Nucleic acid-polypeptide compositions and uses thereof
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.
1. A polynucleotide conjugate molecule comprising a binding moiety and a polynucleotide,
wherein the polynucleotide comprises at least one 5′-vinylphosphonate modified non-natural nucleotide and 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 selected from:
wherein B is a heterocyclic base moiety; and
J is an internucleotide linking group linking to an 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 4 , 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-ethyloxyethyl (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 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 polynucleotide is coupled to the binding moiety via a bond.
13. The molecule of claim 1 , wherein the polynucleotide is coupled to the binding moiety via a C 1 -C 6 alkyl group.
14. The molecule of claim 1 , wherein the polynucleotide is coupled to the binding moiety via a homobifunctional linker or a heterobifunctional linker, optionally conjugated to a C 1 -C 6 alkyl group.
15. The molecule of claim 1 , further comprising a polymer.
16. The molecule of claim 1 , wherein the binding moiety comprises a humanized antibody or antigen binding fragment thereof, a chimeric antibody or antigen binding fragment thereof, a monoclonal antibody or antigen 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 antigen binding fragment thereof.
17. The molecule of claim 1 , wherein the binding moiety comprises a peptide or a small molecule.
18. The molecule of claim 15 , wherein the polymer is polyethylene glycol.
19. The molecule of claim 15 , wherein the polymer has a molecular weight of about 1000 Da, 2000 Da, or 5000 Da.
20. The molecule of claim 1 , further comprising an endosomolytic moiety.