P-ethoxy nucleic acids for igf-1r inhibition

Patent metadata

Field	Value
Publication number	US-2022133775-A1
Application number	US-202117530051-A
Country	US
Kind code	A1
Filing date	Nov 18, 2021
Priority date	Apr 19, 2017
Publication date	May 5, 2022
Grant date	—

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.

First claim

What is claimed is:

1 .- 41 . (canceled)

42 . A pharmaceutical composition for use in a method of treating cancer or an autoimmune disease in a subject, wherein the pharmaceutical composition comprises 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 60% to 75% of the phosphate backbone linkages in each oligonucleotide are P-ethoxy backbone linkages, and wherein 25% to 40% of the phosphate backbone linkages are phosphodiester backbone linkages, phospholipids, wherein the phospholipids are essentially free of cholesterol; and a pharmaceutically acceptable carrier, wherein the oligonucleotides and phospholipids form an oligonucleotide-lipid complex, wherein oligonucleotides of the population comprise a sequence according to either of SEQ ID NOs: 1 or 2.

43 . The composition according to claim 42 , wherein oligonucleotides of the population comprise a sequence according to SEQ ID NO: 1.

44 . The composition according to claim 42 , wherein oligonucleotides of the population comprise a sequence according to SEQ ID NO: 2.

45 . The composition according to claim 42 , wherein the phosphodiester backbone linkages are distributed throughout each oligonucleotide.

46 . The composition according to claim 42 , wherein the oligonucleotides of the population have a size ranging from 18 to 30 nucleotides.

47 . The composition according to claim 42 , wherein the population of oligonucleotides comprises a single species of oligonucleotides.

48 . The composition according to claim 42 , wherein the population of oligonucleotides comprises at least two species of oligonucleotides.

49 . The composition according to claim 42 , wherein the phospholipids are uncharged or have a neutral charge at physiologic pH.

50 . The composition according to claim 42 , wherein the phospholipids are neutral phospholipids, wherein the neutral phospholipids are phosphatidylcholines or dioleoylphosphatidyl choline.

51 . The composition according to claim 42 , wherein the phospholipids and oligonucleotides are present at a molar ratio of from about 5:1 to about 100:1.

52 . The composition according to claim 42 , wherein the oligonucleotide-lipid complex is further defined as a population of liposomes.

53 . The composition according to claim 42 , wherein at least 90% of the liposomes are less than 5 microns in diameter.

54 . The composition according to claim 42 , wherein the subject is a human.

55 . The composition according to claim 42 , 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.

56 . The composition according to claim 42 , wherein the composition is administered subcutaneously, intravenously, or intraperitoneally.

57 . The composition according to claim 42 , wherein the pharmaceutical composition further comprises at least one chemotherapeutic agent, and wherein the at least one chemotherapeutic agent is selected from docetaxel, paclitaxel, cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol, gemcitabien, navelbine, famesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil, vincristin, vinblastin, methotrexate, or combinations thereof.

58 . A method of treating a subject with a cancer or an autoimmune disease comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 42 , wherein administration of the composition reduces expression of IGF-1R protein in the patient.

59 . The method according to claim 58 , wherein the autoimmune disease is a Th2 dominant autoimmune disease, and wherein the Th2 dominant autoimmune disease is lupus, allergic dermatitis, scleroderma, atopic eczema, sinusitis, inflammatory bowel disease, asthma, ulcerative colitis, or multiple chemical sensitivity.

60 . 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 60% to 75% of the phosphate backbone linkages in each oligonucleotide are P-ethoxy backbone linkages, and wherein 25% to 40% of the phosphate backbone linkages are phosphodiester backbone linkages, phospholipids, and a pharmaceutically acceptable carrier, wherein the oligonucleotides and phospholipids form an oligonucleotide-lipid complex, wherein the phospholipids are essentially free of cholesterol.

61 . 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 60% to 75% of the phosphate backbone linkages in each oligonucleotide are P-ethoxy backbone linkages, and wherein 25% to 40% of the phosphate backbone linkages are phosphodiester backbone linkages, phospholipids, and a pharmaceutically acceptable carrier, wherein the oligonucleotides and phospholipids form an oligonucleotide-lipid complex, wherein the phospholipids are essentially free of cholesterol.

Assignees

• Bio Path Holdings Inc
• Univ Jefferson

Inventors

• Ashizawa Ana
• Hooper Douglas Craig
• Andrews David W

Classifications

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• C12N15/1138

  against receptors or cell surface proteins · CPC title

• A61K31/7125 Primary

  Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title