NUCLEIC ACID-POLYPEPTIDE COMPOSITIONS AND USES THEREOF
Disclosed herein are compositions and pharmaceutical formulations that comprise a binding moiety conjugated to a 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 method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising:
a molecule of Formula (I):
A-X—B—Y—C Formula I
wherein,
A is an antibody or its binding fragments thereof;
B consists of a double-stranded polynucleotide consisting of a passenger strand and a guide strand;
C consists of a polymer; and
X and Y are each independently a linker selected from the group consisting of a heterobifunctional linker, a homobifunctional linker, a maleimide group, a dipeptide moiety, a benzoic acid group or a derivatives thereof, a C 1 -C 6 alkyl group, or a combination thereof, and
a pharmaceutically acceptable excipient;
wherein:
the double-stranded polynucleotide comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety;
A and C are not attached to B at the same terminus; and
A-X and Y—C are conjugated to the passenger strand.
2 . The method of claim 1 , wherein the disease or disorder is a cancer.
3 . The method of claim 2 , wherein the cancer is a solid tumor.
4 . The method of claim 2 , wherein the cancer is a hematologic malignancy.
5 . The method of claim 2 , wherein the cancer comprises bladder cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma multiforme, head and neck cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, or thyroid cancer.
6 . The method of claim 2 , wherein the cancer is breast cancer, lung cancer, ovarian cancer, prostate cancer, or skin cancer.
7 . The method of claim 2 , wherein the cancer comprises acute myeloid leukemia, CLL, DLBCL, or multiple myeloma.
8 . The method of claim 1 , wherein the guide strand hybridizes to a target region of a gene selected from the group consisting of KRAS, EGFR, AR, CTNNB1, PIK3CA, PIK3CB, MYC, and HPRT1.
9 . The method of claim 1 , wherein the at least one 2′ modified nucleotide comprises 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl, 2′-deoxy, T-deoxy-2′-fluoro, 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), T-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), or 2′-O—N-methylacetamido (2′-O-NMA) modified nucleotide.
10 . The method of claim 1 , wherein the at least one 2′ modified nucleotide comprises locked nucleic acid (LNA) or ethylene nucleic acid (ENA).
11 . The method of claim 1 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.
12 . The method of claim 1 , wherein the at least one inverted abasic moiety is at at least one terminus.
13 . The method of claim 1 , wherein the passenger strand and the guide strand are RNA molecules.
14 . The method of claim 1 , wherein the guide strand comprises a sequence having at least 80% sequence identity to SEQ ID NOs: 16-75, 452-1955, 1956-1962, 1967-2002, 2013-2032, 2082-2109, or 2117.
15 . The method of claim 1 , wherein the antibody or binding fragment thereof comprises a humanized antibody or binding fragment thereof, chimeric antibody or binding fragment thereof, monoclonal antibody or binding fragment thereof, monovalent Fab′, divalent Fab2, single-chain variable fragment (scFv), diabody, minibody, nanobody, single-domain antibody (sdAb), or camelid antibody or binding fragment thereof.
16 . The method of claim 1 , wherein the antibody or binding fragment thereof is an anti-transferrin antibody or binding fragment thereof.
17 . The method of claim 1 , wherein C is polyethylene glycol.
18 . The method of claim 17 , wherein C has a molecular weight from about 1000 Da to about 5000 Da.
19 . The method of claim 17 , wherein C has a molecular weight of about 1000 Da, 2000 Da, or 5000 Da.
20 . The method of claim 1 , wherein A-X is conjugated to the 5′ end of the passenger strand and Y—C is conjugated to the 3′ end of the passenger strand.
21 . The method of claim 1 , wherein Y—C is conjugated to the 5′ end of the passenger strand and A-X is conjugated to the 3′ end of the passenger strand.