Nucleic acid-polypeptide compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-2025152726-A1
Application number	US-202519031264-A
Country	US
Kind code	A1
Filing date	Jan 17, 2025
Priority date	Oct 4, 2017
Publication date	May 15, 2025
Grant date	—

Abstract

Disclosed herein are compositions and pharmaceutical formulations that comprise a binding moiety conjugated to a modified polynucleic acid molecule and a polymer. Also described herein include methods for treating a cancer which utilize a composition or a pharmaceutical formulation comprising a binding moiety conjugated to a polynucleic acid molecule and a polymer.

First claim

What is claimed is:

1 . A polynucleotide conjugate molecule comprising a binding moiety and a polynucleotide, wherein the polynucleotide comprises (i) at least one 5′-vinylphosphonate modified non-natural nucleotide and (ii) at least one modified internucleotide linkage or at least one inverted abasic moiety; and
wherein the at least one 5′-vinylphosphonate modified non-natural nucleotide is:

wherein B is a heterocyclic base moiety; and
J is an internucleotide linking group linking to the adjacent nucleotide of the polynucleotide.

2 . The molecule of claim 1 , wherein the at least one 5′-vinylphosphonate modified non-natural nucleotide is located at the 5′-terminus of the polynucleotide.

3 . The molecule of claim 1 , wherein the at least one 5′-vinylphosphonate modified non-natural nucleotide is located at an internucleotide linkage of the polynucleotide.

4 . The molecule of claim 1 , wherein the at least one 5′-vinylphosphonate modified non-natural nucleotide is further modified at the 2′-position.

5 . The molecule of claim 5 , wherein the 2′-modification is selected from 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), 2′-O—N-methylacetamido (2′-O-NMA), 2′-O-ethyoxyethyl (2′-O-EOE), 2′-O-(2-N-Methylcarbamoylethyl), PEG1, or PEG2 modified nucleotide.

6 . The molecule of claim 1 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage, a phosphorodithioate linkage, a phosphorodiamidate linkage, a methylphosphonate linkage, or an amide linkage.

7 . The molecule of claim 1 , wherein the at least one inverted abasic moiety is at at least one terminus.

8 . The molecule of claim 1 , wherein the polynucleotide comprises a single-stranded polynucleic acid molecule.

9 . The molecule of claim 1 , wherein the polynucleotide comprises a first polynucleotide and a second polynucleotide hybridized to the first polynucleotide to form a double-stranded polynucleic acid molecule.

10 . The molecule of claim 9 , wherein the second polynucleotide comprises at least one modification.

11 . The molecule of claim 9 , wherein the first polynucleotide and the second polynucleotide are RNA molecules.

12 . The molecule of claim 1 , wherein the binding moiety and the polynucleotide is coupled via a bond; a C 1 -C 6 alkyl group; or a homobifunctional linker or a heterobifunctional linker, optionally conjugated to a C 1 -C 6 alkyl group.

13 . The molecule of claim 1 , further comprising a polymer.

14 . The molecule of claim 1 , wherein the binding moiety comprises an antibody or antigen binding fragment thereof.

15 . The molecule of claim 14 , wherein the antibody or antigen binding fragment thereof comprises a humanized antibody or binding fragment thereof, a chimeric antibody or binding fragment thereof, a monoclonal antibody or binding fragment thereof, a monovalent Fab′, a divalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody or binding fragment thereof.

16 . The molecule of claim 1 , wherein the binding moiety comprises a peptide or a small molecule.

17 . The molecule of claim 16 , wherein the polymer is polyethylene glycol.

18 . The molecule of claim 16 , wherein the polymer has a molecular weight of about 1000 Da, 2000 Da, or 5000 Da.

19 . The molecule of claim 1 , further comprising an endosomolytic moiety.

20 . A compound suitable for the synthesis of an oligonucleotide, wherein the compound is selected from the group:

wherein B is a heterocyclic base moiety.

Assignees

• Avidity Biosciences Inc

Inventors

• Geall Andrew John
• Doppalapudi Venkata Ramana
• Arias Joel Daniel
• Chu David Sai-Ho
• COCHRAN Michael Caramian
• Burke Rob
• Kovach Philip
• Malecova Barbora

Classifications

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• C07H21/00

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K47/6883

  Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy · CPC title

• C12N2310/315

  Phosphorothioates · CPC title