Complexes comprising an anti-transferrin receptor antibody linked to an oligonicleotide and method of delivering oligonucleotide to a subject
Inventors
Subramanian, Romesh R. • Qatanani, Mohammed T. • Weeden, Timothy • Desjardins, Cody A.
Assignees
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Publication Number
US-12428487-B2
Publication Date
2025-09-30
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 activity of a disease allele associated with muscle disease. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.
Core Innovation
The disclosed invention is a complex comprising a humanized, sequence-defined anti-transferrin receptor antibody covalently linked to an antisense oligonucleotide. The antibody comprises specified heavy- and light-chain complementarity determining regions and humanized framework regions to promote receptor-mediated delivery into muscle cells. The oligonucleotide comprises an antisense strand complementary to RNA encoded by a gene associated with a muscle disease, along with specified nucleotide lengths, nucleoside modifications, or backbone modifications.
The description identifies muscle-selective delivery and reduced off-target effects in therapeutic contexts such as DMPK-associated myotonic dystrophy and DUX4-associated facioscapulohumeral muscular dystrophy. Reported animal studies show that the antibody-oligonucleotide conjugates reduce DMPK expression across skeletal, cardiac, and smooth muscle tissues. The observed target knockdown is dose-dependent and persists through 28 days in mice, while monkey studies show tissue reduction with normal blood and clinical chemistry measures.
The background, summary, and abstract sections are not provided in the disclosure, so the problem addressed is not explicitly described in the patent. The provided text details the structural components of the antibody-oligonucleotide conjugate and associated tissue measurements without detailing prior art deficiencies.
Claims Coverage
The relevant claims contain one independent claim comprising three main inventive features.
Humanized anti-transferrin receptor antibody
The complex comprises an anti-transferrin receptor antibody having heavy- and light-chain variable regions with specified complementarity determining regions, including those of SEQ ID NOs: 641 and 642, and humanized framework regions.
Covalently linked antisense oligonucleotide
The antibody is covalently linked at the 5′ or 3′ end to an oligonucleotide of 15 to 30 nucleotides in length comprising an antisense strand with at least 15 nucleotides of complementarity to RNA encoded by a gene associated with a muscle disease.
Modified oligonucleotide chemistry
The oligonucleotide comprises one or more 2′-O-methyl or 2′-fluoro nucleosides, and/or a modified backbone comprising one or more phosphorothioate linkages or a phosphorodiamidate morpholino backbone.
The independent claim covers all elements of the claim for the covalently linked antibody-oligonucleotide complex, with dependent claims further identifying delivery to muscle cells, intravenous administration, linker chemistry, and DUX4 targeting.
Stated Advantages
The complex is intended to promote muscle-selective delivery and reduce off-target effects.
Studies report targeted DMPK knockdown across skeletal, cardiac, and smooth muscle tissues, showing dose-dependent effects persisting through 28 days in mice with little or no reduction in tested non-muscle tissues.
Single-dose administration in cynomolgus monkeys is reported to be tolerated, demonstrating target reduction in muscle and intestinal tissues while maintaining normal clinical chemistry and blood measures.
Documented Applications
Targeting RNA encoded by a gene associated with a muscle disease, specifically identifying DMPK in myotonic dystrophy and DUX4 in facioscapulohumeral muscular dystrophy (FSHD).
Delivery of the antisense oligonucleotide to muscle cells, including skeletal, cardiac, or smooth muscle cells, via intravenous administration of the complex.
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