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 . An oligonucleotide comprising a compound of Formula (IIa) at one of the termini:
wherein;
each R 1 is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl;
L 1 , L 2 , and L 3 are selected such that L 1 -L 2 -L 3 is equivalent to (a) —(CH 2 ) 3 —; (b) —(CH 2 ) 4 —; (c) —(CH 2 ) 5 —; or (d) —(C 2 H 2 )(CH 2 ) 2 —; and
J is an internucleotide linking group linking to the adjacent nucleotide of the oligonucleotide
2 . The oligonucleotide of claim 1 , wherein each R 1 is independently C 1 -C 6 alkyl.
3 . The oligonucleotide of claim 1 , wherein J is a phosphodiester linkage, phosphorothioate linkage, a phosphorodithioate linkage, a methylphosphonate linkage, a phosphotriester linkage or an amide linkage.
4 . The oligonucleotide of claim 1 , wherein the oligonucleotide is a single stranded oligonucleotide, or a double stranded oligonucleotide comprising a sense strand and an antisense strand.
5 . The oligonucleotide of claim 1 , further comprising at least one 2′ modified nucleotide 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) modified nucleotide, locked nucleic acid (LNA) or ethylene nucleic acid (ENA).
6 . The oligonucleotide of claim 1 , wherein the compound of Formula (IIa) is located at the 5′-terminus of the oligonucleotide.
7 . The oligonucleotide of claim 4 , wherein the compound of Formula (IIa) is located at the 5′-terminus of the antisense strand.
8 . The oligonucleotide of claim 1 , wherein the oligonucleotide is conjugated to a binding moiety.
9 . The oligonucleotide of claim 8 , wherein the compound of Formula (IIa) is located at the 5′-terminus of the oligonucleotide, and the binding moiety is conjugated to the 3′-terminus of the oligonucleotide.
10 . The oligonucleotide of claim 8 , 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), a camelid antibody or antigen binding fragment thereof, a peptide, an aptamer, or a small molecule.
11 . The oligonucleotide of claim 4 , wherein the single stranded oligonucleotide and each of the sense strand and the antisense strand comprise from about 15 to about 25 nucleotides.
12 . The oligonucleotide of claim 1 , wherein the oligonucleotide is conjugated with a polymer.
13 . The oligonucleotide of claim 12 , wherein the polymer is polyethylene glycol.
14 . A method of treating a subject having a disease or a condition characterized with a defective protein expression or a protein overexpression, comprising administering to the subject an oligonucleotide of claim 1 to modulate expression of a gene encoding the protein, thereby treating the disease or condition characterized with the defective protein expression or characterized with the protein overexpression.
15 . The method of claim 14 , wherein the disease or the condition is a neuromuscular disease, a muscle dystrophy, a muscle atrophy, a muscle wasting, a genetic disease, cancer, a hereditary disease, or a cardiovascular disease.