Muscle targeting complexes and uses thereof for treating myotonic dystrophy
Inventors
Subramanian, Romesh R. • Qatanani, Mohammed T. • Weeden, Timothy • Desjardins, Cody A.
Assignees
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Publication Number
US-12280122-B2
Publication Date
2025-04-22
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 expression or activity of a DMPK allele comprising a disease-associated-repeat. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.
Core Innovation
The invention provides a composition comprising a plurality of complexes, where each complex includes an anti-transferrin receptor antibody covalently linked, via a protease-sensitive linker, to an oligonucleotide targeting a DMPK RNA. The complexes are configured to deliver the oligonucleotide into muscle cells, and the anti-transferrin receptor antibody binds an extracellular domain of transferrin receptor protein 1 (TfR1).
The oligonucleotide brings about degradation of the DMPK RNA via RNase H mediated degradation. It is constrained to a length of 15, 16, 17, or 18 nucleotides and includes a region of complementarity that is fully complementary along at least 14 contiguous nucleotides to a coding region of a DMPK sequence as set forth in SEQ ID NO: 15.
The oligonucleotide follows a 5′-X-Y-Z-3′ formula with flanking regions X and Z comprising one or more 2′-modified nucleosides selected from 2′-O-methyl, 2′-fluoro, 2′-O-methoxyethyl, and 2′,4′-bridged nucleosides, while Y is a gap region with 2′-deoxyribonucleosides. The oligonucleotide further comprises one or more phosphorothioate internucleoside linkages, and the partial content describes protease-sensitive linker strategies including cleavable protease-sensitive linkers associated with lysosomal/endosomal proteases.
Claims Coverage
The document includes one independent claim, which defines an anti-TfR1 antibody–oligonucleotide covalent complex for delivering an RNase H mediated DMPK RNA degradation oligonucleotide into muscle cells. The inventive features include the complex composition, the antibody target and extracellular binding, the protease-sensitive covalent linker, and the specific constrained oligonucleotide structure and complementarity to SEQ ID NO: 15 with RNase H degradation capability.
Plurality of protease-linked anti-TfR1 antibody/anti-DMPK RNA complexes for muscle delivery
A composition comprising a plurality of complexes, each complex comprising an anti-transferrin receptor antibody covalently linked, via a protease-sensitive linker, to an oligonucleotide that targets a DMPK RNA, wherein each complex is configured for delivering the oligonucleotide into muscle cells.
Oligonucleotide length and fully complementary DMPK coding-region target
The oligonucleotide is 15, 16, 17, or 18 nucleotides in length and comprises a region of complementarity that is fully complementary, along a length of at least 14 contiguous nucleotides, to a coding region of a DMPK sequence as set forth in SEQ ID NO: 15.
RNase H mediated DMPK RNA degradation with 5′-X-Y-Z-3′ gapmer architecture
The oligonucleotide is configured to bring about degradation of the DMPK RNA via RNase H mediated degradation, wherein the oligonucleotide comprises a 5′-X-Y-Z-3′ formula, wherein X and Z are flanking regions comprising one or more 2′-modified nucleosides selected from the group consisting of: 2′-O-methyl, 2′-fluoro, 2′-O-methoxyethyl, and 2′,4′-bridged nucleosides, wherein Y is a gap region and each nucleoside in Y is a 2′-deoxyribonucleoside, and wherein the oligonucleotide comprises one or more phosphorothioate internucleoside linkages.
Anti-TfR1 extracellular domain binding
The anti-transferrin receptor antibody binds an extracellular domain of a transferrin receptor protein 1 (TfR1).
Overall, the claim scope centers on covalently linking an anti-TfR1 antibody to a precisely defined DMPK-targeting RNase H-active oligonucleotide through a protease-sensitive linker, with the antibody configured to deliver the oligonucleotide into muscle cells and the oligonucleotide designed around a 5′-X-Y-Z-3′ phosphorothioate gapmer architecture targeting a fully complementary region of a DMPK coding sequence in SEQ ID NO: 15.
Stated Advantages
Delivers the oligonucleotide into muscle cells.
Brings about degradation of the DMPK RNA via RNase H mediated degradation.
Enables covalent coupling of the anti-transferrin receptor antibody and the DMPK-targeting oligonucleotide via a protease-sensitive linker.
Provides targeting via an anti-transferrin receptor antibody that binds an extracellular domain of TfR1.
Documented Applications
Treatment of myotonic dystrophy type 1 (DM1) using muscle-targeting antibody–oligonucleotide complexes.
DMPK knockdown using DMPK-targeting antisense oligonucleotide complexes.
DMPK knockdown in muscle cells and muscle-related tissues.
Time- and dose-dependent reductions shown with transferrin-receptor antibody–oligonucleotide complexes in mouse tissues and cynomolgus monkey tissues.
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