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-12329824-B1
Publication Date
2025-06-17
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 is defined by specified heavy-chain and light-chain compositions, including variable regions and constant-region domains, and by defined amino acid sequences for those regions. Each oligonucleotide is covalently linked to a lysine residue of the anti-TfR antibody, and the oligonucleotide induces dystrophin exon 45 skipping.
The complex is characterized by antibody formats and attachment-site linkage through the lysine residue, with the oligonucleotide described as being linked at the 5′ end. Structural representations describe covalent attachment via a linker, with linker structural parameters n and m, and with example values for n and m stated. The antibody may be provided as an IgG or Fab format, and attachment-site stoichiometry is described in terms of DAR.
The oligonucleotides are defined by sequence sets provided as SEQ ID NOs and by sequence features such as a region of complementarity. The oligonucleotide length and the complementarity length ranges are specified, and the complementarity region is described as matching target sequences associated with enumerated SEQ ID NOs. Permissible nucleotide substitutions (T↔U) and oligonucleotide chemistry options are also specified, including phosphorodiamidate morpholino oligomer and a cleavable linker comprising a valine-citrulline sequence.
Claims Coverage
The independent claims are clm-00001 and clm-00016. Both independent claims share the core inventive concept of an anti-TfR antibody covalently linked to one or more oligonucleotides via a lysine residue, where the oligonucleotide induces dystrophin exon 45 skipping, while differing in the specific antibody heavy-chain and constant-region definitions through different SEQ ID NO assignments.
Anti-TfR antibody covalently linked to oligonucleotide via lysine residue
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 the oligonucleotide induces dystrophin exon 45 skipping.
Specific heavy-chain and light-chain sequences for anti-TfR antibody in the complex
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.
Specific heavy-chain sequence with heavy-chain constant-region portion and defined light-chain sequence
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.
Across clm-00001 and clm-00016, claim coverage centers on a covalent anti-TfR antibody–oligonucleotide complex where attachment to lysine residues links oligonucleotides that induce dystrophin exon 45 skipping, with independent claims differing by the specified heavy-chain/constant-region and light-chain amino acid sequences.
Stated Advantages
The oligonucleotide induces dystrophin exon 45 skipping.
Treat dystrophinopathies, including Duchenne muscular dystrophy, by administration of the complexes.
Documented Applications
Used for DMD targeting via oligonucleotides that induce dystrophin exon 45 skipping.
Treating dystrophinopathies, including Duchenne muscular dystrophy, by administration of the anti-TfR antibody–oligonucleotide complexes.
DMPK gene knockdown and dystrophin (DMD) exon skipping, including DMD exon 23/51 and DMD patient myotubes exon skipping, using anti-TfR1 antibody-oligonucleotide conjugates.
Serum stability of cleavable linker constructs and exon-skipping potency comparison or improvement when conjugating different exon-skipping PMOs to anti-TfR1 Fab, including exon 53 PMO-A/PMO-B potency improvement.
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