Method of using an anti-transferrin receptor antibody to deliver an oligonucleotide to a subject having facioscapulohumeral muscular dystrophy
Inventors
Subramanian, Romesh R. • Qatanani, Mohammed T. • Weeden, Timothy
Assignees
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Publication Number
US-12325753-B2
Publication Date
2025-06-10
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 DUX4. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.
Core Innovation
The invention relates to a method of delivering an oligonucleotide to a subject by intravenously administering a complex for muscle delivery. The complex comprises an anti-transferrin receptor antibody that binds human transferrin receptor protein 1 (TfR1) within an epitope range of C89 to F760 of the TfR1 amino acid sequence set forth in SEQ ID NO: 1, and the anti-transferrin receptor antibody is covalently linked to a 5′ end or a 3′ end of an oligonucleotide.
The oligonucleotide comprises one or more modifications and includes a region of complementarity of at least 12 nucleotides in length to a nucleotide sequence as set forth in SEQ ID NO: 52, or to an RNA encoded by a gene associated with a disease associated with muscle weakness. The oligonucleotide is in the range of 15-30 nucleotides in length, and the disclosed oligonucleotide target designs include DUX4-targeting FM10 and FM10 PMO.
The disclosures also identify muscle atrophy pathway gene targets, including muscle E3 ubiquitin ligases MuRF1 (TRIM63) and MAFbx (FBX032), using target-gene complementarity for oligonucleotide-mediated downregulation. The described antibody forms include chimeric or humanized antibodies and antibody fragment formats including ScFv, Fab, Fab′, (Fab′)2, and Fv, with covalent linkage arrangements including embodiments using a cleavable linker such as a valine-citrulline sequence.
Claims Coverage
Two independent claims are identified. Across the claims, the coverage centers on intravenous delivery of an oligonucleotide linked to an anti-transferrin receptor antibody or muscle-targeting agent that binds the C89 to F760 epitope range of human TfR1, together with oligonucleotide complementarity and chemistry limitations; the claims explicitly recite two inventive features shared across the independents.
Intravenous administration of anti-TfR1 antibody–oligonucleotide complex for FSHD
A method of delivering an oligonucleotide to a subject having facioscapulohumeral muscular dystrophy by intravenously administering a complex comprising an anti-transferrin receptor antibody covalently linked to a 5′ end or a 3′ end of an oligonucleotide.
TfR1 epitope range binding C89 to F760
The anti-transferrin receptor antibody binds in the range of C89 to F760 of human transferrin receptor protein 1 (TfR1) having an amino acid sequence as set forth in SEQ ID NO: 1.
Oligonucleotide complementarity to SEQ ID NO: 52 with defined length 15-30 nt
The oligonucleotide comprises one or more modifications and a region of complementarity of at least 12 nucleotides in length to the nucleotide sequence as set forth in SEQ ID NO: 52, and the oligonucleotide is in the range of 15-30 nucleotides in length.
2′-modified nucleosides and/or modified backbone options
The one or more modifications comprise 2′-modified nucleosides selected from 2′-O-methyl, 2′-fluoro, 2′-O-methoxyethyl, and 2′,4′-bridged nucleosides, and/or comprise a modified backbone selected from phosphorothioate linkages, a phosphorodiamidate morpholino backbone, and a peptide nucleic acid (PNA) backbone.
Intravenous administration of muscle-targeting agent–oligonucleotide complex for muscle-weakness disease
A method of delivering an oligonucleotide to a subject having a disease associated with muscle weakness by intravenously administering a complex comprising a means for muscle-targeting covalently linked to a 5′ end or a 3′ end of an oligonucleotide.
Muscle-targeting agent binds TfR1 epitope range C89 to F760
The muscle-targeting agent binds in the range of C89 to F760 of human transferrin receptor protein 1 (TfR1) having an amino acid sequence as set forth in SEQ ID NO: 1.
Oligonucleotide complementarity to RNA associated with the muscle-weakness disease with defined length 15-30 nt
The oligonucleotide comprises one or more modifications and comprises a region of complementarity of at least 12 nucleotides in length to an RNA encoded by a gene associated with the disease associated with muscle weakness, and the oligonucleotide is in the range of 15-30 nucleotides in length.
2′-modified nucleosides and/or modified backbone options for muscle-weakness disease targeting
The one or more modifications comprise 2′-modified nucleosides selected from 2′-O-methyl, 2′-fluoro, 2′-O-methoxyethyl, and 2′,4′-bridged nucleosides, and/or comprise a modified backbone selected from phosphorothioate linkages, a phosphorodiamidate morpholino backbone, and a peptide nucleic acid (PNA) backbone.
Overall, the claims cover intravenous delivery of an oligonucleotide using a covalently linked anti-TfR1 or muscle-targeting agent that binds the C89–F760 epitope range, combined with specified complementarity length of at least 12 nucleotides, oligonucleotide length of 15–30 nucleotides, and defined 2′-modified nucleosides and/or modified backbones including phosphorothioate linkages, PMO, and PNA.
Stated Advantages
Treating facioscapulohumeral muscular dystrophy (FSHD) by delivering an oligonucleotide that inhibits DUX4 expression/activity.
Documented Applications
Treatment of facioscapulohumeral muscular dystrophy (FSHD) by delivering an oligonucleotide payload that inhibits DUX4 expression/activity.
Delivery of an oligonucleotide for a subject with a disease associated with muscle weakness.
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