Therapeutic liposome composition and method of preparation

• US 20060246126A1
• Filed: 06/30/2006
• Published: 11/02/2006
• Est. Priority Date: 10/11/1996
• Status: Abandoned Application

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Martin, Francis J., Zalipsky, Samuel, Allen, Theresa M., Uster, Paul
• Application Number:
  US11/479,437
• Publication Number:
  US 20060246126A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 47/544 Phospholipids
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 47/6913 the liposome being modified on its surface by an antibody
• CPC Class Codes: A61K 51/1234 Liposomes
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: C07K 16/2854 against selectins, e.g. CD62
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: Y10S 424/812 Liposome comprising an antibody, antibody fragment, antigen, or other specific or nonspecific immunoeffector
• CPC Class Codes: Y10S 436/829 Liposomes, e.g. encapsulation

Abstract

Reagents for use in preparing a therapeutic liposome composition sensitized to a target cell are described. The reagents include a liposomal composition composed of pre-formed liposomes having an entrapped therapeutic agent and a plurality of targeting conjugates composed of a lipid, a hydrophilic polymer and a targeting ligand. The therapeutic, target-cell sensitized liposome composition is formed by incubating the liposomal composition with a selected conjugate.

Claims

1. A micellar suspension comprising a plurality of conjugates for use in preparing a liposome composition, each conjugate consisting essentially of (i) a lipid having a polar head group and a hydrophobic tail, (ii) a hydrophilic polymer having a proximal end and a distal end, said polymer attached at its proximal end to the head group of the lipid, and (iii) a targeting ligand having binding affinity for a receptor expressed on a cell, said ligand attached to the distal end of the hydrophilic polymer.

2. The micellar suspension of claim 1, wherein the lipid is selected from the group consisting of distearoyl phosphatidylethanolamine, distearoyl-phosphatidylcholine, monogalactosyl diacylglycerols and digalactosyl diacylglycerols.

3. The micelilar suspension of claim 2, wherein the hydrophilic polymer is polyethylene glycol.

4. The micellar suspension of claim 3, wherein the polyethylene glycol has a molecular weight between 500-5,000 daltons.

5. The micellar suspension of claim 1, wherein the targeting ligand is an antibody or an antibody fragment.

6. The micellar suspension of claim 5, wherein the antibody or antibody fragment is a humanized murine antibody.

7. The micellar suspension of claim 1, wherein the targeting ligand specifically binds to an extracellular domain of a growth factor receptor.

8. The micellar suspension of claim 7, wherein the receptors are selected from the group consisting of c-erbB-2 protein product of the HER2/neu oncogene, epidermal growth factor receptor, basic fibroblast growth factor receptor and vascular endothelial growth factor receptor.

9. The micellar suspension of claim 1, wherein the targeting ligand binds a receptor selected from the group consisting of E-selectin receptor, L-selectin receptor, P-selectin receptor, folate receptor, CD4 receptor, CD19 receptor, α

β

integrin receptors and chemokine receptors.

10. The micellar suspension of claim 1, wherein the targeting ligand binds a receptor on a malignant B-cell or T-cell, said receptor selected from the group consisting of CD19, CD20, CD22, CD4, CD7 and CD8.

11. The micellar suspension of claim 1, wherein the targeting ligand is selected from the group consisting of folic acid, pyridoxal phosphate, vitamin B12, sialyl Lewis^x, transferrin, epidermal growth factor, basic fibroblast growth factor, vascular endothelial growth factor, VCAM-1, ICAM-1, PECAM-1, RGD peptides and NGR peptides.

12. The micellar suspension of claim 1, wherein the targeting ligand is selected from the group consisting of water soluble vitamins, apolipoproteins, insulin, galactose, Mac-1, PECAM-1/CD31, fibronectin, osteopontin, RGD sequences of matrix proteins, HIV GP 120/41 domain peptomers, GP120 C4 domain peptomers, T cell tropic isolates, SDF-1 chemokines, Macrophage tropic isolates, anti-cell surface receptor antibodies or fragments thereof, pyridoxyl ligands, biotin, RGD peptide mimetics, YIGSRG protein, avB5, IL-8, anti-E-selectin Fab.

13. The micellar suspension of claim 12, wherein the anti-cell surface receptor antibodies or fragments thereof is selected from the group consisting of anti-HER2/neu, anti-selectin and anti-VEGF pyridoxyl.

14. The micellar suspension of claim 12, wherein the pyridoxyl ligand is selected from the group consisting of pyridoxal, pyridoxine, pyridoxamine, pyridoxal 5′

-phosphate and N-(4′

-pyridoxyl)amines.

15. A conjugate consisting essentially of (i) a lipid having a polar head group and a hydrophobic tail, (ii) a polyethylene glycol polymer chain, said polymer having a proximal end, a distal end, and a molecular weight of between about 500-5000 Daltons, said polymer attached at its proximal end to the head group of the lipid, and (iii) a targeting ligand having binding affinity for a receptor expressed on a cell, said ligand attached to the distal end of the polymer.

16. The conjugate of claim 15, wherein the targeting ligand is an antibody or an antibody fragment.

17. The conjugate of claim 16, wherein the antibody or antibody fragment is a humanized murine antibody.

18. The conjugate of claim 15, wherein the targeting ligand specifically binds to an extracellular domain of a growth factor receptor.

19. The conjugate of claim 18, wherein the receptors are selected from the group consisting of c-erbB-2 protein product of the HER2/neu oncogene, epidermal growth factor receptor, basic fibroblast growth factor receptor and vascular endothelial growth factor receptor.

20. The conjugate of claim 15, wherein the targeting ligand binds a receptor selected from the group consisting of E-selectin receptor, L-selectin receptor, P-selectin receptor, folate receptor, CD4 receptor, CD19 receptor, α

β

integrin receptors and chemokine receptors.

21. The conjugate of claim 15, wherein the targeting ligand binds a receptor on a malignant B-cell or T-cell, said receptor selected from the group consisting of CD19, CD20, CD22, CD4, CD7 and CD8.

22. The conjugate of claim 15, wherein the targeting ligand is selected from the group consisting of folic acid, pyridoxal phosphate, vitamin B12, sialyl Lewisx, transferrin, epidermal growth factor, basic fibroblast growth factor, vascular endothelial growth factor, VCAM-1, ICAM-1, PECAM-1, RGD peptides and NGR peptides.

23. The conjugate of claim 15, wherein the targeting ligand is selected from the group consisting of water soluble vitamins, apolipoproteins, insulin, galactose, Mac-1, PECAM-1/CD31, fibronectin, osteopontin, RGD sequences of matrix proteins, HIV GP 120/41 domain peptomers, GP120 C4 domain peptomers, T cell tropic isolates, SDF-1 chemokines, Macrophage tropic isolates, anti-cell surface receptor antibodies or fragments thereof, pyridoxyl ligands, biotin, RGD peptide mimetics, YIGSRG protein, avB5, IL-8, and anti-E-selectin Fab.

24. The conjugate of claim 23, wherein the anti-cell surface receptor antibodies or fragments thereof is selected from the group consisting of anti-HER2/neu, anti-selectin and anti-VEGF pyridoxyl.

25. The conjugate of claim 23, wherein the pyridoxyl ligand is selected from the group consisting of pyridoxal, pyridoxine, pyridoxamine, pyridoxal 5′

-phosphate and N-(4′

-pyridoxyl)amines.