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JP-2026514441-A - Lipid composition of Archexin

JP2026514441AJP 2026514441 AJP2026514441 AJP 2026514441AJP-2026514441-A

Abstract

This specification describes lipid nanoparticle (LNP) formulations for delivering activators (including Archexin).

Inventors

  • メン，ユーシン
  • ジャオ，シャオビン
  • ワン，チャオ
  • リー，ロバート
  • ヤン，ヨンション
  • ウェイ，ジア

Assignees

  • ザ・ホワイトオーク・グループ・インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20240321
Priority Date
20230331

Claims (20)

  1. A pharmaceutical composition comprising lipid nanoparticles encapsulating an activator, wherein the lipid nanoparticles are 2.5 mol% to 15 mol% of one or more cationic lipids, 30 mol% to 50 mol% of one or more types of ionized lipids, A pharmaceutical composition comprising 30 mol% to 65 mol% of one or more neutral lipids and 2.5 mol% to 15 mol% of one or more PEG-modified lipids.
  2. The composition according to claim 1, wherein the activator comprises RX-0201, 5' gctgcatgattcctttgggcg 3', SEQ ID NO: 1.
  3. The composition according to claim 2, wherein RX-0201 is an antisense oligonucleotide.
  4. The composition according to any one of claims 2 to 3, wherein RX-0201 has at least one modified nucleoside bond which is a phosphorothioate bond.
  5. The composition according to any one of claims 1 to 4, wherein the one or more cationic lipids are present in the lipid nanoparticles in an amount of 2.5 mol% to 12.5 mol%, or 2.5 mol% to 10 mol%.
  6. The aforementioned one or more cationic lipids are DOTMA:[1-(2,3-silyloxy)propyl]-N,N,N-trimethylammonium chloride, DMRIE, di-C14-amidine, DOTIM, SAINT, DC-Chol, BGTC, CTAP, DODAP, DOSPA(2,3-dioleoyloxy-N-[2-(spermidinecarboxamide)ethyl]-N,N-dimethyl-1-propanaminonium trifluoroacetate), DORIE(N-[1-(2,3-dioleoyl) [Dimyristoyloxypropyl]-N,N-dimethyl-N-hydroxyethylammonium bromide), DODAB, DOIC, DMEPC, DOGS: Dioctadecylamide glycidylamine, DIMRI: Dimyristoyloxypropyl dimethylhydroxyethylammonium bromide, DOTAP: Dioleoyloxy-3-(trimethylammonium)propane, DC-6-14: O,O-ditetradecanoyl-N-α-trimethylaminoacetyl)diethanolamine chloride, CLIP 1: Racemy-[(2,3-dioctadecyloxypropyl)(2-hydroxyethyl)]-dimethylammonium chloride, CLIP6: Racemy-[2(2,3-dihexadecyloxypropoxymethoxy)ethyl]-trimethylammonium, CLIP9: Racemy-[2(2,3-dihexadecyloxypropoxysuccinoyloxy)ethyl]-trimethylammonium, oligofectamine, lipids described in U.S. Patent No. 5,049,386, N-[1-(2,3-dioleoyloxypropyl)]-N, disclosed in International Publication Nos. WO91/16024 and WO97/019675 A composition according to any one of claims 1 to 5, comprising N-dimethyl-N-hydroxyethylammonium bromide (DORIE), 2,3-dioleoyloxy-N-[2-(spermidinecarboxamide)ethyl]-N,N-dimethyl-1-propanaminonium trifluoroacetate (DOSPA), and (3R,4R)-3,4-bis((Z)-hexadeca-9-enoxy)-1-methylpyrrolidine and N-methyl-N,N-bis(2-((Z)-octadeca-6-enoxy)ethyl)amine, as disclosed in International Publication WO 2011/13636, or any combination thereof.
  7. The composition according to any one of claims 1 to 6, wherein the one or more types of neutral lipids are present in the lipid nanoparticles in an amount of 40 mol% to 55 mol%.
  8. The composition according to any one of claims 1 to 7, wherein the one or more neutral lipids include dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylethanolamine (DOPE), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), palmitoyloleoylphosphatidylcholine (POPC), phosphatidylcholine (EPC), distearoylphosphatidylcholine (DSPC), cholesterol, or any combination thereof.
  9. The composition according to any one of claims 1 to 8, wherein the one or more types of neutral lipids include cholesterol.
  10. The composition according to any one of claims 1 to 9, wherein the one or more types of PEG-modified lipids are present in the lipid nanoparticles in an amount of 2.5 mol% to 10 mol%, or 5 mol% to 10 mol%.
  11. The composition according to any one of claims 1 to 10, wherein the one or more PEGylated lipids include PEG-ditetradecylacetamide, PEG-myristoylglycerol diester, PEG-diacylglycerol, PEG-dialkoxypropyl, PEG-phospholipid, PEG-ceramide, PEG-DMG, PEG-DSPE, or any combination thereof.
  12. The composition according to any one of claims 1 to 11, wherein the one or more PEG-modified lipids include 1,2-dimiristoyl-sn-glycero (DMG-PEG).
  13. The composition according to any one of claims 1 to 12, wherein the one or more ionized lipids are present in the lipid nanoparticles in an amount of 35 mol% to 45 mol%.
  14. The aforementioned one or more ionized lipids are N,N-dimethyl-2,3-dioleoyloxypropylamine (DODMA), [(4-hydroxybutyl)azadiyl]bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315), 8-{(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino}octanoic acid 9-heptadecyl ester (SM-102), International Publication No. WO2 A composition according to any one of claims 1 to 13, comprising DLin-MC3-DMA, DLin-KC2-DMA, DLinDMA, etc., disclosed in Publication No. 005/121348, DLin-K-DMA, etc., disclosed in International Publication No. WO2009/086558, 1-(2,3-bis(((9Z,12Z)-octadecenyl-9,12-dien-1-yl)oxy)propyl)pyrrolidine (A066), or any combination thereof.
  15. The composition according to any one of claims 1 to 14, wherein the one or more ionized lipids include N,N-dimethyl-2,3-dioleoyloxypropylamine (DODMA).
  16. The composition according to any one of claims 1 to 15, wherein the lipid nanoparticles comprise DOTAP, DODMA, DOPC, cholesterol, and DMG-PEG.
  17. The composition according to claim 16, wherein the DOTAP, DODMA, DOPC, cholesterol, and DMG-PEG are present in a molar ratio of 5:40:25:20:10 for DOTAP:DODMA:DOPC:cholesterol:DMG-PEG.
  18. The composition according to claim 16, wherein the DOTAP, DODMA, DOPC, cholesterol, and DMG-PEG are present in a molar ratio of 5:40:27.5:20:7.5 for DOTAP:DODMA:DOPC:cholesterol:DMG-PEG.
  19. The composition according to claim 16, wherein the DOTAP, DODMA, DOPC, cholesterol, and DMG-PEG are present in a molar ratio of 5:40:30:20:5 for DOTAP:DODMA:DOPC:cholesterol:DMG-PEG.
  20. The composition according to any one of claims 1 to 19, wherein the lipid nanoparticles and the activator are present in a weight ratio of lipid nanoparticles to activator of 5:1 to 20:1, 7.5:1 to 15:1, 7.51:1 to 10:1, 7.5:1 to 12:1, 10:1 to 12:1, 10.1 to 15:1, or 12:1 to 15:1.

Description

Cross-reference of related applications This application claims priority and interest in U.S. Provisional Application No. 63/493,576, filed on March 31, 2023, the contents of which are incorporated herein by reference in their entirety. Quote from the sequence list The sequence listing submitted on March 21, 2024, is incorporated by reference as a text file named "11650-003PV1_2023_03_30_Sequence_Listing," created on March 30, 2023, with a file size of 2,566 bytes, pursuant to 37 C.F.R. § 1.52(e)(5). AKT-1 (Archexin) is a protein product of the akt-1 proto-oncogene that exerts its effects on cancer progression by promoting cell proliferation and suppressing apoptosis in cancer cells (see Revathidevi S, et al., Semin Cancer Biol. 2019;59:80-91, and Uko NE, et al., Curr Top Med Chem. 2020;20(10):883-900). Archexin is a fully thiolated 20-mer antisense oligonucleotide that can specifically bind to AKT-1 mRNA and induce downregulation of AKT-1 based on RNA enzyme H. Archexin suppresses the translation of AKT-1 mRNA and inhibits tumor growth. However, due to its low membrane permeability and in vivo stability, as well as the need for a 14-day continuous infusion regimen, Archexin is limited by challenges inherent to antisense oligonucleotides. The intracellular delivery and circulation time of oligonucleotides (e.g., Archexin) needs to be enhanced. The compositions and methods disclosed herein address these and other requirements. This specification describes a pharmaceutical composition comprising lipid nanoparticles encapsulating an activator. The lipid nanoparticles may include 2.5 mol% to 15 mol% of one or more cationic lipids, 30 mol% to 50 mol% of one or more ionized lipids, 30 mol% to 65 mol% of one or more neutral lipids, and 2.5 mol% to 15 mol% of one or more PEGylated lipids. In some embodiments, the activator may include RX-0201,5' gctgcatuatctcctttggcg 3',SEQ ID NO: 1. This specification further describes methods for the treatment of cancer, the prevention of cancer, the prevention of cancer metastasis, the prevention of cancer recurrence, or the prevention of angiogenesis. These methods may include the step of administering the pharmaceutical compositions described herein to subjects in need. This specification further describes methods for inducing cytotoxicity in cancer cells. These methods may include the step of contacting the cells with the pharmaceutical compositions described herein. This specification further describes a method for producing lipid nanoparticle groups encapsulated with activators. The method may include: (a) mixing one or more ethanol solutions containing a lipid mixture with an aqueous solution and oxidizing them to induce the formation of empty lipid nanoparticle groups; (b) contacting the empty lipid nanoparticle groups with an aqueous solution containing an activator to encapsulate the activator in the empty lipid nanoparticle groups, thereby producing lipid nanoparticle groups encapsulated with the activator; and (c) performing tangential flow filtration on the lipid nanoparticle groups encapsulated with the activator to replace the buffer solution and remove residual ethanol. In some embodiments, the lipid mixture includes 2.5 mol% to 15 mol% of one or more cationic lipids, 30 mol% to 50 mol% of one or more ionized lipids, 30 mol% to 65 mol% of one or more neutral lipids, and 2.5 mol% to 15 mol% of one or more PEGylated lipids. This figure shows the effect of the Hepa1-6 gene of WGI-0301 on tumor growth in a hepatocellular carcinoma model.This figure shows the effect of the Hepa1-6 gene of WGI-0301 on survival in a hepatocellular carcinoma model.This is a diagram showing the number of branching points in relation to concentration.This is a diagram showing the relationship between capillary length and concentration.This figure shows the anti-angiogenic effects of WGI-0301 monotherapy and combination therapy (0.1% DMSO and WGI-0301).This figure shows the anti-angiogenic effects of WGI-0301 monotherapy and combination therapy (2 μM sorafenib and WGI-0301).This figure shows the anti-angiogenic effects of WGI-0301 monotherapy and combination therapy (5 μM lenvatinib and WGI 0301).This flowchart shows the manufacturing process for lipid nanoparticles described herein.This study demonstrates the effect of the test product on mouse body weight in the Hepa 1-6 model.This study demonstrates the effect of the test product on body weight changes in mice in the Hepa 1-6 model.This study demonstrates the effect of the test sample on tumor volume in the Hepa 1-6 model.The survival curves for the test specimens in the Hepa 1-6 model are shown.This figure shows the command voltage program for an hERG test using manual patch clamps.Archexin free acid: Concentration response curve is shown.This graph shows the change in body weight after administration of the test substance to female Balb/c nude mice carrying Hep3B-luc tumor cells. Each data point represents the group mean body weight. Er