Rna interference compositions and methods for malignant tumors

Patent metadata

Field	Value
Publication number	US-2016186182-A1
Application number	US-201514979566-A
Country	US
Kind code	A1
Filing date	Dec 28, 2015
Priority date	Dec 26, 2014
Publication date	Jun 30, 2016
Grant date	—

Abstract

This invention provides compositions for use in distributing active agents for treating a malignant tumor in a subject. The compositions contain RNAi molecules targeted to a human GST-π, along with RNAi molecules targeted to a human p21, and a pharmaceutically acceptable carrier. The carrier can include nanoparticles composed of an ionizable lipid, a structural lipid, one or more stabilizer lipids, and a lipid for reducing immunogenicity of the nanoparticles. This invention further provides methods for preventing or treating a malignant tumor by administering a therapeutically effective amount of an RNAi composition.

First claim

What is claimed is:

1 . A composition comprising RNAi molecules targeted to a human GST-π, RNAi molecules targeted to a human p21, and a pharmaceutically acceptable carrier.

2 . The composition of claim 1 , wherein each of the RNAi molecules targeted to GST-π has an antisense strand SEQ ID NOs:131 and a sense strand SEQ ID NOs:157.

3 . The composition of claim 1 , wherein each of the RNAi molecules targeted to p21 has an antisense strand SEQ ID NOs:341 and a sense strand SEQ ID NOs:355.

4 . The composition of claim 1 , wherein each of the RNAi molecules targeted to GST-π has an antisense strand SEQ ID NOs:156 and a sense strand SEQ ID NOs:182.

5 . The composition of claim 1 , wherein each of the RNAi molecules targeted to p21 has an antisense strand SEQ ID NOs:343 and a sense strand SEQ ID NOs:357.

6 . The composition of claim 1 , wherein one or more of the nucleotides in the duplex region of the RNAi molecules is modified or chemically-modified.

7 . The composition of claim 6 , wherein the modified or chemically-modified nucleotides are 2′-deoxy nucleotides, 2′-O-alkyl substituted nucleotides, 2′-deoxy-2′-fluoro substituted nucleotides, phosphorothioate nucleotides, locked nucleotides, or any combination thereof.

8 . The composition of claim 1 , wherein each of the RNAi molecules contains a 2′-deoxynucleotide in one or more of positions 2 to 8 from the 5′ end of the antisense strand.

9 . The composition of claim 1 , wherein the antisense strand of each of the RNAi molecules has deoxynucleotides in a plurality of positions, the plurality of positions being one of the following:
each of positions 4, 6 and 8, from the 5′ end of the antisense strand; each of positions 3, 5 and 7, from the 5′ end of the antisense strand; each of positions 1, 3, 5 and 7, from the 5′ end of the antisense strand; each of positions 3-8, from the 5′ end of the antisense strand; or each of positions 5-8, from the 5′ end of the antisense strand.

10 . The composition of claim 1 , wherein the composition inhibits expression of GST-π mRNA with an 1050 of less than 50 pM, and inhibits expression of p21 mRNA with an 1050 of less than 50 pM.

11 . The composition of claim 1 , wherein a single administration of the composition inhibits expression of GST-π mRNA levels in vivo by at least 25%.

12 . The composition of claim 1 , wherein the carrier comprises liposome nanoparticles that encapsulate the RNAi molecules.

13 . The composition of claim 1 , wherein the carrier comprises liposome nanoparticles that encapsulate the RNAi molecules and retain at least 80% of the encapsulated RNAi molecules after 1 hour exposure to human serum.

14 . The composition of claim 1 , wherein the carrier comprises liposome nanoparticles having a size of 10 to 1000 nm, or 10 to 150 nm.

15 . The composition of claim 1 , wherein the composition is active for treating malignant tumor.

16 . The composition of claim 15 , wherein the malignant tumor is located in the lung, colon, kidney, pancreas, liver, bone, skin, or intestine.

17 . The composition of claim 1 , wherein the carrier comprises liposome nanoparticles comprising an ionizable lipid, a structural lipid, one or more stabilizer lipids, and a lipid for reducing immunogenicity of the nanoparticles.

18 . The composition of claim 17 , wherein the ionizable lipid is selected from the group of compound 81, compound 71, compound 57, compound 84, compound 49, compound 76, compound 78, and compound 102.

19 . A method for preventing, treating or ameliorating one or more symptoms of a malignant tumor in a subject in need, the method comprising administering to the subject an effective amount of a composition of claim 1 .

20 . The method of claim 19 , wherein the malignant tumor is associated with KRAS mutation, the method further comprising identifying a tumor cell in the subject, the tumor cell comprising at least one of: (i) a mutation of the KRAS gene, and (ii) an aberrant expression level of KRAS protein.

21 . The method of claim 19 , wherein the malignant tumor overexpresses GST-π.

22 . The method of claim 19 , wherein the RNAi molecules decrease expression of GST-π and p21 in the subject.

23 . The method of claim 19 , wherein the administration decreases expression of GST-π and p21 in the subject by at least 5% for at least 5 days.

24 . The method of claim 19 , wherein the administration decreases the volume of the malignant tumor in the subject by at least 5%, or at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%.

25 . The method of claim 19 , wherein the method reduces one or more symptoms of the malignant tumor, or delays or terminates the progression of the malignant tumor.

26 . The method of claim 19 , wherein the administration reduces growth of malignant tumor cells in the subject.

27 . The method of claim 19 , wherein the administration reduces growth for at least 2%, or at least 5%, or at least 10%, or at least 15%, or at least 20% of the malignant tumor cells in the subject.

28 . The method of claim 19 , wherein the malignant tumor is colon cancer, pancreatic cancer, kidney cancer, lung cancer, breast cancer, or fibrosarcoma.

29 . The method of claim 19 , wherein the malignant tumor is lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, or colorectal carcinoma.

30 . The method of claim 19 , wherein the administration is performed from 1 to 12 times per day.

31 . The method of claim 19 , wherein the administration is performed for a duration of 1, 2, 3, 4, 5, 6 or 7 days.

32 . The method of claim 19 , wherein the administration is performed for a duration of 1, 2, 3, 4, 5, 6, 8, 10 or 12 weeks.

33 . The method of claim 19 , wherein the administration is a dose of from 0.01 to 2 mg/kg of the RNAi molecules at least once per day for a period up to twelve weeks.

34 . The method of claim 19 , wherein the administration provides a mean AUC(0-last) of from 1 to 1000 ug*min/mL and a mean C max of from 0.1 to 50 ug/mL for the GST-π RNAi molecule.

35 . The method of claim 19 , wherein the administration provides a mean AUC(0-last) of from 1 to 1000 ug*min/mL and a mean C max of from 0.1 to 50 ug/mL for the p21 RNAi molecule.

36 . The method of claim 19 , wherein the administration is intravenous injection, intradermal injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, oral, topical, infusion, or inhalation.

Assignees

• Nitto Denko Corp

Inventors

• Niitsu Yoshiro
• Minomi Kenjirou
• Majeti Bharat
• Harborth Jens
• Wang Li
• Liu Jihua
• Liu Yun
• Adami Roger
• Ying Wenbin

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C12N2310/322

  2'-R Modification · CPC title

• C07F9/6533

  Six-membered rings · CPC title

• C12N2310/531

  Stem-loop; Hairpin · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title