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-12239716-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 provides anti-transferrin receptor (TfR) antibody or Fab conjugates covalently linked to at least one oligonucleotide. The antibody or Fab is described with defined heavy chain and light chain sequence features, including embodiments with a human IgG CH1 domain, a human kappa light chain constant region, and SEQ ID NO-defined variable or constant-region portions, and in some embodiments the heavy chain lacks a human IgG CH2 domain and CH3 domain.
The oligonucleotide payload is configured to induce dystrophin exon 51 skipping and is described as a DMD-targeting oligonucleotide or antisense oligonucleotide, including phosphorodiamidate morpholino oligomers (PMOs). The disclosure also describes DMD-targeting sequences, complementarity to dystrophin RNA and exonic splicing enhancers, and related RNA-targeting formats including gapmers, mixmers, siRNA, shRNA, miRNA, aptamers, ribozymes, and guide RNAs.
The covalent conjugation architecture uses linkage to a lysine residue of the anti-TfR antibody or Fab, with linker structures including cleavable valine-citrulline (Val-cit) linkers and other cleavable covalent linker embodiments. The disclosure further describes attachment sites at the 5′ end, 3′ end, or internal positions, variable spacer or linker parameters, and conjugate frameworks with specified drug-to-antibody ratio ranges.
Claims Coverage
The consolidated claim coverage centers on anti-TfR antibody or Fab conjugates covalently linked to at least one oligonucleotide, with the core inventive features being lysine-based covalent attachment, SEQ ID NO-defined antibody heavy and light chain configurations, and an oligonucleotide configured to induce dystrophin exon 51 skipping. Three independent claim variants are represented across the inputs.
Anti-TfR antibody covalently linked to an oligonucleotide that induces dystrophin exon 51 skipping
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 51 skipping.
Defined anti-TfR antibody heavy and light chain sequence configuration
An antibody comprising a heavy chain with a heavy chain variable region and a human IgG CH1 domain lacking a human IgG CH2 domain and CH3 domain, where the heavy chain comprises SEQ ID NO: 101, and a light chain comprising a light chain variable region and a human kappa light chain constant region, where the light chain comprises SEQ ID NO: 90.
Alternative defined anti-TfR antibody heavy-chain portion and SEQ ID NOs
An antibody comprising a heavy chain with a heavy chain variable region comprising SEQ ID NO: 76 and a portion of a heavy chain constant region consisting of SEQ ID NO: 96, and a light chain comprising SEQ ID NO: 90, wherein each oligonucleotide is covalently linked to a lysine residue of the anti-TfR antibody and the oligonucleotide induces dystrophin exon 51 skipping.
Across the independent claims, the scope is directed to anti-TfR antibody or Fab conjugates in which at least one oligonucleotide is covalently attached to a lysine residue and is configured to induce dystrophin exon 51 skipping, with the antibody identity set by specified VH/VL and heavy-chain constant-region features using SEQ ID NOs.
Stated Advantages
Strong binding to human and cynomolgus monkey TfR1, with no detectable binding to mouse/rat TfR1 and no detectable binding to human TfR2.
Serum stability of an anti-TfR Fab-ASO conjugate across species, reported as stable through 72 h.
In vivo increases in exon skipping and dystrophin protein expression, including dystrophin exon 51 skipping in cynomolgus monkeys and increased exon skipping with measurable tissue ASO accumulation in mdx mice.
Improved exon skipping in DMD patient cells using anti-TfR1 Fab conjugation, including at lower PMO doses.
Documented Applications
Inducing dystrophin exon 51 skipping in cynomolgus monkeys using PMO conjugated to an ESE-targeting ASO (SEQ ID NO: 419), with reported dystrophin exon 51 skipping and tissue ASO distribution/persistence.
Increasing exon skipping and dystrophin protein expression in mdx mice following single-dose anti-TfR Fab-ASO conjugates, including reported exon 23 skipping and measurable tissue ASO accumulation.
Assessing exon skipping in DMD patient cells (KM1328) where anti-TfR1 Fab conjugation improves exon 53 skipping.
Inducing dystrophin exon 51 skipping in muscle cells of a subject by administering a composition comprising the complex.
A method embodiment narrowed to a subject with Duchenne muscular dystrophy.
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