P-ethoxy nucleic acids for igf-1r inhibition

Abstract

Provided herein are methods of treating cancer or an autoimmune disease comprising administering a liposome that comprises neutral phospholipids and a P-ethoxy oligonucleotide that targets a IGF-1R-encoding polynucleotide.

What is claimed is: 
     
         1 . A method of treating a subject with a cancer or an autoimmune disease comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising a population of oligonucleotides, wherein the oligonucleotides hybridize to an IGF-1R polynucleotide gene product, wherein oligonucleotides of the population are composed of nucleoside molecules linked together through phosphate backbone linkages, wherein at least one of the phosphate backbone linkages in each oligonucleotide is a P-ethoxy backbone linkage, and wherein no more than 80% of the phosphate backbone linkages in each oligonucleotide are P-ethoxy backbone linkages, phospholipids, and a pharmaceutically acceptable carrier, wherein the oligonucleotides and phospholipids form an oligonucleotide-lipid complex. 
     
     
         2 . The method of  claim 1 , wherein the pharmaceutical composition further comprises a chemotherapeutic agent. 
     
     
         3 . The method of  claim 1 , wherein oligonucleotides of the population comprise a sequence according to either of SEQ ID NOs: 1 or 2. 
     
     
         4 . The method of  claim 3 , wherein oligonucleotides of the population comprise a sequence according to SEQ ID NO: 1. 
     
     
         5 . The method of  claim 3 , wherein oligonucleotides of the population comprise a sequence according to SEQ ID NO: 2. 
     
     
         6 . The method of  claim 1 , wherein 50% to 80% of the phosphate backbone linkages are P-ethoxy backbone linkages. 
     
     
         7 . The method of  claim 6 , wherein 60% to 75% of the phosphate backbone linkages are P-ethoxy backbone linkages. 
     
     
         8 . The method of  claim 1 , wherein 20% to 50% of the phosphate backbone linkages are phosphodiester backbone linkages. 
     
     
         9 . The method of  claim 8 , wherein 25% to 40% of the phosphate backbone linkages are phosphodiester backbone linkages. 
     
     
         10 . The method of  claim 1 , wherein the phosphodiester backbone linkages are distributed throughout each oligonucleotide. 
     
     
         11 . The method of  claim 1 , wherein the phosphodiester backbone linkages are not clustered within a portion of each oligonucleotide. 
     
     
         12 . The method of  claim 1 , wherein the population of oligonucleotides is heterogeneous as to the number of P-ethoxy backbone linkages and phosphodiester backbone linkages present in the oligonucleotides of the population. 
     
     
         13 . The method of  claim 1 , wherein the oligonucleotides of the population have a size ranging from 18 to 30 nucleotides. 
     
     
         14 . The method of  claim 13 , wherein the oligonucleotides of the population have an average size of 18 nucleotides, wherein no more than 14 of the phosphate backbone linkages in each oligonucleotide is a P-ethoxy backbone linkage. 
     
     
         15 . The method of  claim 13 , wherein the oligonucleotides of the population have an average size of 20 nucleotides, wherein no more than 16 of the phosphate backbone linkages in each oligonucleotide is a P-ethoxy backbone linkage. 
     
     
         16 . The method of  claim 13 , wherein the oligonucleotides of the population have an average size of 25 nucleotides, wherein no more than 20 of the phosphate backbone linkages in each oligonucleotide is a P-ethoxy backbone linkage. 
     
     
         17 . The method of  claim 13 , wherein the oligonucleotides of the population have an average size of 30 nucleotides, wherein no more than 24 of the phosphate backbone linkages in each oligonucleotide is a P-ethoxy backbone linkage. 
     
     
         18 . The method of  claim 1 , wherein the population of oligonucleotides comprises a single species of oligonucleotides. 
     
     
         19 . The method of  claim 1 , wherein the population of oligonucleotides comprises at least two species of oligonucleotides. 
     
     
         20 . The method of  claim 1 , wherein the population of oligonucleotides is heterogeneous as to the distribution of phosphodiester backbone linkages among the oligonucleotides of the population. 
     
     
         21 . The method of  claim 1 , wherein the phospholipids are uncharged or have a neutral charge at physiologic pH. 
     
     
         22 . The method of  claim 21 , wherein the phospholipids are neutral phospholipids. 
     
     
         23 . The method of  claim 22 , wherein the neutral phospholipids are phosphatidylcholines. 
     
     
         24 . The method of  claim 23 , wherein the neutral phospholipids are dioleoylphosphatidyl choline. 
     
     
         25 . The method of  claim 1 , wherein the phospholipids are essentially free of cholesterol. 
     
     
         26 . The method of  claim 1 , wherein the phospholipids and oligonucleotides are present at a molar ratio of from about 5:1 to about 100:1. 
     
     
         27 . The method of  claim 1 , wherein the oligonucleotide-lipid complex is further defined as a population of liposomes. 
     
     
         28 . The method of  claim 27 , wherein at least 90% of the liposomes are less than 5 microns in diameter. 
     
     
         29 . The method of  claim 27 , wherein at least 90% of the liposomes are less than 4 microns in diameter. 
     
     
         30 . The method of  claim 27 , wherein the population of oligonucleotides is incorporated in the population of liposomes. 
     
     
         31 . The method of  claim 15 , wherein the subject is a human. 
     
     
         32 . The method of  claim 1 , wherein the cancer is a non-small cell lung cancer, pancreatic adenocarcinoma, breast cancer, prostate cancer, melanoma, colon cancer, leukemia, lymphoma, glioma, glioblastoma, astrocytoma, osteosarcoma, oral cavity cancer, ovarian cancer, uterine cancer, bone cancer, brain cancer, prostate cancer, kidney cancer, stomach cancer, esophageal cancer, rectal cancer, bladder cancer, testicular cancer, or liver cancer. 
     
     
         33 . The method of  claim 32 , wherein the astrocytoma is glioblastoma multiforme. 
     
     
         34 . The method of  claim 1 , wherein the composition is administered subcutaneously, intravenously, or intraperitoneally. 
     
     
         35 . The method of  claim 1 , further comprising administering at least a second anticancer therapy to the subject. 
     
     
         36 . The method of  claim 24 , wherein the second anticancer therapy is a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormone therapy, immunotherapy, anti-viral therapy, immune suppression therapy, anti-bacterial therapy, anti-parasite therapy, anti-fungal therapy, or cytokine therapy. 
     
     
         37 . The method of  claim 1 , wherein the autoimmune disease is a Th2 dominant autoimmune disease. 
     
     
         38 . The method of  claim 37 , wherein the Th2 dominant autoimmune disease is lupus, allergic dermatitis, scleroderma, atopic eczema, sinusitis, inflammatory bowel disease, asthma, ulcerative colitis, or multiple chemical sensitivity. 
     
     
         39 . The method of  claim 1 , wherein administration of the composition reduces expression of IGF-1R protein in the patient. 
     
     
         40 . A method for reducing the expression level of IGF-1R protein in a cell, comprising contacting the cell with a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising a population of oligonucleotides, wherein the oligonucleotides hybridize to an IGF-1R polynucleotide gene product, wherein oligonucleotides of the population are composed of nucleoside molecules linked together through phosphate backbone linkages, wherein at least one of the phosphate backbone linkages in each oligonucleotide is a P-ethoxy backbone linkage, and wherein no more than 80% of the phosphate backbone linkages in each oligonucleotide are P-ethoxy backbone linkages, phospholipids, and a pharmaceutically acceptable carrier, wherein the oligonucleotides and phospholipids form an oligonucleotide-lipid complex. 
     
     
         41 . A method for delivering a therapeutically effective amount of an oligonucleotide to a cell comprising contacting the cell with a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising a population of oligonucleotides, wherein the oligonucleotides hybridize to an IGF-1R polynucleotide gene product, wherein oligonucleotides of the population are composed of nucleoside molecules linked together through phosphate backbone linkages, wherein at least one of the phosphate backbone linkages in each oligonucleotide is a P-ethoxy backbone linkage, and wherein no more than 80% of the phosphate backbone linkages in each oligonucleotide are P-ethoxy backbone linkages, phospholipids, and a pharmaceutically acceptable carrier, wherein the oligonucleotides and phospholipids form an oligonucleotide-lipid complex.