Muscle-targeting complexes and uses thereof
AssigneeDyne Therapeutics, Inc.
InventorsRomesh R. Subramanian, Mohammed T. Qatanani, Timothy Weeden, Jason P. Rhodes
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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.
Claims21
-91. (canceled)
A method of delivering an oligonucleotide to a muscle cell in a subject, the method comprising administering to the subject a muscle-targeting complex that comprise an anti-transferrin receptor antibody covalently linked to an oligonucleotide;
- wherein the oligonucleotide is covalently linked at the 5′ end to a lysine residue of the anti-transferrin receptor antibody via a cleavable linker that comprises a valine-citrulline sequence, wherein the complexes are obtained by a cycloaddition reaction between an azide and an alkyne to form a triazole, wherein prior to the cycloaddition reaction, the azide is located on the cleavable linker that is covalently linked to the 5′ end of the oligonucleotide and the alkyne is provided in a bicyclononyne moiety that further covalently links to the anti-transferrin receptor antibody;
- wherein the oligonucleotide i) comprises at least one modified nucleoside and/or at least one modified internucleoside linkage, ii) is 15-35 nucleotides in length, and iii) comprises a region of complementarity to an RNA encoded by a muscle disease gene in the muscle cell, wherein the region of complementarity is at least 12 nucleotides in length;
- 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;
- and
- wherein the muscle-targeting complexes are administered to the subject by infusion and the oligonucleotide is released into the muscle cell following cleavage of the cleavable linker.
Dependencies are inferred from the claim text.