Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2000-03-02
2001-11-13
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C436S829000, C424S812000
Reexamination Certificate
active
06316024
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a target-cell sensitized therapeutic liposome composition and to a method of preparing the composition. A library for preparation of the composition is also described.
BACKGROUND OF THE INVENTION
Liposomes, spherical, self-enclosed vesicles composed of amphipathic lipids, have been widely studied and are employed as vehicles for in vivo administration of therapeutic agents. In particular, the so-called long circulating liposomes formulations which avoid uptake by the organs of the mononuclear phagocyte system, primarily the liver and spleen, have found commercial applicability. Such long-circulating liposomes include a surface coat of flexible water soluble polymer chains, which act to prevent interaction between the liposome and the plasma components which play a role in liposome uptake.
More recently, efforts have focused on ways to achieve site specific delivery of long-circulating liposomes. In one approach, targeting ligands, such as an antibody, are attached to the liposomes' surfaces. This approach, where the targeting ligand is bound to the polar head group residues of liposomal lipid components, results in interference by the surface-grafted polymer chains, inhibiting the interaction between the bound ligand and its intended target (Klibanov, A. L., et al.,
Biochim. Biophys. Acta.,
1062:142-148 (1991); Hansen, C. B., et al.,
Biochim. Biophys. Acta,
1239:133-144 (1995)).
In another approach, the targeting ligand is attached to the free ends of the polymer chains forming the surface coat on the liposomes (Allen. T. M., et al.,
Biochim. Biophys. Acta,
1237:99-108 (1995); Blume, G. , et al.,
Biochim. Biophys. Acta,
1149:180-184 (1993)). Two approaches have been described for preparing a liposome having a targeting ligand attached to the distal end of the surface polymer chains. One approach involves preparation of lipid vesicles which include an end-functionalized lipid-polymer derivative; that is, a lipid-polymer conjugate where the free polymer end is reactive or “activated”. Such an activated conjugate is included in the liposome composition and the activated polymer ends are reacted with a targeting ligand after liposome formation. The disadvantage to this approach is the difficulty in reacting all of the activated ends with a ligand. The approach also requires a subsequent step for separation of the unreacted ligand from the liposome composition.
In another approach, the lipid-polymer-ligand conjugate is included in the lipid composition at the time of liposome formation. This approach has the disadvantage that some of the valuable ligand faces the inner aqueous compartment of the liposome and is unavailable for interaction with the intended target.
Both approaches suffer from a lack of flexibility in designing a therapeutic composition that is specific for a target cell for a specific patient. There is then a need for a liposome composition which provides flexibility in choice of the entrapped agent and the targeting ligand.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the invention to provide a therapeutic liposome composition that is readily tailored and designed for a particular patient.
It is another object of the invention to provide a kit for formation of a therapeutic, target-cell sensitive liposome composition.
In one aspect, the invention includes a therapeutic liposome composition sensitized to a target cell, comprising
(i) a liposomal composition composed of pre-formed liposomes having an entrapped therapeutic agent; and
(ii) a plurality of conjugates, each conjugate composed of (a) a lipid having a polar head group and a hydrophobic tail, (b) a hydrophilic polymer having a proximal end and a distal end, where the polymer is attached at its proximal end to the head group of the lipid, and (c) a targeting ligand attached to the distal end of the polymer. The therapeutic, target-cell sensitized liposome composition is formed by combining the liposomal composition with a conjugate selected from the plurality of conjugates.
In one embodiment, the targeting ligand is an antibody or an antibody fragment. In one embodiment, the antibody or antibody fragment is of mouse origin and is humanized to remove murine epitopes.
In another embodiment, the targeting ligand specifically binds to an extracellular domain of a growth factor receptor. Such receptors are selected from c-erbB-2 protein product of the HER2
eu oncogene, epidermal growth factor receptor, basic fibroblast growth factor receptor, and vascular endothelial growth factor receptor.
In another embodiment, the targeting ligand binds a receptor selected from E-selectin receptor, L-selectin receptor, P-selectin receptor, folate receptor, CD4 receptor, CD19 receptor, &agr;&bgr; integrin receptors and chemokine receptors.
The targeting ligand can also be 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, an RGD peptide or an NGR peptide.
The hydrophilic polymer surrounding the preformed liposomes 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.
In one embodiment, the hydrophilic polymer is polyethylene glycol of molecular weight between 500-5,000 daltons.
The entrapped therapeutic agent is, in one embodiment, a cytotoxic drug. The drug can be an anthracycline antibiotic selected from doxorubicin, daunorubicin, epirubicin and idarubicin and analogs thereof.
The cytotoxic agent can also be 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)).
In another embodiment, 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.
In another embodiment, the cytotoxic agent is a vinca alkaloid selected from the group consisting of vincristine, vinblastine, vinleurosine, vinrodisine, vinorelbine and vindesine.
In another embodiment, the entrapped agent is a nucleic acid. The nucleic acid can be an antisense oligonucleotide or ribozyme or 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.
In another aspect, the invention includes a plurality of targeting conjugates for use in preparing a targeted, therapeutic liposome composition. Each conjugate is composed of a (i) a lipid having a polar head group and a hydrophobic tail, (ii) a hydrophilic polymer having a proximal end and a distal end, the 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.
The lipid in the conjugates is, in one embodiment, distearoyl phosphatidylethanolamine, distearoyl-phosphatidylcholine, monogalactosyl diacylglycerols or digalactosyl diacylglycerols.
The hydrophilic polymer in the conjugates is selected from the group consisting of polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethylenegly
Allen Theresa M.
Martin Francis J.
Uster Paul
Zalipsky Samuel
Kishore Gollamudi S.
Mohr Judy M.
Perkins Coie LLP
Sequus Pharmaceuticals, Inc.
Simboli Paul B.
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