Nucleic acid-polypeptide compositions and uses thereof

Abstract

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.

What is claimed is: 
     
         1 . A molecule of Formula (I):
   A-X-B-Y-C   Formula I
   wherein,
 A is an antibody or its binding fragments thereof; 
 B is a polynucleotide; 
 C is a polymer; 
 X is a bond or first non-polymeric linker; and 
 Y is a bond or second linker; 
   wherein the polynucleotide comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety; and   wherein A and C are not attached to B at the same terminus.   
     
     
         2 . The molecule 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. 
     
     
         3 . The molecule of  claim 1  or  2 , wherein the at least one 2′ modified nucleotide comprises locked nucleic acid (LNA) or ethylene nucleic acid (ENA). 
     
     
         4 . The molecule of any one of the  claims 1 - 3 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage. 
     
     
         5 . The molecule of  claim 1 , wherein the at least one inverted abasic moiety is at at least one terminus. 
     
     
         6 . The molecule of any one of the  claims 1 - 5 , wherein the polynucleotide comprises a single strand. 
     
     
         7 . The molecule of any one of the  claims 1 - 5 , wherein the polynucleotide comprises a first polynucleotide and a second polynucleotide hybridized to the first polynucleotide to form a double-stranded polynucleic acid molecule. 
     
     
         8 . The molecule of  claim 7 , wherein the second polynucleotide comprises at least one modification. 
     
     
         9 . The molecule of any one of the  claims 1 - 8 , wherein the first polynucleotide and the second polynucleotide are RNA molecules. 
     
     
         10 . The molecule of any one of the  claims 1 - 9 , wherein the first polynucleotide comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 16-75, 452-1955, 1956-1962, 1967-2002, 2013-2032, 2082-2109, or 2117. 
     
     
         11 . The molecule of any one of the  claims 1 - 10 , wherein the second polynucleotide comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 16-75, 452-1955, 1956-1962, 1967-2002, 2013-2032, 2082-2109, or 2117. 
     
     
         12 . The molecule of any one of the  claims 1 - 11 , wherein Y is a non-polymeric linker group. 
     
     
         13 . The molecule of any one of the  claims 1 - 12 , wherein X is a bond. 
     
     
         14 . The molecule of any one of the  claims 1 - 12 , wherein X is a C 1 -C 6  alkyl group. 
     
     
         15 . The molecule of any one of the  claims 1 - 14 , wherein Y is a C 1 -C 6  alkyl group. 
     
     
         16 . The molecule of any one of the  claims 1 - 14 , wherein X is a homobifuctional linker or a heterobifunctional linker, optionally conjugated to a C 1 -C 6  alkyl group. 
     
     
         17 . The molecule of any one of the  claims 1 - 14 , wherein Y is a homobifuctional linker or a heterobifunctional linker. 
     
     
         18 . The molecule of any one of the  claims 1 - 17 , 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. 
     
     
         19 . The molecule of any one of the  claims 1 - 18 , wherein C is polyethylene glycol. 
     
     
         20 . The molecule of any one of the  claims 1 - 19 , wherein C has a molecular weight of about 1000 Da, 2000 Da, or 5000 Da. 
     
     
         21 . The molecule of any one of the  claims 1 - 20 , wherein A-X is conjugated to the 5′ end of B and Y-C is conjugated to the 3′ end of B. 
     
     
         22 . The molecule of any one of the  claims 1 - 20 , wherein Y-C is conjugated to the 5′ end of B and A-X is conjugated to the 3′ end of B. 
     
     
         23 . The molecule of any one of the  claims 1 - 22 , further comprising D. 
     
     
         24 . The molecule of  claim 23 , wherein D is conjugated to C or to A. 
     
     
         25 . The molecule of  claim 23  or  24 , wherein D is conjugated to the molecule of Formula (I) according to Formula (II):
   (A-X-B-Y-C c )-L-D   Formula II
 
 wherein,
 A is an antibody or its binding fragments thereof; 
 B is a polynucleotide; 
 C is a polymer; 
 X is a bond or first non-polymeric linker; 
 Y is a bond or second linker; 
 L is a bond or third linker; 
 D is an endosomolytic moiety; and 
 c is an integer between 0 and 1; 
 
 wherein the polynucleotide comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety; 
 wherein A and C are not attached to B at the same terminus; and 
 wherein D is conjugated anywhere on A or C or to a terminus of B. 
 
     
     
         26 . The molecule of any one of the  claims 23 - 25 , wherein D is INF7 or melittin. 
     
     
         27 . The molecule of any one of the  claims 23 - 25 , wherein D is an endosomolytic polymer. 
     
     
         28 . The molecule of  claim 25 , wherein L is a C 1 -C 6  alkyl group. 
     
     
         29 . The molecule of  claim 25 , wherein L is a homobifuctional linker or a heterobifunctional linker. 
     
     
         30 . The molecule of any one of the  claims 1 - 29 , further comprising at least a second binding moiety. 
     
     
         31 . The molecule of  claim 30 , wherein the at least second binding moiety is conjugated to A, to B, or to C. 
     
     
         32 . The molecule of  claim 30  or  31 , wherein the at least second binding moiety is cholesterol. 
     
     
         33 . The molecule of any one of the  claims 1 - 32 , further comprising at least an additional polynucleotide B. 
     
     
         34 . The molecule of  claim 33 , wherein the at least an additional polynucleotide B is conjugated to A, to B, or to C. 
     
     
         35 . The molecule of any one of the  claims 1 - 34 , further comprising at least an additional polymer C. 
     
     
         36 . The molecule of  claim 35 , wherein the at least an additional polymer C is conjugated to A, to B, or to C. 
     
     
         37 . A pharmaceutical composition comprising:
 a molecule of  claims 1 - 36 ; and   a pharmaceutically acceptable excipient.   
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the pharmaceutical composition is formulated as a nanoparticle formulation. 
     
     
         39 . The pharmaceutical composition of  claim 37  or  38 , wherein the pharmaceutical composition is formulated for parenteral, oral, intranasal, buccal, rectal, or transdermal administration. 
     
     
         40 . A method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a composition comprising a molecule of  claims 1 - 36 . 
     
     
         41 . The method of  claim 40 , wherein the disease or disorder is a cancer. 
     
     
         42 . The method of  claim 41 , wherein the cancer is a solid tumor. 
     
     
         43 . The method of  claim 41 , wherein the cancer is a hematologic malignancy. 
     
     
         44 . The method of any one of the  claims 40 - 43 , wherein the cancer comprises a KRAS-associated, an EGFR-associated, an AR-associated cancer, a β-catenin associated cancer, a PIK3C-associated cancer, or a MYC-associated cancer. 
     
     
         45 . The method of any one of the  claims 40 - 44 , 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. 
     
     
         46 . The method of any one of the  claims 40 - 44 , wherein the cancer comprises acute myeloid leukemia, CLL, DLBCL, or multiple myeloma. 
     
     
         47 . The method of  claim 40 , wherein the method is an immuno-oncology therapy. 
     
     
         48 . A method of inhibiting the expression of a target gene in a primary cell of a patient, comprising administering a molecule of  claims 1 - 36  to the primary cell. 
     
     
         49 . The method of  claim 48 , wherein the method is an in vivo method. 
     
     
         50 . The method of any one of the  claims 40 - 49 , wherein the patient is a human. 
     
     
         51 . An immuno-oncology therapy comprising a molecule of  claims 1 - 36  for the treatment of a disease or disorder in a patient in need thereof.