Muscle-targeting complexes comprising an anti-transferin receptor antibody linked to an oligonucleotide and method of use thereof to induce exon skipping
Inventors
Subramanian, Romesh R. • Qatanani, Mohammed T. • Weeden, Timothy
Assignees
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Publication Number
US-12357703-B2
Publication Date
2025-07-15
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 is a muscle-targeting complex in which an anti-transferrin receptor antibody is covalently linked through a linker to an exon-skipping oligonucleotide. The antibody binds human transferrin receptor 1, and the oligonucleotide is a phosphorodiamidate morpholino oligomer with complementarity to exon 44 of a DMD transcript. The complex is configured to induce skipping of exon 44 of DMD pre-mRNA in a muscle cell.
The delivery approach directs the exon-skipping oligonucleotide to muscle cells to promote functional dystrophin expression in dystrophinopathies. Related anti-transferrin receptor antibody–siHPRT complexes demonstrate reduced HPRT expression in cultured cells as well as in mouse gastrocnemius and heart without evident reduction in tested non-muscle tissues. The content proposes the DMD-targeting antibody–oligonucleotide complex, though DMD exon-skipping screening results are not reported.
Claims Coverage
The claims identify one independent claim encompassing four inventive features directed to an antibody–oligonucleotide conjugate.
Anti-transferrin receptor antibody
The complex includes an anti-transferrin receptor antibody having human or humanized framework regions that binds human transferrin receptor 1.
Exon 44-skipping oligonucleotide
The oligonucleotide is a phosphorodiamidate morpholino oligomer comprising a region complementary to exon 44 of a DMD transcript, configured to induce exon 44 skipping.
Covalent antibody–oligonucleotide linkage
A linker connects the oligonucleotide to the anti-transferrin receptor antibody via linker chemistry, such as linkage to the 5′ or 3′ end.
Exon skipping in a muscle cell
The complex is configured to induce skipping of exon 44 of DMD pre-mRNA in a muscle cell.
The independent claim centers on an antibody–oligonucleotide complex targeting human transferrin receptor 1 to induce DMD exon 44 skipping in muscle cells, with dependent claims providing further structural and compositional details.
Stated Advantages
Increased muscle delivery and selectivity, potentially reducing off-target toxicity.
Documented Applications
Dystrophinopathies, including inducing DMD exon 44 skipping in a muscle cell upon administration of the complex to promote functional dystrophin expression.
Reduction of HPRT expression in cultured cells and in mouse gastrocnemius and heart using anti-transferrin receptor antibody–siHPRT complexes.
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