Muscle targeting complexes comprising an anti-transferrin receptor antibody linked to an oligonucleotide and method of use thereof to induce exon skipping of exon 44 of dystrophin in a subject

Inventors

Subramanian, Romesh R. • Qatanani, Mohammed T. • Weeden, Timothy

Assignees

Dyne Therapeutics Inc

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 disclosure relates to muscle-targeting covalent complexes in which an anti-transferrin receptor antibody is covalently linked to an exon-skipping oligonucleotide, in particular a phosphorodiamidate morpholino oligomer (PMO). The complexes target cells that express the transferrin receptor (TFRC/CD71/TFR1) through internalizing cell surface receptor binding, and deliver a molecular payload intended to modulate dystrophin pre-mRNA splicing.

A central concept is exon skipping of dystrophin (DMD) by designing an oligonucleotide with a complementary region to an exon-44 DMD transcript (SEQ ID NO: 295), and inducing skipping of exon 44 of the DMD mRNA transcript. The antibody includes defined heavy and light chain variable regions containing CDR-H1, CDR-H2, CDR-H3, and CDR-L1, CDR-L2, and CDR-L3, with humanized framework regions and specified CDR sequence assignments.

The disclosure further defines the oligonucleotide and linkage constraints for the covalent complex, including oligonucleotide length and complementarity constraints and PMO identity. Linker strategies are described as cleavable or non-cleavable, and the covalent attachment between the antibody and the oligonucleotide is defined to support delivery of the exon-skipping payload to muscle cells for treating dystrophinopathies such as Duchenne muscular dystrophy.

Claims Coverage

The document includes one independent claim, directed to a specific antibody–PMO covalent complex that induces skipping of exon 44 of dystrophin (DMD) via targeting a complementary region in an exon-44 DMD transcript. The claim is supported by numerous dependent refinements that constrain CDR definitions, antibody framework/format, Fc substitutions, oligonucleotide length/sequence/complementarity, covalent attachment/linker chemistry, and related administration for inducing exon skipping.

Claim coverage centers on a covalent antibody–PMO complex that targets the transferrin receptor and induces exon 44 skipping of dystrophin by hybridization/complementarity to an exon-44 DMD transcript region (SEQ ID NO: 295). The claim further fixes the antibody to humanized variable regions defined by specified CDR sets and SEQ ID NO: 438 (VH) and SEQ ID NO: 439 (VL), and fixes the PMO to defined length and complementarity requirements.

Stated Advantages

Documented Applications