Method for treatment of a leukocyte related disease by delivery of nucleic acid molecules to leukocytes using targeted lipid particles

Patent metadata

Field	Value
Publication number	US-12065664-B2
Application number	US-202017128736-A
Country	US
Kind code	B2
Filing date	Dec 21, 2020
Priority date	May 26, 2015
Publication date	Aug 20, 2024
Grant date	Aug 20, 2024

Abstract

Disclosed are targeted lipid based particles for delivery of nucleic acid molecules (such as siRNA) to leukocytes (such as T-Cells and B-cells). Further disclosed are uses of the targeted lipid based particles for treating Leukocytes-associated diseases, such as, cancer.

First claim

The invention claimed is:

1. A method for treating a leukocyte associated disease, wherein the leukocyte associated disease is lymphoma, leukemia or multiple myeloma and the leukocyte is selected from a B-cell and a T-cell, comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising a particle for targeted delivery of a nucleic acid to a leukocyte, the particle comprising a lipid membrane comprising a cationic lipid, a membrane stabilizing lipid and a DSPE-PEG maleimide conjugated to a targeting moiety; and a nucleic acid molecule encapsulated within the particle,
wherein the targeting moiety is an antibody selected from the group consisting of an anti-CD38 antibody, an anti-CD4 antibody, an anti-CD8 antibody and an anti-CD3 antibody, or an antigen binding fragment thereof.

2. The method of claim 1 , wherein the cationic lipid is selected from: DLinDMA, DLin-MC3-DMA, DLin-KC2-DMA, Di-oleyl-succinyl-serinyl-tobramycin, Di-oleyl-adipyltobramycin, Di-oleyl-suberyl-tobramycin, N,N-dimethyl-N′,N′-di[(9Z, 12Z)-octadeca-9,12-dien-1-yl] ethane-1,2-diamine, Di-oleyl-sebacyl-tobramycin, Di-oleyl-dithioglycolyl-tobramycin, monocationic lipid N-[1-(2,3-Dioleoyloxy)]-N,N,N-trimethylammonium propane (DOTAP), BCAT O-(2R-1,2-di-O-(1′Z, 9′Z-octadecadienyl)-glycerol)-3-N-(bis-2-aminoethyl)-carbamate, BGSC (Bis-guanidinium-spermidine-cholesterol), BGTC (Bis-guanidinium-tren-cholesterol), CDAN (N′-cholesteryl oxycarbony 1-3,7-diazanonane-1,9-diamine), CHDTAEA (Cholesteryl hemidithiodiglycolyl tris(amino(ethyl)amine), DCAT (O-(1,2-di-O-(9′Z-octadecanyl)-glycerol)-3-N-(bis-2-aminoethyl)-carbamate), DC-Chol (3B [N—(N′, N′-dimethylaminoethane)-carbamoyl] cholesterol), DLKD (O,O′-Dilauryl N-lysylaspartate), DMKD (O,O′-Dimyristyl Nlysylaspartate), DOG (Diolcylglycerol, DOGS (Dioctadecylamidoglycylspermine), DOGSDSO (1,2-Dioleoyl-sn-glycero-3-succinyl-2-hydroxyethyl disulfide ornithine), DOPC (1,2-Dioleoylsn-glycero-3-phosphocholine), DOPE (1,2-Dioleoyl-sn-glycerol-3-phosphoethanolamine, DOSN (Dioleyl succinyl ethylthioneomycin), DOSP (Dioleyl succinyl paromomycin), DOST (Dioleyl succinyl tobramycin), 1,2-Uiolcoyl-3-trimethyl ammoniopropane, DOTMA (N′[1-(2,3-Dioleyloxy)propyl]-N,N,N-trimethvlammonium chloride), DPPES (Di-palmitoyl phosphatidyl ethanolamidosperminc), DDAB and DODAP, or any combination thereof.

3. The method of claim 1 , wherein the membrane stabilizing lipid is selected from the group consisting of cholesterol, phospholipids, cephalins, sphingolipids and glycoglycerolipids.

4. The method of claim 1 , wherein the lipid membrane further comprises phosphatidylamine selected from: 1,2-dilauroyl-L-phosphatidyl-ethanolamine (DLPE), 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) 1,2-Diphytanoyl-sn-glycero-3-phosphoethanolamine (DPhPE) 1,3-Dipalmitoyl-sn-glycero-2-phosphoethanolamine (1,3-DPPE) 10 1-Palmitoyl-3-oleoyl-sn-glycero-2-phosphoethanolamine (1,3-POPE), Biotin-Phosphatidylethanolamine, 1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine(DMPE), 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and Dipalmitoylphosphatidylethanolamine (DPPE).

5. The method of claim 1 , wherein the particle further comprises an additional PEG derivative, wherein the PEG derivative is selected from: PEG-DMG, PEG-CDMA, 3-N-(-methoxy poly(ethylene glycol)2000)carbamoyl-1,2-dimyristyloxy-propylamine; PEG-cDSA, 3-N-(-methoxy poly(ethylene glycol)2000)carbamoyl-1,2-distearyloxy-propylamine, PEG-Amine, or combinations thereof.

6. The method of claim 1 , wherein the lipid membrane comprises a cationic lipid selected from: DLin-MC3-DMA, DLinDMA and DLin-KC2-DMA; cholesterol; DSPC; and PEG-DMG.

7. The method of claim 1 , wherein the lymphoma is selected from B-cell lymphoma and T-cell lymphoma.

8. The method of claim 7 , wherein the B-cell lymphoma is selected from Hodgkin's lymphoma and non-Hodgkin's lymphoma.

9. The method of claim 7 , wherein the B-cell lymphoma is Mantle cell lymphoma (MCL).

10. The method of claim 1 , wherein the nucleic acid comprises an interfering RNA selected from the group consisting of siRNA, miRNA, shRNA, and antisense RNA, modified forms thereof, and combinations thereof.

11. The method of claim 10 , wherein the nucleic acid molecule is siRNA.

12. The method of claim 11 , wherein the siRNA is directed against a cell cycle regulator.

13. The method of claim 12 , wherein the cell cycle regulator is selected from the group consisting of: Polo-like Kinase 1 (PLK), Cyclin D1, CHK1, Notch pathway genes, PDGFRA, EGFRVIII, PD-L1, RelB, STAT1, STAT3, MCL1, CKAP5, RRM1, SF3A1 and CDK11B, and a combination thereof.

14. The method of claim 13 , wherein the cell cycle regulator is Cyclin D1.

15. The method of claim 1 , wherein the administration is systemic.

Assignees

• Univ Ramot

Inventors

• Peer Dan
• Weinstein Shiri
• Toker Itai Antoine
• Ramishetti Srinivas

Classifications

• A61K48/0066

  Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid · CPC title

• A61K9/513

  Organic macromolecular compounds; Dendrimers · 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

• A61P35/02

  specific for leukemia · CPC title

• A61K47/6911

  the form being a liposome · CPC title