Immunoliposomes that optimize internalization into target cells

• US 6,214,388 B1
• Filed: 04/18/1996
• Issued: 04/10/2001
• Est. Priority Date: 11/09/1994
• Status: Expired due to Term

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Hong, Keelung, Benz, Christopher C., Park, John W., Papahadjopoulos, Demetrios P., Kirpotin, Dmitri
• Primary Examiner(s): Nolan, Patrick J.
• Application Number:
  US08/634,197
• Time in Patent Office: 1,818 Days
• Field of Search: 424/178, 424/179.1, 424/450, 424/181.1, 424/178.1, 424/183.1, 424/812, 424/85.1, 530/388.22, 530/387.3, 530/387.1, 530/2, 530/389.7, 530/391.7, 530/391.9, 530/866
• US Class Current: 424/143.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6913 the liposome being modified on its surface by an antibody
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/77 Internalization into the cell

Abstract

The present invention provides for immunoliposomes that optimizes internalization of a drug into target cells bearing a characteristic cell surface marker. The immunoliposomes comprise an Fab′ domain of an antibody that specifically binds the characteristic marker, an amphipathic vesicle-forming lipid, and a polyethylene glycol derivatized lipid. The invention also provides for growth-inhibiting immunoliposomes that lack growth-inhibiting therapeutic agents and yet are capable of inhibiting the growth and proliferation of target cells.

Claims

1. An immunoliposome that is internalizd into a cell bearing a HER2 growth factor receptor, said immunoliposome comprising:

a recombinantly produced antibody fragment specifically binding to the HER2 receptor said fragment attached to a polyethylene glycol derivatized lipid,

an amphipathic vesicle-forming lipid, said vesicle-forming lipid forming a liposome;

a polyethylene glycol derivatized lipid;

wherein when said immunoliposome is contacted with said cell, said immunoliposome is internalized into the cell.

2. The immunoliposome of claim 1, wherein said polyethylene glycol has an average molecular weight of between about 750 D and 5000 D.

3. The immunoliposome of claim 1, wherein the antibody fragment is a Fab′

.

4. The immunoliposome of claim 1 wherein the antibody fragment is a humanized Fab′

domain of a monoclonal antibody.

5. The immunoliposome of claim 1, wherein said vesicle forming lipid is selected from the group consisting of a phospholipid, a glycolipid, a sphingolipid, and a sterol.

6. The immunoliposome of claim 1 which further comprises a therapeutic agent.

7. The immunoliposome of claim 6, wherein said therapeutic agent is selected from the group consisting of daunomycin, idarubicin, mitoxantrone, mitomycin, cisplatin and other Platinum II analogs, vincristine, epirubicin, aclacinomycin, methotrexate, etoposide, doxorubicin, cytosine arabinoside, fluorouracil and other fluorinated pyrimidines, purines, or nucleosides, bleomycin, mitomycin, plicamycin, dactinomycin, cyclophosphamide and derivatives thereof, thiotepa, BCNU, taxol, taxotere and other taxane derivatives and isolates, camptothecins, polypeptides, a nucleic acid, a nucleic acid having a phosphorothioate internucleotide linkage, and a nucleic acid having a polyamide internucleotide linkage.

8. The immunoliposome of claim of claim 1, wherein:

the antibody fragment is attached to the distal terminus of PEG derivatized distearoylphosphatidylethanolamine (DSPE).

9. The immunoliposome of claim 8 wherein the antibody fragment is a fab′

.