Therapeutic liposome composition and method of preparation

• US 20040191307A1
• Filed: 04/07/2004
• Published: 09/30/2004
• Est. Priority Date: 10/11/1996
• Status: Abandoned Application

• Current Assignee: ALZA Corporation (Johnson & Johnson), SEQUUS Pharmaceuticals, Inc. (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson), SEQUUS Pharmaceuticals, Inc. (Johnson & Johnson)
• Inventors: Allen, Theresa M., Martin, Francis J., Zalipsky, Samuel, Uster, Paul
• Application Number:
  US10/821,021
• Publication Number:
  US 20040191307A1
• 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 composition comprising reagents for use in preparing a therapeutic liposome composition sensitized to a target cell, said reagents comprised of (a) a liposomal composition composed of pre-formed liposomes having an entrapped therapeutic agent;

and (b) a plurality of conjugates, each conjugate composed 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 attached to the distal end of the polymer;

wherein said reagents are mixed to form the therapeutic, target-cell sensitized liposome composition.

2. The composition of claim 1, wherein the targeting ligand is an antibody or an antibody fragment.

3. The composition of claim 2, wherein the antibody or antibody fragment is a humanized murine antibody.

4. The composition of claim 2, wherein the targeting ligand specifically binds to an extracellular domain of a growth factor receptor.

5. The composition of claim 4, 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.

6. The composition of claim 2, 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.

7. The composition 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.

8. The composition 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.

9. The composition of claim 1, wherein the hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, polyaspartamide and hydrophilic peptide sequences.

10. The composition of claim 1, wherein the hydrophilic polymer is polyethylene glycol.

11. The composition of claim 10, wherein the polyethylene glycol has a molecular weight between 500-5,000 daltons.

12. The composition of claim 1, wherein the liposomes further contain a cationic lipid.

13. The composition of claim 1, wherein the entrapped therapeutic agent is a cytotoxic drug.

14. The composition of claim 13, wherein the cytotoxic drug is an anthracycline antibiotic selected from the group consisting of doxorubicin, daunorubicin, epirubicin and idarubicin and analogs thereof.

15. The composition of claim 13, wherein the cytotoxic agent is a platinum compound selected from cisplatin, carboplatin, ormaplatin, oxaliplatin, zeniplatin, enloplatin, lobaplatin, spiroplatin, ((−

)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutane dicarboxylato)platinum), (SP-4-3(R)-1,1-cyclobutane-dicarboxylato(2-)-(2-methyl-1,4-butanediamine-N,N′

)platinum), nedaplatin and (bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV)).

16. The composition of claim 13, wherein the cytotoxic agent is a topoisomerase 1 inhibitor selected from the group consisting of topotecan, irinotecan, (7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(S)-camptothecin), 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin, 9-aminocamptothecin and 9-nitrocamptothecin.

17. The composition of claim 13, wherein the cytotoxic agent is a vinca alkaloid selected from the group consisting of vincristine, vinblastine, vinleurosine, vinrodisine, vinorelbine and vindesine.

18. The composition of claim 1, wherein the entrapped agent is a nucleic acid.

19. The composition of claim 18, wherein the nucleic acid is an antisense oligonucleotide or ribozyme.

20. The composition of claim 18, wherein the nucleic acid is a plasmid containing a therapeutic gene which when internalized by the target cells achieves expression of the therapeutic gene to produce a therapeutic gene product.

21-56. -56 (Canceled)

57. A therapeutic liposome composition having sensitivity to a target cell, comprising

pre-formed liposomes having an entrapped therapeutic agent;

and

one or more conjugates composed 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 attached to the distal end of the polymer;

wherein said pre-formed liposomes and said one or more conjugates are in individual containers prior to formation of the therapeutic liposome composition having sensitivity to a target cell.

58. The composition of claim 57, wherein said conjugate is comprised of a vesicle-forming lipid, polyethylene glycol, and a targeting ligand having binding affinity for a cell surface receptor.

59. The composition of claim 57, wherein said pre-formed liposomes include as the entrapped therapeutic agent doxorubicin.

60. The composition of claim 58, wherein said pre-formed liposomes include as the entrapped therapeutic agent doxorubicin.