Complexes comprising an anti-transferrin receptor antibody linked to an oligonucleotide 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-12319743-B2
Publication Date
2025-06-03
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 a DMPK allele comprising a disease-associated-repeat. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.
Core Innovation
An antibody–oligonucleotide conjugate complex is provided in which an anti-transferrin receptor antibody is covalently linked to a 5′ end or a 3′ end of an oligonucleotide via a linker. The anti-transferrin receptor antibody binds in a specified range of human transferrin receptor protein 1 (TfR1), and the oligonucleotide comprises one or more modifications and an antisense strand with complementarity to a specified nucleotide sequence within a specified length range.
The one or more modifications include a 2′-modified nucleoside selected from the group consisting of a 2′-O-methyl nucleoside, a 2′-fluoro nucleoside, and combinations thereof, and/or a modified backbone comprising one or more phosphorothioate linkages. The complex is formed by reacting a first electrophile of a linker precursor compound with a nucleophile of the anti-transferrin receptor antibody.
In illustrated embodiments, a cathepsin-cleavable Val-cit linker is attached to the 5′ end, 3′ end, or internally of a DMPK-targeting antisense oligonucleotide. The Val-cit linker is thiol-reactively coupled via an antibody cysteine to a transferrin receptor antibody, and an example conjugate is described using a DTX-A-002 anti-transferrin receptor antibody linked to DTX-P-060 (DMPK ASO).
Claims Coverage
The independent claim coverage centers on one antibody–oligonucleotide conjugate structure with five inventive features: antibody binding region and sequence identity, antisense complementarity and length range, nucleoside and/or backbone modifications, covalent linker formation via electrophile–nucleophile reaction, and oligonucleotide end-positioning.
Anti-transferrin receptor antibody covalently linked to an oligonucleotide via a linker
A complex comprising an anti-transferrin receptor antibody covalently linked to a 5′ end or a 3′ end of an oligonucleotide via a linker.
TfR1 binding to a defined region of SEQ ID NO: 1
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.
Modified antisense oligonucleotide with SEQ ID NO: 15 complementarity
The oligonucleotide comprises one or more modifications and comprises an antisense strand comprising a region of complementarity of at least 15 nucleotides in length to the nucleotide sequence as set forth in SEQ ID NO: 15, wherein the oligonucleotide is in the range of 15-30 nucleotides in length.
2′-modified nucleosides and/or phosphorothioate linkages
The one or more modifications comprise a 2′-modified nucleoside selected from the group consisting of a 2′-O-methyl nucleoside, a 2′-fluoro nucleoside, and combinations thereof, and/or comprise a modified backbone comprising one or more phosphorothioate linkages.
Linker electrophile reacts with antibody nucleophile
The complex is formed by reacting a first electrophile of a linker precursor compound with a nucleophile of the anti-transferrin receptor antibody.
The claims are directed to a covalent anti-TfR1 antibody–oligonucleotide conjugate with defined TfR1 binding, defined antisense complementarity to SEQ ID NO: 15, defined 2′-modified nucleoside and/or phosphorothioate modifications, and linker formation by electrophile–nucleophile coupling.
Stated Advantages
Treating myotonic dystrophy type 1 (DM1) by reducing DMPK expression in muscle tissues while having minimal effects in non-muscle tissues.
Assessment includes drug-to-antibody ratio (DAR) and evaluation in mouse and cynomolgus monkey.
Documented Applications
Treating myotonic dystrophy type 1 (DM1).
Intravenous administration of the complex to deliver an oligonucleotide to a subject.
Treating myotonic dystrophy (DM1), including delivery of antisense/RNAi payloads targeting expanded DMPK CUG trinucleotide repeat sequences into muscle cells via transferrin receptor-mediated internalization.
DMPK knockdown and tissue selectivity.
Safety/biomarker observations in monkeys in the myotonic dystrophy use context.
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