comprising a valine-citrulline sequence or via a five-prime terminal lysine.
Promotion of DMD protein expression or activity
A dependent claim describes promoting DMD protein expression or activity in a cell by contacting the cell with the complex in an amount effective to promote oligonucleotide internalization into the cell.
The independent claim recites a sequence-defined anti-transferrin receptor antibody covalently linked to a DMD exon-skipping oligonucleotide, with dependent claims further defining target sequences, cleavable linkers, and cellular delivery.
Stated Advantages
The reported antibody-conjugated oligonucleotides increase DMD exon skipping and dystrophin restoration compared with unconjugated oligonucleotide controls in cell and mdx-mouse studies.
The conjugates increase oligonucleotide delivery to tissues compared with unconjugated oligonucleotide, with sustained levels reported in muscle and heart.
The conjugates induce DMD exon skipping and increase dystrophin in quadriceps, heart, and diaphragm in mdx mice, whereas unconjugated oligonucleotide shows little or no effect.
Anti-transferrin receptor antibody conjugation improves exon skipping in DMD patient cells compared with naked oligonucleotide at tested doses.
Contacting a cell with the complex promotes DMD protein expression or activity.
The examples report improved functional measures in mdx mice.
Documented Applications
Use of the antibody–oligonucleotide complex for the treatment of dystrophinopathies.
Promoting DMD protein expression or activity in a cell through oligonucleotide internalization.
Exon-skipping and dystrophin-restoration evaluations in human DMD Δ52 myotubes and mdx models, including measurements in quadriceps, heart, and diaphragm.
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