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-12239717-B2
Publication Date
2025-03-04
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 invention relates to a complex comprising an anti-transferrin receptor (TfR) antibody covalently linked to at least one oligonucleotide. The antibody comprises a heavy chain and a light chain with defined variable regions and human constant-region domain characteristics, including a heavy chain comprising a human IgG CH1 domain and lacking a human IgG CH2 domain and CH3 domain, and a light chain comprising a human kappa light chain constant region. Each oligonucleotide is covalently linked to a lysine residue of the anti-TfR antibody.
The oligonucleotide induces dystrophin exon 53 skipping, and the disclosure also refers to dystrophin exon 51 skipping and exon 23 skipping. The payload is described as antisense/PMO oligonucleotides used to promote functional dystrophin restoration through exon skipping, in the context of dystrophinopathies including Duchenne muscular dystrophy.
Additional disclosure describes oligonucleotide and conjugation features, including phosphorodiamidate morpholino oligomers, target-complementary regions, exonic splicing enhancers, and cleavable linker or spacer frameworks, including valine-citrulline and piperazine-containing motifs. The complex is presented as an anti-TfR targeting antibody format for delivery of oligonucleotide payloads into muscle cells and for exon skipping of the dystrophin transcript.
Claims Coverage
The consolidated claim coverage centers on two independent anti-TfR antibody–oligonucleotide complexes. In both, each oligonucleotide is covalently linked to a lysine residue of the anti-TfR antibody and is configured to induce dystrophin exon 53 skipping; the main distinctions are the defined antibody heavy-chain and light-chain sequence features.
Anti-TfR antibody covalently linked to lysine-linked oligonucleotide inducing dystrophin exon 53 skipping
A complex comprising an anti-transferrin receptor (TfR) antibody covalently linked to at least one oligonucleotide, wherein each oligonucleotide is covalently linked to a lysine residue of the anti-TfR antibody, and wherein the oligonucleotide induces dystrophin exon 53 skipping.
Defined antibody heavy chain and light chain sequences for exon 53 skipping
The antibody comprises a heavy chain comprising a heavy chain variable region (VH) and a human IgG CH1 domain and lacking a human IgG CH2 domain and CH3 domain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 101; and a light chain comprising a light chain variable region (VL) and a human kappa light chain constant region, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 90.
Alternative heavy-chain constant-region portion with specified VH sequence for exon 53 skipping
The antibody comprises a heavy chain comprising a heavy chain variable region (VH) and a portion of a heavy chain constant region, wherein the VH comprises the amino acid sequence of SEQ ID NO: 76 and the portion of the heavy chain constant region consists of the amino acid sequence of SEQ ID NO: 96, and a light chain comprising the amino acid sequence of SEQ ID NO: 90; each oligonucleotide is covalently linked to a lysine residue of the anti-TfR antibody and induces dystrophin exon 53 skipping.
Oligonucleotide and linker constraints
The oligonucleotide is described as a phosphorodiamidate morpholino oligomer, with target-complementary region constraints, oligonucleotide length constraints, and cleavable linker frameworks including a valine-citrulline sequence.
Overall, the claims cover anti-transferrin receptor antibody–oligonucleotide complexes in which lysine-covalently linked oligonucleotides induce dystrophin exon 53 skipping, with independent coverage defined by specific heavy-chain and light-chain sequence features and additional disclosed oligonucleotide and linker constraints.
Stated Advantages
Improved DMD exon-skipping outcomes, including dystrophin exon skipping and increased dystrophin expression.
Enhanced potency from PMOs when covalently linked to anti-TfR1 Fab versus naked ASO.
Internalization and payload delivery efficacy is supported by internalization and DMPK knockdown data.
Serum stability of the linker is reported.
Biophysical and thermal stability metrics are reported for the humanized anti-TfR1 variants.
Documented Applications
Inducing dystrophin exon 53 skipping.
Application to a subject with Duchenne muscular dystrophy.
Inducing dystrophin exon skipping in muscle cells by administering a subject a composition containing the complex.
DMPK knockdown and internalization in NHP/DM1-derived cells are reported as part of efficacy testing for anti-TfR1 antibody–payload conjugates.
DMD exon-skipping outcomes and increased dystrophin expression are reported in mdx mice and cynomolgus monkeys.
Exon skipping improvements are reported in patient myotubes, including exon 51/52 deletion context.
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