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Tnp-470 polymer conjugates and use thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Solid Synthetic Organic Polymer As Designated Organic Active Ingredient (doai), Aftertreated Polymer (e.g., Grafting, Blocking, Etc.), Polymer Derived From Ethylenic Monomers Only, Chemical Treating Agent Contains Element Other Than C, H, O, Alkali, Or Alkaline Earth Metal, Nitrogen Or SulfurTnp-470 polymer conjugates and use thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080112919, Tnp-470 polymer conjugates and use thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] In recent years, it has become clear that angiogenesis, the growth of new capillary blood vessels from pre-existing vasculature, is important not only in physiological processes such as embryonic development, the female reproductive cycle, wound healing, and organ and tissue regeneration, but also in pathological processes such as tumor progression and metastasis.sup.1. Angiogenesis is now recognized as a critical process for all malignancies.sup.2,3. As a result, the microvascular endothelial cell, which is recruited by tumors, has become an important second target in cancer therapy. It is widely accepted that the endothelial cell target, unlike the tumor cells themselves, is genetically stable.sup.1. Antiangiogenic agents have recently emerged as a new class of drugs; however, the optimal means to use these agents alone or in combination with drug delivery systems and with conventional chemotherapy have not yet been fully elucidated. [0002] The hypothesis that tumor growth is angiogenesis-dependent is supported by biological and pharmacological evidence.sup.4 and confirmed by genetic evidence.sup.3,5-7. Both types of evidence provide a scientific basis for current clinical trials of angiogenesis inhibitors. Increased tumor angiogenesis.sup.4,8 and elevated levels of proangiogenic factors such as vascular endothelial growth factor (VEGF/VPF).sup.8,9, basic fibroblast growth factor (bFGF).sup.8, and interleukin-8 (IL-8).sup.10 correlate with decreased survival and increased risk of relapse in studies of patients with malignant solid tumors. The importance of angiogenesis is further supported by the observation that antiangiogenic agents inhibit tumor growth in a variety of animal models. [0003] In the U.S. there are currently more than 30 angiogenesis inhibitors in various clinical trials for late-stage cancer. One of these angiogenesis inhibitors, O-(chloracetyl-carbamoyl) fumagillol (TNP-470), is a low molecular weight synthetic analogue of fumagillin.sup.11, a compound secreted by the fungus Aspergillus fumigatus fresenius. TNP-470 is a potent endothelial inhibitor in vitro.sup.12. Recently, TNP-470 has been tested as a potential new anticancer agent. In animal models, TNP-470 has the broadest anticancer spectrum of any known agent.sup.4,13. TNP-470 inhibited the growth of murine tumors up to 91%, human tumors up to 100% and metastatic tumors up to 100% in mice (reviewed in ref..sup.13). In most studies, mice were treated at the same optimal dose of 30 mg/kg subcutaneously every other day. In clinical trials TNP-470 has shown evidence of antitumor activity when used as a single agent, with a number of objective responses reported with relapsed and refractory malignancies.sup.14-16. It has also shown promise when used in combination with conventional chemotherapy.sup.17,18. However, many patients experience neurotoxicity (malaise, rare seizures, asthenia, anxiety and dysphoria).sup.16,17,19,20 at doses where antitumor activity has been seen. Because of dose-limiting neurotoxicity, TNP-470 has been tested using multiple dosing regimens, but these attempts to limit its toxicity have been unsuccessful. With few exceptions, weight loss or failure to gain weight was observed in animals receiving TNP-470.sup.21, and two reports noted a decrease in splenic weight.sup.22,23. Therefore, modifications of TNP-470 that can retain or increase its activity while reducing its toxicity are highly desirable. SUMMARY OF THE INVENTION [0004] The present invention relates to conjugates of water-soluble polymers and o-(chloracetyl-carbamoyl) fumagillol (TNP-470) and use of those conjugates as specific intracellular carriers of the TNP-470 into tumor vessels. The present invention further relates to use of those conjugates to lower the neurotoxicity of TNP-470. Preferably, the polymer has a molecular weight in the range of 100 Da to 800 kDa. More preferably, the polymer has a molecular weight no greater than 60 kDa. Most preferably, the polymer has a molecular weight in the range of 15 kDa to 40 kDa. [0005] Preferred polymers are HPMA copolymers. HPMA copolymers are biocompatible, non-immunogenic and non-toxic carriers that enable specific delivery into tumor endothelial cells overcoming limitations of drug-related toxicities (Duncan, et al., Hum Exp Toxicol, 17:93-104 (1998)). Moreover, their body distribution is well characterized and they are known to accumulate selectively in the tumor site due to the enhanced permeability and retention (EPR) effect (Maeda, et al., J Controlled Release, 65:271-284 (2000)). The conjugate can also include a targeting moiety to direct the conjugate to sites of endothelial cell proliferation or cancer cells or to specific receptors or markers associated with proliferating endothelial cells. [0006] The data presented herein demonstrate that TNP-470 conjugated to an HPMA copolymer: (i) avoid high peak drug levels in the circulation (ii) avoid penetration of TNP-470 to the cerebrospinal fluid and thus prevent the problem of neurotoxicity; (iii) prolong its half-life; (iv) facilitate the accumulation of TNP-470 in tissues involving neovascularization; (v) convert TNP-470 to a highly effective and widely useful angiogenesis inhibitor. We have also surprisingly discovered that conjugating TNP-470 to HPMA results in a water soluble composition. [0007] The present invention further relates to use of the conjugates in methods of treating angiogenic diseases and decreasing neurotoxicity of TNP-470. Angiogenic disease amenable to treatment with the present invention include but are not limited to diabetic retinopathy, macular degeneration, retrolental fibroplasia, trachoma, neovascular glaucoma, psoriases, angio-fibromas, immune and non-immune inflammation, capillary formation within atherosclerotic plaques, hemangiomas, excessive wound repair, solid tumors, metastases, Kaposi's sarcoma and the like. [0008] In accordance with the present invention, if polymer a having a molecular weight greater than 60 kDa is used, it is preferred that the polymer be a degradable polymer or inert. As used herein, a "degradable" polymer is one that breaks down in vivo to components having a molecular weight no greater than 60 kD. As defined herein, poly vinyl alcohol (PVA) is not a degradable polymer. [0009] Other aspects of the invention are disclosed infra. BRIEF DESCRIPTION OF THE DRAWINGS [0010] FIG. 1A illustrates the structure of HPMA copolymer-Gly-Phe-Leu-Gly-ethylenediamine-TNP-470. FIG. 1B shows in vitro release of TNP-470 from HPMA copolymer in the presence (-.box-solid.-) and absence (-.diamond-solid.-) of cathepsin B. [0011] FIG. 2A shows inhibition of BCE proliferation in vitro after 72 h. TNP-470 (-.tangle-solidup.-) and HPMA copolymer-Gly-Phe-Leu-Gly-en-TNP-470 (-.box-solid.-) had similar cytostatic effect on bFGF-induced proliferation of endothelial cells at doses lower than 1 .mu.g/ml and cytotoxic effect at doses higher than 1 .mu.g/ml. The dotted line represents the proliferation of bFGF-induced BCE cells ( - - - ) and the solid line represents the BCE cell proliferation in the absence of bFGF (-). FIG. 2B shows the chick aortic ring endothelial sprouting assay. The effect of TNP-470 (central panel) and HPMA copolymer-Gly-Phe-Leu-Gly-en-TNP-470 (right panel) at 100 pg/ml TNP-470 equivalent-dose are shown; and a control chick aortic ring (left panel) with abundant sprouting. [0012] FIG. 3A shows a schematic representation of the hepatectomy model. Untreated livers regenerate in 8 days, but they do not regenerate when treated with TNP-470 30 mg/kg/q.o.d s.c. FIG. 3B shows that free TNP-470 (stripes columns) inhibited liver regeneration when used at 30 mg/kg/q.o.d s.c. However, it did not inhibit liver regeneration at other dosing schedules. Conjugated TNP-470 (solid columns) inhibited liver regeneration at 30 mg/kg/q.o.d s.c. or 60 mg/kg/q.2.d s.c. or even at a single dose of 120 mg/kg/day of operation s.c. compared to the control regenerated group (dotted columns). FIG. 3C shows that free TNP-470 (-.circle-solid.-) causes delay in newborn mice development, but did not affect body weight when used in the conjugated form (-.tangle-solidup.-) similar to the control mice (-.box-solid.-). Arrows represent days of treatment. Data represent mean .+-.SE, n=9 mice per group. [0013] FIG. 4 shows antitumour activity measured using male SCID mice bearing A2058 human melanoma. FIG. 4A shows the effect of TNP-470 (-.circle-solid.-); HPMA copolymer-Gly-Phe-Leu-Gly-en-TNP-470 (-.tangle-solidup.-); and control mice (-.box-solid.-) on tumors. Data represent mean .+-.SE, n=8 mice per group. P values of <0.05 were marked as *, P<0.03 **, P<0.01 ***. FIG. 4B shows SCID mice and excised tumors correlating to panel (A) at day 8 of treatment. FIG. 4C shows H & E staining of tumors excised from animals in different groups on day 8 at high and low power. [0014] FIG. 5 shows antitumour activity measured using male C57 mice bearing LLC. FIG. 5A shows the effect of TNP-470 at 30 mg/kg/q.o.d. s.c. (-.circle-solid.-); HPMA copolymer-Gly-Phe-Leu-Gly-en-TNP-470 at 30 mg/kg/q.o.d. s.c. (-.tangle-solidup.-) on tumor growth; control mice (-.box-solid.-) are also shown. Data represent mean .+-.SE, n=10 mice per group. FIG. 5B shows representative C57 mice correlating to (A) on day 10 following treatment. FIG. 5C shows dose escalation of HPMA copolymer-Gly-Phe-Leu-Gly-en-TNP-470: at 30 (-.tangle-solidup.-), at 60 (-.circle-solid.-) and at 90 mg/kg/q.o.d. (-.diamond-solid.-) and control mice (-.box-solid.-) are shown. Data are mean .+-.SE, n=10 mice per group. FIG. 5D shows C57 mice correlating to (C). P values of <0.05 were marked as *, P<0.03 as **, P<0.01 as ***. [0015] FIG. 6 shows the results of a Miles assay. DETAILED DESCRIPTION OF THE INVENTION [0016] The present invention relates to polymer and copolymer conjugates of TNP-470. [0017] In accordance with the present invention, the TNP-470 is linked to a water soluble degradable or non-degradable polymer having a molecular weight in the range of 100 Da to 800 kDa. The components of the polymeric backbone may comprise acrylic polymers, alkene polymers, urethanepolymers, amide polymers, polyimines, polysaccharides and ester polymers. Preferably the polymer is synthetic rather than being a natural polymer or derivative thereof. Preferably the backbone components comprise derivatised polyethyleneglycol and poly(hydroxyalkyl(alk)acrylamide), most preferably amine derivatised polyethyleneglycol or hydroxypropyl(meth)acrylamide-methacrylic acid copolymer or derivative thereof. Dextran/dextrin and polyethylene glycol polymers, or derivatives thereof, may also be used. Preferably, the polymer has a molecular weight no greater than 60 kDa. A most preferred molecular weight range is 15 to 40 kDa. [0018] The TNP-470 and the polymer are conjugated by use of a linker, preferably a cleavable peptide linkage. Most preferably, the peptide linkage is capable of being cleaved by preselected cellular enzymes, for instance, those found in lysosomes of cancerous cells or proliferating endothelial cells. Alternatively, an acid hydrolysable linker could comprise an ester or amide linkage and be for instance, a cis-aconityl linkage. A pH sensitive linker may also be used. [0019] Cleavage of the linker of the conjugate results in release of active TNP-470. Thus the TNP-470 must be conjugated with the polymer in a way that does not alter the activity of the agent. The linker preferably comprises at least one cleavable peptide bond. Preferably the linker is an enzyme cleavable oligopeptide group preferably comprising sufficient amino acid units to allow specific binding and cleavage by a selected cellular enzyme. Preferably the linker is at least two amino acids long, more preferably at least three amino acids long. [0020] Preferred polymers for use with the present invention are HPMA copolymers with methacrylic acid with pendent oligopeptide groups joined via peptide bonds to the methacrylic acid with activated carboxylic terminal groups such as paranitrophenyl derivatives or ethylene diamine. Continue reading about Tnp-470 polymer conjugates and use thereof... 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