WO2014001956A2 - Combinational use of pegylated recombinant human arginase with chemotherapeutic/target therapeutic drug in cancer treatment - Google Patents

Combinational use of pegylated recombinant human arginase with chemotherapeutic/target therapeutic drug in cancer treatment Download PDF

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WO2014001956A2
WO2014001956A2 PCT/IB2013/054971 IB2013054971W WO2014001956A2 WO 2014001956 A2 WO2014001956 A2 WO 2014001956A2 IB 2013054971 W IB2013054971 W IB 2013054971W WO 2014001956 A2 WO2014001956 A2 WO 2014001956A2
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arginine
chemotherapeutic
cancer
therapeutic drug
inhibitor
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WO2014001956A3 (en
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Ning Man Cheng
Li Chen
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Ning Man Cheng
Li Chen
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to method of treating cancer with the combination of arginase and a chemotherapeutic/target therapeutic drug.
  • the method relates to treatment of cancer with the combination of arginine degrading enzyme and a mammalian target of rapamycin (mTOR) inhibitor, an alkylating agent, a mitotic inhibitor, or a small molecular inhibitor of tyrosine protein kinases and Raf kinases.
  • mTOR mammalian target of rapamycin
  • Pegylated recombinant human arginase has been reported to be used for the treatment of cancer; however, the combinational application of pegylated recombinant human arginase with other chemotherapeutic/target therapeutic/target therapeutic drug(s) has not been studied and so it would be difficult, even for one skilled in the art, to predict whether such combinational application would lead to a synergistic effect in the treatment of human malignancies.
  • the present invention in one aspect, provides a method of treating cancer in a human patient comprising administering to the patient a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug, wherein said arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating cancer.
  • the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases (such as receptors for vascular endothelial growth factor, VEGFR, and platelet- derived growth factor receptors, PDGFR) and Raf kinases, and the arginine reducing compound is arginine degrading enzyme.
  • mTOR mammalian target of rapamycin
  • alkylating agent mitotic inhibitor
  • mitotic inhibitor such as receptors for vascular endothelial growth factor, VEGFR, and platelet- derived growth factor receptors, PDGFR
  • tyrosine protein kinases such as receptors for vascular endothelial growth factor, VEGFR, and platelet- derived growth factor receptors, PDGFR
  • Raf kinases Raf kinases
  • the mTOR inhibitor is everolimus.
  • the alkylating agent is oxaliplatin.
  • the mitotic inhibitor is paclitaxel.
  • the small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
  • the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof.
  • the arginase is pegylated recombinant human arginase.
  • the cancer is liver cancer or prostate cancer.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug for treating cancer, wherein the arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating cancer.
  • the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases and Raf kinases, and the arginine reducing compound is arginine degrading enzyme.
  • mTOR mammalian target of rapamycin
  • alkylating agent mitotic inhibitor
  • mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases and Raf kinases
  • the arginine reducing compound is arginine degrading enzyme.
  • the mTOR inhibitor is everolimus.
  • the alkylating agent is oxaliplatin.
  • the mitotic inhibitor is paclitaxel.
  • the small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
  • the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof.
  • the arginase is pegylated recombinant human arginase.
  • the cancer is liver cancer or prostate cancer.
  • the present invention provides a method to increase the effectiveness of a chemotherapeutic/target therapeutic drug to treat cancer in a human patient, comprising:
  • the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor, and a small molecular inhibitor of tyrosine protein kinases and Raf kinases, and the arginine reducing compound is arginine degrading enzyme.
  • mTOR mammalian target of rapamycin
  • alkylating agent a small molecular inhibitor of tyrosine protein kinases and Raf kinases
  • the arginine reducing compound is arginine degrading enzyme.
  • the mTOR inhibitor is everolimus.
  • the alkylating agent is oxaliplatin.
  • the mitotic inhibitor is paclitaxel.
  • the small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
  • the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof.
  • the arginase is pegylated recombinant human arginase.
  • the cancer is liver cancer or prostate cancer.
  • the present invention provides a use of an arginine reducing compound in combination with a chemotherapeutic/target therapeutic drug for the manufacture of a medicament for the treatment of cancer, wherein the arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating cancer.
  • the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases and Raf kinases, and the arginine reducing compound is arginine degrading enzyme.
  • mTOR mammalian target of rapamycin
  • alkylating agent mitotic inhibitor
  • mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases and Raf kinases
  • the arginine reducing compound is arginine degrading enzyme.
  • the mTOR inhibitor is everolimus.
  • the alkylating agent is oxaliplatin.
  • the mitotic inhibitor is paclitaxel.
  • the small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
  • the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof.
  • the arginase is pegylated recombinant human arginase.
  • the cancer is liver cancer or prostate cancer.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug for treating liver cancer, wherein the arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating liver cancer.
  • the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent and a small molecular inhibitor of tyrosine protein kinases and Raf kinases, and the arginine reducing compound is arginine degrading enzyme.
  • mTOR mammalian target of rapamycin
  • alkylating agent a small molecular inhibitor of tyrosine protein kinases and Raf kinases
  • the arginine reducing compound is arginine degrading enzyme.
  • the mTOR inhibitor is everolimus.
  • the alkylating agent is oxaliplatin.
  • the small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
  • the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof.
  • the arginase is pegylated recombinant human arginase.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug for treating prostate cancer, wherein the arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating prostate cancer.
  • the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor and mitotic inhibitor, and the arginine reducing compound is arginine degrading enzyme.
  • the mTOR inhibitor is everolimus.
  • the mitotic inhibitor is paclitaxel.
  • the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof.
  • the arginase is pegylated recombinant human arginase.
  • Figure 1 shows the results of a study of the combinational use of pegylated recombinant human arginase (BCT-100) and oxaliplatin on the inhibition of HCC xenograft according to one embodiment of the present invention.
  • Figure 2 shows the result of a study of the combinational use of BCT-100 and oxaliplatin on increasing survival rate of the tested subjects according to one embodiment of the present invention.
  • Combined administration or “combined with administering” merely refers to a general period of time in which both arginase and a chemotherapeutic/target therapeutic drug (such as a mTOR inhibitor, an alkylating agent, a mitotic inhibitor or a small molecular inhibitor of tyrosine protein kinases and Raf kinases) are administered to the human body for the treatment of human malignancies. It does not restrict the method of treatment to a simultaneous administration of the two types of compounds.
  • a chemotherapeutic/target therapeutic drug such as a mTOR inhibitor, an alkylating agent, a mitotic inhibitor or a small molecular inhibitor of tyrosine protein kinases and Raf kinases
  • “combined with” merely refers to a general period of time in which the two steps of treatment for cancer are performed, which includes and is not limited to the possibility of simultaneous performance of the two steps.
  • the sequence of steps mentioned merely refers to a general period of time in which those steps of administration are performed, and this includes but is not limited to the possibility of simultaneous performance of the two steps.
  • the term “medicament” may refer to two different compounds applied at different times, as long as the two compounds belong to the same combinational treatment.
  • pegylated arginase refers to arginase of the present invention modified by pegylation to increase the stability of the enzyme and minimize immunoreactivity.
  • the present invention provides the use of arginase in treating cancer.
  • pegylated recombinant human arginase is used for the treatment of various types of cancer.
  • the pegylated recombinant human arginase is BCT-100 and the preparation of BCT-100 is disclosed in, e.g., US 10/518,223 and is incorporated in its entirety by reference.
  • the present invention provides the method of treating cancer in a human patient, comprising administrating to the patient a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug, wherein the combination of the arginine reducing compound and the chemotherapeutic/target therapeutic drug has an improved efficacy in the treatment of cancer over treatment with the arginine reducing compound alone and over treatment with the at least one chemotherapeutic/target therapeutic drug alone.
  • the present invention provides the pharmaceutical composition comprising a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug for treating cancer, wherein the composition has an improved efficacy in the treatment of cancer over treatment with the arginine reducing compound alone and over treatment with the at least one chemotherapeutic/target therapeutic drug alone.
  • the present invention provides the use of an arginine reducing compound in combination with a chemotherapeutic/target therapeutic drug for the manufacture of a medicament for the treatment of cancer, wherein the combination has an improved efficacy in the treatment of cancer over treatment with the arginine reducing compound alone and over treatment with the at least one chemotherapeutic/target therapeutic drug alone.
  • Example 1 In-vitro study on the inhibitory effect of BCT-100 combined with oxaliplatin in various solid tumors
  • Various tumor cell lines were thawed and cultured to 70-80% confluence in complete media supplemented with 10% FBS, 100 units/mL penicillin, lOOug/mL streptomycin, and 2mM L-glutamine. Cells were then washed and trypsinized gently to yield single cell suspension. After re-suspended in complete media, specific number of cells in complete medium was seeded in 96-well plates. On the following day, BCT-100, chemotherapeutic/target therapeutics (oxaliplatin) or their combinations were added at different concentrations and incubated for 72 h. Vehicle (DPBS containing lOmM PB, pH7.4) treated wells will be used as negative controls. The viability of tumor cells was measured by MTT assay (Sigma) using 550 nm as test wavelength and 630 nm as the reference wavelength, and calculated using the following equation:
  • T72 Mean Absorbance of Treatment at 72 h;
  • C72 Mean Absorbance of Vehicle control at 72 h.
  • B72 Mean Absorbance of blank well (with all reagents but no cells) at 72 h.
  • IC 50 of each agent was calculated by XLfit software according to the curve of cell viability.
  • the IC 50 values of BCT-100 and oxaliplatin are 146.2 and 166.0 ng/mL in the single-agent study, which are decreased to 56.3 and 112.6 ng/mL respectively in the combination study, indicating that there may be a synergistic effect in the combinational use of BCT-100 with oxaliplatin in treating liver cancer.
  • the dose of oxaliplatin in combinational use with BCT-100 is significantly reduced in achieving IC 50 value as compared to the case that oxaliplatin is used as a single agent.
  • Example 2 In vivo Study on Enhancement of therapeutic efficacy of BCT-100 in combination with oxaliplatin in hepatocellular carcinoma grafted mice
  • Human hepatoma PLC/PRF/5 cells were obtained from ATCC and were propagated for four passages from the frozen master stocks as recommended. Forty male nude mice were implanted with 3 mm solid tumors, and the tumors were allowed to grow until they reached an average diameter of 5 or 8 mm. The mice were then randomly divided into the four aforesaid groups (10 mice/group) and were treated. The implanted animals were observed once every 2 weeks and at the end of the study, the growth of the solid tumor in situ was evaluated by digital caliper measurements to determine tumor size and weight. The rate of tumor growth inhibition was calculated as IR ( ).
  • BCT-100 (named as BCT400U on Fig. 1) exerted significant inhibitory effects on the growth of hepatoma in nude mice grafted with PLC/PRF/5 tumors. The inhibitory effects were further enhanced when it was combined with oxaliplatin.
  • BCT-100 (named as BCT400U on Fig. 2) prolonged the survival of nude mice grafted with PLC/PRF/5 tumors and the effect was further enhanced when it was combined with oxaliplatin, indicating a significant therapeutic benefit in the combinational use of BCT-100 with oxaliplatin in treating liver cancer.
  • Example 3 Study on synergistic effect of BCT-100 with paclitaxel, everolimus and sorafenib in various cancer cell lines
  • BCT-100 tested in this series of studies was the pegylated recombinant human arginase. It is a clear liquid formulated in sterile phosphate buffer with purity of >95.0 .
  • Paclitaxel was purchased from National Institutes for Food and Drug control (NIFDC) with purity of >97.0 .
  • Everolimus and sorafenib tosylate were purchased from Selleck with purity of >97.0 and >99.0 respectively.
  • test material was provided in 3.0 mg/niL in saline and stored at 4°C.
  • the stock solution was diluted in culture medium to get serials of working solutions (the concentrations were specified for each cell line).
  • the stock solution was mixed by vortex, and the serials of working solutions were diluted by pipetting about 18-20 times.
  • the reference materials were dissolved in DMSO to get a stock solution of 10 mM and stored in -20°C.
  • the reference materials were diluted by culture medium to get serials of working solutions.
  • the stock solution was mixed by vortex, and the serials of working solutions were diluted by pipetting about 18-20 times.
  • Cell culture medium and fetal bovin serum were purchased from Hyclone (Logan, UT, USA). 0.25% Trypsin-EDTA was purchased from Invitrogen Life Technologies (San Diego, CA, USA). DMSO, Trypan Blue, Thiazolyl Blue Tetrazolium Bromide, MTT were purchased from Sigma Chemical Company (St. Louis, MO, USA).
  • Cell line was thawed and cultured to 70-80% confluence in complete media supplemented with 10% FBS, 100 units/mL penicillin, 100 ug/mL streptomycin, and L- glutamine.
  • CI is combination index
  • TA is BCT-100
  • CT is the chemotherapeutic/target therapeutic drug studied.
  • BCT-100 was studied at six different concentrations of 2000, 1000, 500, 250, 125, 62.5, 31.25, 15.625 and 7.8125 ng/m.
  • Pachtaxel was studied at six concentrations of 4000, 1600, 640, 256, 102.4, 40.96, 16.384, 6.5536 and 2.62144 ng/mL.
  • BCT-100 was studied at six different concentrations of 600, 400, 266.67, 177.78, 118.52, and 79.01 ng/mL.
  • Everohmus was studied at six concentrations of 1000, 250, 62.5 15.63, 3.91, and 0.98 ng/mL.
  • BCT-100 was studied at six different concentrations of 500, 333.33, 222.22, 148.15, 98.77, 65.84 ng/mL.
  • Everolimus was studied at six concentrations of 1000, 250, 62.5, 15.63, 3.91, 0.98 ng mL.
  • the CI values of the combinational application of BCT-100 with everolimus in the Huh-7 cells and PC-3 cells are 0.67 and 1.00 respectively. Therefore, there is a synergistic effect on the combinational use of BCT-100 with everolimus in the treatment of liver cancer and prostate cancer.
  • BCT-100 was studied at six different concentrations of 750, 500, 333.33, 222.22, 148.15, 98.77 ng/mL.
  • Sorafenib was studied at six concentrations of 10000, 5000, 2500, 1250, 625, 312.5 ng/mL.

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Abstract

The present invention provides a method for treatment of cancer comprising administration of an arginine reducing compound and a chemotherapeutic/target therapeutic drug to a subject in need thereof. In one embodiment, the cancer is liver cancer or prostate cancer. In another embodiment, the arginine reducing compound is pegylated recombinant human arginase and the chemotherapeutic/target therapeutic drug is oxaliplatin, everolimus, paclitaxel or sorafenib.

Description

Combinational Use of Pegylated Recombinant Human Arginase with
Chemotherapeutic/Target Therapeutic Drug in Cancer Treatment
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application having Serial No. 61/663,632 filed June 25, 2012, which is hereby incorporated by reference herein in its entirety.
FIELD OF INVENTION
[0002] This invention relates to method of treating cancer with the combination of arginase and a chemotherapeutic/target therapeutic drug. In particular, the method relates to treatment of cancer with the combination of arginine degrading enzyme and a mammalian target of rapamycin (mTOR) inhibitor, an alkylating agent, a mitotic inhibitor, or a small molecular inhibitor of tyrosine protein kinases and Raf kinases.
BACKGROUND OF INVENTION
[0003] Cancer remains one of the most life-threatening diseases in mankind and it is still very difficult to treat cancer. For certain forms of cancer, such as liver cancer, there is no known effective drug available.
[0004] Human tumors often display heterogeneity in various features including histology, gene expression, genotype, and metastatic and proliferative potential. In addition, the complex signaling networks that interact through crosstalk and feedback loops added the difficulties in the treatment of tumors, which may not be easily achieved by single agent with limited efficacy and narrow therapeutic indices. It is necessary to study the drug combination to overcome the tumor heterogeneity in drug sensitivity or reverse tumor drug resistance. [0005] Preparation of recombinant human arginase and the steps for pegylating the same was described in, e.g., US 10/518,223, which is included by reference in its entirety. Pegylated recombinant human arginase has been reported to be used for the treatment of cancer; however, the combinational application of pegylated recombinant human arginase with other chemotherapeutic/target therapeutic/target therapeutic drug(s) has not been studied and so it would be difficult, even for one skilled in the art, to predict whether such combinational application would lead to a synergistic effect in the treatment of human malignancies.
SUMMARY OF INVENTION
[0006] It is therefore an object of the present invention to provide improved methods and pharmaceutical compositions for the treatment of cancer.
[0007] Accordingly, the present invention, in one aspect, provides a method of treating cancer in a human patient comprising administering to the patient a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug, wherein said arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating cancer.
[0008] In an exemplary embodiment, the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases (such as receptors for vascular endothelial growth factor, VEGFR, and platelet- derived growth factor receptors, PDGFR) and Raf kinases, and the arginine reducing compound is arginine degrading enzyme.
[0009] In another exemplary embodiment, the mTOR inhibitor is everolimus. In yet another exemplary embodiment, the alkylating agent is oxaliplatin. In one exemplary embodiment, the mitotic inhibitor is paclitaxel. In yet another exemplary embodiment, the small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib. [0010] In another exemplary embodiment, the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof. In yet another exemplary embodiment of the present invention, the arginase is pegylated recombinant human arginase.
[0011] In a further exemplary embodiment, the cancer is liver cancer or prostate cancer.
[0012] In yet another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug for treating cancer, wherein the arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating cancer.
[0013] In an exemplary embodiment, the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases and Raf kinases, and the arginine reducing compound is arginine degrading enzyme.
[0014] In another exemplary embodiment, the mTOR inhibitor is everolimus. In yet another exemplary embodiment, the alkylating agent is oxaliplatin. In one exemplary embodiment, and the mitotic inhibitor is paclitaxel. In yet another exemplary embodiment, the small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
[0015] In yet another exemplary embodiment, the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof. In another exemplary embodiment, the arginase is pegylated recombinant human arginase.
[0016] In a further exemplary embodiment, the cancer is liver cancer or prostate cancer. [0017] In yet another aspect, the present invention provides a method to increase the effectiveness of a chemotherapeutic/target therapeutic drug to treat cancer in a human patient, comprising:
(a) administering the chemotherapeutic/target therapeutic drug to the human patient; and
(b) applying an arginine reducing compound, wherein the arginine reducing compound synergistically affects the activity of the chemotherapeutic/target therapeutic drug by increasing the effectiveness of the chemotherapeutic/target therapeutic drug on treating cancer.
[0018] In an exemplary embodiment, the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor, and a small molecular inhibitor of tyrosine protein kinases and Raf kinases, and the arginine reducing compound is arginine degrading enzyme.
[0019] In another exemplary embodiment, the mTOR inhibitor is everolimus. In another exemplary embodiment, the alkylating agent is oxaliplatin. In one exemplary embodiment, the mitotic inhibitor is paclitaxel. In yet another exemplary embodiment, the small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
[0020] In another exemplary embodiment, the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof. In another exemplary embodiment, the arginase is pegylated recombinant human arginase.
[0021] In a further exemplary embodiment, the cancer is liver cancer or prostate cancer.
[0022] In yet another aspect, the present invention provides a use of an arginine reducing compound in combination with a chemotherapeutic/target therapeutic drug for the manufacture of a medicament for the treatment of cancer, wherein the arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating cancer.
[0023] In an exemplary embodiment, the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases and Raf kinases, and the arginine reducing compound is arginine degrading enzyme.
[0024] In another exemplary embodiment, the mTOR inhibitor is everolimus. In yet another exemplary embodiment, the alkylating agent is oxaliplatin. In one exemplary embodiment, the mitotic inhibitor is paclitaxel. In yet another exemplary embodiment, the small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
[0025] In another exemplary embodiment, the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof. In yet another exemplary embodiment of the present invention, the arginase is pegylated recombinant human arginase.
[0026] In a further exemplary embodiment, the cancer is liver cancer or prostate cancer.
[0027] In yet another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug for treating liver cancer, wherein the arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating liver cancer.
[0028] In an exemplary embodiment, the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent and a small molecular inhibitor of tyrosine protein kinases and Raf kinases, and the arginine reducing compound is arginine degrading enzyme. [0029] In another exemplary embodiment, the mTOR inhibitor is everolimus. In yet another exemplary embodiment, the alkylating agent is oxaliplatin. In yet another exemplary embodiment, the small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
[0030] In another exemplary embodiment, the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof. In yet another exemplary embodiment of the present invention, the arginase is pegylated recombinant human arginase.
[0031] In yet another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug for treating prostate cancer, wherein the arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating prostate cancer.
[0032] In an exemplary embodiment, the chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor and mitotic inhibitor, and the arginine reducing compound is arginine degrading enzyme.
[0033] In another exemplary embodiment, the mTOR inhibitor is everolimus. In yet another exemplary embodiment, the mitotic inhibitor is paclitaxel.
[0034] In another exemplary of the present invention, the arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof.
[0035] In yet another exemplary embodiment of the present invention, the arginase is pegylated recombinant human arginase.
BRIEF DESCRIPTION OF FIGURES [0036] Figure 1 shows the results of a study of the combinational use of pegylated recombinant human arginase (BCT-100) and oxaliplatin on the inhibition of HCC xenograft according to one embodiment of the present invention.
[0037] Figure 2 shows the result of a study of the combinational use of BCT-100 and oxaliplatin on increasing survival rate of the tested subjects according to one embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0038] As used herein and in the claims, "comprising" means including the following elements but not excluding others.
[0039] "Combined administration" or "combined with administering" merely refers to a general period of time in which both arginase and a chemotherapeutic/target therapeutic drug (such as a mTOR inhibitor, an alkylating agent, a mitotic inhibitor or a small molecular inhibitor of tyrosine protein kinases and Raf kinases) are administered to the human body for the treatment of human malignancies. It does not restrict the method of treatment to a simultaneous administration of the two types of compounds. When in reference to treatments that do not require the administration of a compound (such as dialysis or embolization), "combined with" merely refers to a general period of time in which the two steps of treatment for cancer are performed, which includes and is not limited to the possibility of simultaneous performance of the two steps. Also, when in reference to treatments requiring the administration of multiple compounds (such as administration of arginine reducing compound and a chemotherapeutic/target therapeutic drug), in which a number of steps are involved therein, the sequence of steps mentioned merely refers to a general period of time in which those steps of administration are performed, and this includes but is not limited to the possibility of simultaneous performance of the two steps. [0040] Similarly, the term "medicament" may refer to two different compounds applied at different times, as long as the two compounds belong to the same combinational treatment.
[0041] As used herein, the term "pegylated arginase" refers to arginase of the present invention modified by pegylation to increase the stability of the enzyme and minimize immunoreactivity.
[0042] The present invention provides the use of arginase in treating cancer. In certain embodiments, pegylated recombinant human arginase is used for the treatment of various types of cancer. In a further embodiment, the pegylated recombinant human arginase is BCT-100 and the preparation of BCT-100 is disclosed in, e.g., US 10/518,223 and is incorporated in its entirety by reference.
[0043] The present invention provides the method of treating cancer in a human patient, comprising administrating to the patient a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug, wherein the combination of the arginine reducing compound and the chemotherapeutic/target therapeutic drug has an improved efficacy in the treatment of cancer over treatment with the arginine reducing compound alone and over treatment with the at least one chemotherapeutic/target therapeutic drug alone.
[0044] The present invention provides the pharmaceutical composition comprising a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug for treating cancer, wherein the composition has an improved efficacy in the treatment of cancer over treatment with the arginine reducing compound alone and over treatment with the at least one chemotherapeutic/target therapeutic drug alone.
[0045] Likewise, the present invention provides the use of an arginine reducing compound in combination with a chemotherapeutic/target therapeutic drug for the manufacture of a medicament for the treatment of cancer, wherein the combination has an improved efficacy in the treatment of cancer over treatment with the arginine reducing compound alone and over treatment with the at least one chemotherapeutic/target therapeutic drug alone.
[0046] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to describe and disclose specific information for which the reference was cited in connection with.
[0047] All references cited above and in the following description are incorporated by reference herein. The practice of the invention is exemplified in the following non- limiting examples. The scope of the invention is defined solely by the appended claims, which are in no way limited by the content or scope of the examples.
[0048] In the course of the present invention, inventors have selected, among an exhaustive list of chemotherapeutic/target therapeutic drugs, the chemotherapeutic/target therapeutic drugs disclosed throughout this specification and the non-limiting examples below, and discovered that there is a synergistic effect of using these chemotherapeutic/target therapeutic drugs with an arginine reducing compound in cancer treatment.
Example 1: In-vitro study on the inhibitory effect of BCT-100 combined with oxaliplatin in various solid tumors
[0049] Various tumor cell lines were thawed and cultured to 70-80% confluence in complete media supplemented with 10% FBS, 100 units/mL penicillin, lOOug/mL streptomycin, and 2mM L-glutamine. Cells were then washed and trypsinized gently to yield single cell suspension. After re-suspended in complete media, specific number of cells in complete medium was seeded in 96-well plates. On the following day, BCT-100, chemotherapeutic/target therapeutics (oxaliplatin) or their combinations were added at different concentrations and incubated for 72 h. Vehicle (DPBS containing lOmM PB, pH7.4) treated wells will be used as negative controls. The viability of tumor cells was measured by MTT assay (Sigma) using 550 nm as test wavelength and 630 nm as the reference wavelength, and calculated using the following equation:
[0050] % Viability = [(T72-B72) / (C72-B72)] x 100%
[0051] wherein,
[0052] T72: Mean Absorbance of Treatment at 72 h;
[0053] C72: Mean Absorbance of Vehicle control at 72 h; and
[0054] B72: Mean Absorbance of blank well (with all reagents but no cells) at 72 h.
[0055] IC50 of each agent was calculated by XLfit software according to the curve of cell viability.
[0056] As shown in Table 1, the combinational use of BCT-100 with oxaliplatin could significantly reduce the dose of oxaliplatin to achieve the similar inhibitory effect. The IC50 values of BCT-100 and oxaliplatin in the single-agent study are 249.1 and 3247.6 ng/mL respectively for tumor cell line Huh7. In the combination study, the corresponding IC50 values are decreased to 241.6 and 967.9 ng/mL respectively. For tumor cell line HepG2, the IC50 values of BCT-100 and oxaliplatin are 146.2 and 166.0 ng/mL in the single-agent study, which are decreased to 56.3 and 112.6 ng/mL respectively in the combination study, indicating that there may be a synergistic effect in the combinational use of BCT-100 with oxaliplatin in treating liver cancer. Especially the dose of oxaliplatin in combinational use with BCT-100 is significantly reduced in achieving IC50 value as compared to the case that oxaliplatin is used as a single agent. Table- 1 IC50 of BCT-100 and oxaliplatin in single agent or in combination in HepG2 and
Huh7 cell lines
Figure imgf000012_0001
Example 2: In vivo Study on Enhancement of therapeutic efficacy of BCT-100 in combination with oxaliplatin in hepatocellular carcinoma grafted mice
[0057] Study of in vivo efficacy of BCT-100 alone and in combination with oxaliplatin was carried out in the murine model of PLC/PRF/5. The tested mice were separated into a saline control group, a BCT-100 group, an oxaliplatin group, and a combination group. In the BCT-100 group, BCT-100 was administered at 400 U/20g, i.p. once a week, while in the oxaliplatin group, oxaliplatin was administered weekly at 10 mg/kg given i.p. In the combination group, BCT-100 and oxaliplatin were administered at 400 U/20g and 10 mg/kg respectively, i.p. once a week.
[0058] Human hepatoma PLC/PRF/5 cells were obtained from ATCC and were propagated for four passages from the frozen master stocks as recommended. Forty male nude mice were implanted with 3 mm solid tumors, and the tumors were allowed to grow until they reached an average diameter of 5 or 8 mm. The mice were then randomly divided into the four aforesaid groups (10 mice/group) and were treated. The implanted animals were observed once every 2 weeks and at the end of the study, the growth of the solid tumor in situ was evaluated by digital caliper measurements to determine tumor size and weight. The rate of tumor growth inhibition was calculated as IR ( ).
[0059] As shown in Figure 1, BCT-100 (named as BCT400U on Fig. 1) exerted significant inhibitory effects on the growth of hepatoma in nude mice grafted with PLC/PRF/5 tumors. The inhibitory effects were further enhanced when it was combined with oxaliplatin. [0060] As observed in Figure 2, BCT-100 (named as BCT400U on Fig. 2) prolonged the survival of nude mice grafted with PLC/PRF/5 tumors and the effect was further enhanced when it was combined with oxaliplatin, indicating a significant therapeutic benefit in the combinational use of BCT-100 with oxaliplatin in treating liver cancer.
Example 3: Study on synergistic effect of BCT-100 with paclitaxel, everolimus and sorafenib in various cancer cell lines
[0061] A series of studies was carried out on studying the synergistic effect of BCT-100 with chemotherapeutic/target therapeutic drugs (paclitaxel, everolimus and sorafenib) in a number of cell lines by MTT assay. The IC50 values were obtained and the combination index (CI) was also calculated to determine and evaluate the synergy effect between BCT- 100 and the tested chemotherapeutic/target therapeutic drugs.
3.1 Test materials
[0062] BCT-100 tested in this series of studies was the pegylated recombinant human arginase. It is a clear liquid formulated in sterile phosphate buffer with purity of >95.0 . Paclitaxel was purchased from National Institutes for Food and Drug control (NIFDC) with purity of >97.0 . Everolimus and sorafenib tosylate were purchased from Selleck with purity of >97.0 and >99.0 respectively.
3.1.1 Test material preparation
[0063] The test material was provided in 3.0 mg/niL in saline and stored at 4°C. The stock solution was diluted in culture medium to get serials of working solutions (the concentrations were specified for each cell line). The stock solution was mixed by vortex, and the serials of working solutions were diluted by pipetting about 18-20 times.
3.1.2 Reference materials preparation
[0064] The reference materials were dissolved in DMSO to get a stock solution of 10 mM and stored in -20°C. The reference materials were diluted by culture medium to get serials of working solutions. The stock solution was mixed by vortex, and the serials of working solutions were diluted by pipetting about 18-20 times.
3.2 Cell lines
[0065] Total 4 cell lines (Huh-7, PC-3, DU145 and HepG2) were used in this study.
3.3 Reagents and Consumable
[0066] Cell culture medium and fetal bovin serum were purchased from Hyclone (Logan, UT, USA). 0.25% Trypsin-EDTA was purchased from Invitrogen Life Technologies (San Diego, CA, USA). DMSO, Trypan Blue, Thiazolyl Blue Tetrazolium Bromide, MTT were purchased from Sigma Chemical Company (St. Louis, MO, USA).
3.4 Experimental Procedures 3.4.1 MTT assay
[0067] 1. Cell line was thawed and cultured to 70-80% confluence in complete media supplemented with 10% FBS, 100 units/mL penicillin, 100 ug/mL streptomycin, and L- glutamine.
[0068] 2. Cells were washed with PBS 7.4 and trypsinized gently to yield single cell suspension.
[0069] 3. Cells were re- suspended in complete media and counted.
[0070] 4. Specific number of cells (specified in the result section) in complete medium was seeded in wells of 96 well plates. (100 μΐ/well)
[0071] 5. On the following day, BCT-100, chemotherapeutic/target therapeutic drugs or their combinations was added in duplicate (in IC50 determination test) at different concentrations. Vehicle (DPBS) treated wells were used as negative controls. Wells with all reagents but no cells were used as blank in which the absorbance value thereof was subtracted from all the absorbance values of other wells before statistical calculation. [0072] 6. Micro-plates were incubated at 37°C for 72 h.
[0073] 7. The viability of tumor cells was measured by MTT assay (Sigma) using 550 nm as test wavelength and 630 nm as the reference wavelength. IC50 of each agent was calculated by XLfit software according to the curve of cell viability.
3.4.2 Statistics
[0074] When applicable, the combination index (CI) was calculated by PharmToosPro software, (McCary Group Inc), or determined using the equation:
[0075]
IC50 TA comb IC50 CT comb
IC50 TA Alone + IC50 CT Alone
[0076] wherein CI is combination index, TA is BCT-100 and CT is the chemotherapeutic/target therapeutic drug studied.
[0077] Evaluation criteria:
[0078] 1. If CI calculated is less than or equal to 1.0, there is synergistic effect between BCT-100 and the chemotherapeutic/target therapeutic drug studied.
[0079] 2. If CI calculated is greater than 1.0, there is antagonistic effect between BCT- 100 and the chemotherapeutic/target therapeutic drug studied.
3.5 Study on synergistic effect of BCT-100 with pachtaxel in prostate cancer cells (DU145 cell)
[0080] BCT-100 was studied at six different concentrations of 2000, 1000, 500, 250, 125, 62.5, 31.25, 15.625 and 7.8125 ng/m. Pachtaxel was studied at six concentrations of 4000, 1600, 640, 256, 102.4, 40.96, 16.384, 6.5536 and 2.62144 ng/mL.
[0081] The IC50 (ng/mL) value and CI value calculated were tabulated in Table 3 below: Table 3
Figure imgf000016_0001
[0082] From Table 3, it can be observed that the there is a synergistic effect on the combinational use of BCT-100 with paclitaxel in the treatment of prostate cancer.
3.6 Synergistic effect of BCT-100 with everohmus
3.6.1 Study on synergistic effect of BCT-100 with everohmus in liver cancer cells (Huh-7 Cell)
[0083] BCT-100 was studied at six different concentrations of 600, 400, 266.67, 177.78, 118.52, and 79.01 ng/mL. Everohmus was studied at six concentrations of 1000, 250, 62.5 15.63, 3.91, and 0.98 ng/mL.
[0084] The IC50 (ng/mL) value and CI value calculated was tabulated in Table 4 below:
Table 4
Figure imgf000016_0002
[0085] From Table 4, it can be observed that the there is a synergistic effect on the combinational use of BCT-100 with everohmus in the treatment of liver cancer. Especially, the dose of everohmus in combinational use with BCT-100 is significantly reduced in achieving IC50 value as compared to the case that everohmus is used as a single agent.
3.6.2 Study on synergistic effect of BCT-100 with everohmus in prostate cancer cells (PC-3 Cell) [0086] BCT-100 was studied at six different concentrations of 500, 333.33, 222.22, 148.15, 98.77, 65.84 ng/mL. Everolimus was studied at six concentrations of 1000, 250, 62.5, 15.63, 3.91, 0.98 ng mL.
[0087] The IC50 (ng/mL) value and CI value calculated was tabulated in Table 5 below:
Table 5
Figure imgf000017_0001
[0088] From Table 5, it can be observed that the there is a synergistic effect on the combinational use of BCT-100 with everolimus in the treatment of prostate cancer.
[0089] In summary, the CI values of the combinational application of BCT-100 with everolimus in the Huh-7 cells and PC-3 cells are 0.67 and 1.00 respectively. Therefore, there is a synergistic effect on the combinational use of BCT-100 with everolimus in the treatment of liver cancer and prostate cancer.
3.7 Study on synergistic effect of BCT-100 with sorafenib in liver cancer cells (Hep2 cell)
[0090] BCT-100 was studied at six different concentrations of 750, 500, 333.33, 222.22, 148.15, 98.77 ng/mL. Sorafenib was studied at six concentrations of 10000, 5000, 2500, 1250, 625, 312.5 ng/mL.
[0091] The IC50 (ng/mL) value and CI value calculated was tabulated in Table 6 below:
Table 6
Figure imgf000017_0002
[0092] From Table 6, it can be observed that the there is a synergistic effect on the combinational use of BCT-100 with sorafenib in the treatment of liver cancer. Especially, the dose of sorafenib in combinational use with BCT-100 is significantly reduced in achieving IC50 value as compared to the case that sorafenib is used as a single agent.
[0093] The exemplary embodiments of the present invention are thus fully described. Although the description referred to particular embodiments, it will be clear to one skilled in the art that the present invention may be practiced with variation of these specific details. Hence this invention should not be construed as limited to the embodiments set forth herein.
<DocRef#00101202-CX >

Claims

What is claimed is:
1. A method of treating cancer in a human patient comprising administering to the patient a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug, wherein said arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating cancer.
2. The method according to claim 1, wherein said chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases and Raf kinases; said arginine reducing compound is arginine degrading enzyme.
3. The method according to claim 2, wherein said mTOR inhibitor is everolimus.
4. The method according to claim 2, wherein said alkylating agent is oxaliplatin.
5. The method according to claim 2, wherein said mitotic inhibitor is paclitaxel.
6. The method according to claim 2, wherein said small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
7. The method according to any one of claims 2-6, wherein said arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications and combinations thereof.
8. The method according to claim 7, wherein said arginase is pegylated recombinant human arginase.
9. The method according to any one of claims 1, 3, 4 and 6, wherein said cancer is liver cancer.
10. The method according to any one of claims 1, 3 and 5, wherein said cancer is prostate cancer.
11. A pharmaceutical composition comprising a therapeutically effective amount of an arginine reducing compound and a chemotherapeutic/target therapeutic drug for treating cancer, wherein said arginine reducing compound exhibits a synergistic effect with said chemotherapeutic/target therapeutic drug and/or significantly reduce the dose of chemotherapeutic/target therapeutic drug used in treating cancer.
12. The pharmaceutical composition according to claim 11, wherein said chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases and Raf kinases, and said arginine reducing compound is arginine degrading enzyme.
13. The pharmaceutical composition according to claim 12, wherein said mTOR inhibitor is everolimus.
14. The pharmaceutical composition according to claim 12, wherein said alkylating agent is oxaliplatin.
15. The pharmaceutical composition according to claim 12, wherein said mitotic inhibitor is paclitaxel.
16. The pharmaceutical composition according to claim 12, wherein said small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
17. The pharmaceutical composition according to any one of claims 12-16, wherein said arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications thereof and combinations thereof.
18. The pharmaceutical composition according to claim 17, wherein said arginase is pegylated recombinant human arginase.
19. The pharmaceutical composition according to any one of claims 11, 13, 14 and 16, wherein said cancer is liver cancer.
20. The pharmaceutical composition according to any one of claims 11, 13 and 15, wherein said cancer is prostate cancer.
21. A method to increase the effectiveness of a chemotherapeutic/target therapeutic drug to treat cancer in a human patient, comprising:
(a) administering said chemotherapeutic/target therapeutic drug to said human patient; and
(b) applying an arginine reducing compound, wherein said arginine reducing compound synergistically affects the activity of said chemotherapeutic/target therapeutic drug by increasing the effectiveness of said chemotherapeutic/target therapeutic drug on treating cancer.
22. The method according to claim 21, wherein said chemotherapeutic/target therapeutic drug is selected from a group consisting of mammalian target of rapamycin (mTOR) inhibitor, alkylating agent, mitotic inhibitor and a small molecular inhibitor of tyrosine protein kinases and Raf kinases; said arginine reducing compound is arginine degrading enzyme.
23. The method according to claim 21, wherein said mTOR inhibitor is everolimus.
24. The method according to claim 21, wherein said alkylating agent is oxaliplatin.
25. The method according to claim 21, wherein said mitotic inhibitor is paclitaxel.
26. The method according to claim 21, wherein said small molecular inhibitor of tyrosine protein kinases and Raf kinases is sorafenib.
27. The method according to any one of claims 22-26, wherein said arginine degrading enzyme is selected from a group consisting of arginase, arginine deiminase, arginine decarboxylase, modifications and combinations thereof.
28. The method according to claim 27, wherein said arginase is pegylated recombinant human arginase.
29. The method according to any one of claims 21, 23, 24 and 26, wherein said cancer is liver cancer.
30. The method according to any one of claims 21, 23 and 25, wherein said cancer is prostate cancer.
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US9789169B2 (en) 2014-04-29 2017-10-17 Bio-Cancer Treatment International Limited Methods and compositions for modulating the immune system with arginase I
US9867875B2 (en) 2014-04-29 2018-01-16 Bio-Cancer Treatment International Limited Methods and compositions for modulating the immune system with Arginase I
US10532086B2 (en) 2014-04-29 2020-01-14 Bio-Cancer Treatment International Limited Methods and compositions for modulating the immune system with arginase I
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