Muscle-targeting complexes comprising an anti-transferrin receptor antibody linked to an oligonucleotide
Inventors
Subramanian, Romesh R. • Qatanani, Mohammed T. • Weeden, Timothy
Assignees
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Publication Number
US-12173079-B2
Publication Date
2024-12-24
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 disclosure describes muscle-targeting complexes in which a muscle-targeting agent is covalently linked to a 5′ end or a 3′ end of an oligonucleotide. In one embodiment, the muscle-targeting agent is an anti-transferrin receptor antibody that 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. The oligonucleotide includes one or more modifications and a complementarity region.
The oligonucleotide payload is defined by a length range of 15–30 nucleotides and a region of complementarity of at least 12 nucleotides to a nucleotide sequence or to an RNA encoded by a gene associated with a disease associated with muscle weakness. The modifications include 2′-modified nucleosides selected from 2′-O-methyl nucleoside, 2′-fluoro nucleoside, 2′-O-methoxyethyl nucleoside, and 2′,4′-bridged nucleosides, and combinations thereof. The oligonucleotide may also include a modified backbone comprising one or more phosphorothioate linkages, a phosphorodiamidate morpholino backbone, and/or a peptide nucleic acid (PNA) backbone.
The disclosure also frames the targeting approach around an internalizing transferrin receptor mechanism and addresses endosomal trafficking and cleavage via cleavable or non-cleavable linkers. It further includes antibody definitions using CDRs and variants and formats including chimeric and humanized antibodies and antibody fragment formats such as ScFv, Fab, F(ab′)2, and Fv. The context is DUX4-driven facioscapulohumeral muscular dystrophy (FSHD) associated with D4Z4 repeat deletions and DUX4-inhibiting oligonucleotides.
Claims Coverage
Two independent claims are provided, each requiring a covalently linked antibody- or muscle-targeting agent/oligonucleotide complex with a TfR1 C89–F760 binding requirement and defined oligonucleotide length and complementarity region, plus specified nucleoside and/or backbone modifications.
Covalently linked anti-transferrin receptor antibody/oligonucleotide complex with specified TfR1 epitope binding and oligonucleotide modifications
A complex comprising an anti-transferrin receptor antibody covalently linked to a 5′ end or a 3′ end of an oligonucleotide; wherein 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; wherein 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, wherein the oligonucleotide is in the range of 15-30 nucleotides in length; wherein the one or more modifications comprise a 2′-modified nucleoside selected from the group consisting of 2′-O-methyl nucleoside, a 2′-fluoro nucleoside, a 2′-O-methoxyethyl nucleoside, and 2′,4′-bridged nucleosides, and combinations thereof, and/or comprise a modified backbone selected from a backbone comprising one or more phosphorothioate linkages, a phosphorodiamidate morpholino backbone, and a peptide nucleic acid (PNA) backbone.
Covalently linked muscle-targeting agent/oligonucleotide complex with specified TfR1 epitope binding and disease-associated muscle-weakness RNA complementarity
A complex comprising a muscle-targeting agent covalently linked to a 5′ end or a 3′ end of an oligonucleotide; wherein 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; wherein 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 a disease associated with muscle weakness, wherein the oligonucleotide is in the range of 15-30 nucleotides in length; wherein the one or more modifications comprise a 2′-modified nucleoside selected from the group consisting of 2′-O-methyl nucleoside, a 2′-fluoro nucleoside, a 2′-O-methoxyethyl nucleoside, and 2′,4′-bridged nucleosides, and combinations thereof, and/or comprise a modified backbone selected from a backbone comprising one or more phosphorothioate linkages, a phosphorodiamidate morpholino backbone, and a peptide nucleic acid (PNA) backbone.
Across both independent claims, the coverage centers on covalent complexes where an agent that binds TfR1 in the C89–F760 range (SEQ ID NO: 1) is covalently linked to an oligonucleotide of 15–30 nucleotides with at least a 12-nucleotide complementarity region and specified 2′-nucleoside modifications and/or modified backbones, with one claim additionally anchoring the complementarity to RNA from a muscle-weakness-associated gene.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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