WO2012061015A2 - Supplémentation en l-citrulline au cours d'une thérapie de déplétion d'arginine par l'arginase - Google Patents
Supplémentation en l-citrulline au cours d'une thérapie de déplétion d'arginine par l'arginase Download PDFInfo
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- WO2012061015A2 WO2012061015A2 PCT/US2011/056831 US2011056831W WO2012061015A2 WO 2012061015 A2 WO2012061015 A2 WO 2012061015A2 US 2011056831 W US2011056831 W US 2011056831W WO 2012061015 A2 WO2012061015 A2 WO 2012061015A2
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- WIPO (PCT)
- Prior art keywords
- citrulline
- arginase
- polypeptide
- composition
- arginine
- Prior art date
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- 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
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- A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention generally concerns the fields of biology, cell biology, molecular biology, chemoprotection, and oncology.
- the invention also generally concerns the field of combination anticancer therapy.
- Arginine is an essential amino acid for humans. Cells that are auxotropic for arginine require arginine uptake from their surroundings. Arginine auxotropes tend to be auxotropic because they lack the ability to produce their own arginine via the enzyme arginino succinate synthase (ASS) that participates in the pathway to convert citrulline into L-arginine.
- ASS arginino succinate synthase
- Arginase given systemically, can reduce physiologic levels of L-arginine and starve the tumor of an essential amino acid leading to tumor death. However, the enzyme generates ornithine from arginine. Normal cells lack ornithine transcarbamylase to recover arginine.
- OTC ornithine transcarbamylase
- ASS arginine succinate lyase
- the present invention in part pertains to methods of reducing the toxicity of an anticancer therapy in a subject that involves administering to a subject with cancer a pharmaceutically effective amount of a composition that comprises citrulline. More particularly, the present inventors have identified methods of reducing the toxicity of an arginine depletion agent in a subject that involves administering to a subject in need of an arginine depletion agent a pharmaceutically effective amount of a composition that includes citrulline.
- a “subject” or “patient” is a vertebrate, e.g., a mammal, including especially a human. Mammals include, but are not limited to, humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, rats, mice, etc.
- the subject in need of an arginine depletion agent may be, for example, a subject that has cancer.
- cancer refers to the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
- cancers include squamous cell cancer, small-cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer, melanoma, and various types of head and neck cancer.
- the cancer is cancer of the breast, brain, prostate, kidney, pancreas, lung, thyroid, colon, cervix, ovary, testes, rectum, gall bladder, anus, spleen, liver, skin, bone, pituitary, endometrium, stomach, blood, or lymph gland.
- the cancer is malignant melanoma, hepatocellular carcinoma, or mesothelioma.
- the subject may have a cancer that requires extracellular L-arginine to synthesize proteins.
- the cancer cells are deficient in arginino succinate synthase (ASS).
- the arginine depletion agent may be any arginine depletion agent known to those of ordinary skill in the art.
- Non-limiting examples of arginine depletion agents include arginase polypeptides, arginine deiminase polypeptides, arginine decarboxylase polypeptides, and arginine kinase polypeptides.
- the anticancer therapy is arginase, which is given systemically to reduce physiologic levels of arginine to starve the tumor of an essential amino acid, leading to cell death.
- arginase therapy with citrulline that will avoid normal tissue toxicities and yet preserve the anti-tumor effects of arginase therapy (i.e., citrulline has a protective effect on normal cells during cancer therapy with arginase).
- citrulline is administered to a mammal to reduce the side effects of arginase toxicity in a mammal, including, for example, toxic effects to normal cells in the mammal.
- there are methods and compositions related to combination therapy of arginase and citrulline supplementation for the treatment of cancer including, for example, ASS-negative tumors.
- the invention is useful for cancer therapy and/or prevention of side effects from cancer therapy.
- the present invention concerns enhancement of the use of arginase as a therapy by providing a means to receive arginase therapy for a longer period of time with reduced toxicities.
- Arginase molecules having one or more amino acid variations may also be employed.
- Some embodiments of the present invention provide that one can administer arginine depletion drugs with citrulline supplementation to patients with ASS-negative tumors. This would allow normal cells that contain ASS to maintain their nutritional arginine needs while starving tumor cells that require systemic sources of arginine.
- combination therapy of arginase with citrulline will avoid normal tissue toxicities and yet preserve anti-tumor effects for malignancies lacking ASS.
- arginase plus citrulline preserves anti-cancer efficacy for arginine auxotrophy secondary to ASS deficiency.
- the present invention allows arginase to be used in cancer therapy by providing the ability to stay on arginase therapy for a longer period of time with reduced toxicity to the normal cells, tissues, or unaffected organs of the individual.
- the arginine depletion agent may be a recombinant human arginase I polypeptide.
- the recombinant human arginase I polypeptide may be a polypeptide that includes at least 50 contiguous amino acids of a human arginase I protein (SEQ ID NO: l).
- the arginine depletion agent is a recombinant human arginase II polypeptide.
- the recombinant human arginase II polypeptide may be a polypeptide that includes at least 50 contigous amino acids of a human arginase II protein (SEQ ID NO:2).
- the arginine depletion agent is an arginase polypeptide that includes a non-native metal cofactor that is a cobalt atom instead of a manganese atom to more effectively kill tumor cells that are ASS negative in the presence of citrulline.
- ASS levels can predict arginase activity.
- the cobalt-containing arginase polypeptide may be any such polypeptide as described in WO2010/051533, herein specifically incorporated by reference in its entirety.
- the arginine depletion agent is a polypeptide comprising a domain comprising at least 50 contiguous amino acids of human arginine decarboxylase (SEQ ID NO:3).
- the arginine depletion agent is pegylated.
- the citruUine is further defined as L-citrulline.
- an analog of citruUine may be employed in the present invention rather than citruUine or stereoisomer thereof. Any citruUine analog known to those of ordinary skill in the art is contemplated as a citruUine analog.
- the citruUine analog is a citruUine molecule in which a hydrogen atom is substituted with a halogen atom (e.g., fluorine, chlorine, bromine, iodine).
- the citruUine analog is a substituted citruUine molecule.
- the method may further include administering one or more anticancer agents prior to, concurrently with, or following administration of the citruUine.
- the additional anticancer agent may be any of the arginine-depletion therapies set forth above, or any other agent that can be applied in the treatment of cancer.
- the subject is administered an additional therapy for cancer other than an anticancer agent, such as surgery, radiation, immunotherapy, and/or hormone therapy.
- composition including citruUine may be administered using any method known to those of ordinary skill in the art.
- the composition comprising citruUine may be administered once or administration may be repeated one or more times. In some embodiments, the dose is repeated after about 12 hours.
- the composition that includes citruUine is administered at a dose of about 0.01 g/kg to about 30.0 g/kg. In other embodiments, the composition is administered to a subject at a dose of about 0.1 g/kg to about 20.0 g/kg. In even further embodiments, the citruUine is administered to a subject at a dose of about 0.5 g/kg to about 10.0 g/kg. In still further embodiments, the citruUine is administered to a subject at a dose of about 1.0 g/kg to about 8.0 g/kg.
- composition that includes citruUine can be administered by any route or using any method known to those of ordinary skill in the art.
- routes of administration include intravenous administration, oral administration, intrathecal administration, topical administration, aerosol administration, or administration directly into the biliary tract.
- the composition is administered intravenously.
- the citruUine is administered orally.
- oral administration include administration via a tablet, powder, lozenge, capsule, troche, a hard candy, a chewable composition, or a paste.
- the citrulline is formulated as a nutraceutical.
- the present invention also includes pharmaceutical compositions that include citrulline and one or more anticancer agents.
- the anticancer agent is an arginine depletion agent.
- arginine depletion agents and other anticancer agents are set forth elsewhere in this specification.
- the citrulline is further defined as L-citrulline.
- kits that include a pharmaceutically effective amount of citrulline in one or more sealed vials and a pharmaceutically effective amount of an anticancer agent in one or more sealed vials.
- anticancer agents include arginine depletion agents such as those set forth elsewhere in this specification.
- the arginine depletion agent is a recombinant human arginase polypeptide.
- the recombinant human arginase polypeptide is a recombinant human arginase I polypeptide.
- the citrulline and the one or more arginine depletion agents are included in separate vials.
- the citrulline and the one or more arginine depletion agents are included in the same vial.
- the kit may optionally include a package insert providing information on the content of the kit and instructions for administration of the citrulline and anticancer agent to a subject, or electronic storage media containing similar information.
- the present invention also includes methods of reducing the toxicity of arginase therapy in a normal cell in contact with a tumor cell that involve administering to a normal cell in contact with a tumor cell a composition comprising citrulline.
- the normal cell is deficient in OTC.
- the tumor cell is deficient in ASS.
- the citrulline is further defined as L-citrulline.
- there is a method of reducing the toxicity of arginase therapy in a normal cell in contact with a tumor cell comprising administering to a normal cell in contact with a tumor cell a composition comprising citrulline.
- the normal cells are deficient in OTC.
- the tumor cell may be deficient in ASS.
- compositions that includes citrulline may be any of the pharmaceutical compositions set forth in this specification.
- the foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the detailed description of the invention that follows may be better understood. Additional features and advantages of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention.
- FIG. 1 provides a summary table of cell lines treated with HuArg(Co)PEG500 in vitro.
- the IC50s are all essentially the same and suggest that HuArg(Co)PEG500 is toxic to all cells.
- FIG. 2 is a summary table of cell lines treated with HuArg(Co)PEG500 + 400uM citrulline. In the presence of citrulline, HuArg(Co)PEG500 is no longer toxic to all cell types.
- FIG. 3A, 3B FIG. 3A is a Western blot analysis of representative tumor cell lines tested in FIGS. 1-2, for example.
- FIG. 3B shows a ratio of arginino succinate synthase (ASS) to beta- actin for particular exemplary tumor cell lines.
- ASS arginino succinate synthase
- FIG. 4 shows that tumor ASS level predicts recombinant human arginase (CO)-PEG5000 + citrulline response.
- FIG. 5 shows co-arginaseI-PEG5000 cell cytotoxicity.
- FIG. 6 Kaplan-Meier plot of mice survival at different dose levels of Human recombinant arginase I cobalt coupled to polyethylene glycol (HuArg I [Co]-PEG5000) therapy. Animals dosed ip twice weekly for four weeks.
- FIG. 7 Percent mean weight loss from baseline for HuArg I [Co]-PEG5000 treated mice at different times of post-initiation therapy. Error bars represent standard error of the mean. Arrows indicate days of arginase injections. *: p ⁇ 0.001; #: p ⁇ 0.005; +: p ⁇ 0.05 compared to control.
- FIG. 8 Kaplan-Meier plot of mice survival of HuArg I [Co]-PEG5000 lOmg/kg treated mice with L-citrulline supplementation. Mice were treated twice weekly for two weeks.
- FIG. 9 Percent mean weight loss from baseline for HuArg I [Co]-PEG5000 lOmg/kg treated mice at different times of post-initiation therapy with or without L-citrulline supplementation. Error bars represent standard error of the mean. Arrows indicate days of arginase injections. *: p ⁇ 0.01; #: p ⁇ 0.001.
- FIG. 10 Urea cycle pathway and arginine deiminase.
- ASS arginino succinate synthetase
- OTC ornithine transcarbamylase
- ADI arginine deiminase
- ASL arginino succinate lyase
- ARGase arginase. Tumors often lack ASS. Normal tissues frequently lack OTC.
- ADI is from microbial source.
- ARGase are intracellular enzymes of liver and other organs.
- the present invention concerns the reduction of toxic side effects on normal cells or tissue of a cancer therapy by utilizing a particular agent.
- the cancer therapy includes arginase or any compound that reduces arginine levels in a cell
- the agent that reduces the toxic effects of arginase is citrulline or citrulline analogs, in particular embodiments.
- Arginase or any arginine depletion agent may be employed in any suitable form and/or amount that is therapeutically effective.
- therapeutically effective amount of arginase or arginine depletion agent concerns an amount that inhibits proliferation of cancer cells.
- Arginase I and Arginase II are two isozymes of arginase, Arginase I and Arginase II, and either may be employed in the invention.
- An arginine depletion agent is any compound or compounds that are known or demonstrated to catabolize arginine or that detectably reduce the levels of arginine in a cell, such as a cancer cell, for example.
- Examples of arginine depletion agents other than arginase are encompassed in the invention.
- the arginine depletion agent lacks immogenicity.
- an arginine depletion agent that has immunogenicity may be modified to reduce immune reaction.
- the arginine depletion agent has reduced immunogenicity by being modified with polyethylene glycol, for example. Amino acid modification of immunogenic epitopes may also be employed, in certain cases.
- Arginase is a manganese metalloenzyme, and in specific embodiments the arginine depletion agent is also a metalloenzyme.
- the ion of the metalloenzyme may be replaced with any ion, although in specific embodiments the new ion increases catalytic activity at physiological pH, depresses the pKa of the active site hydroxide, and/or increases the affinity for substrate and product ligands.
- the composition is employed such that it retains its natural Mn 2+ co-factor, in some cases the enzyme has a different, non- natural co-factor, such as Co 2+ , for example.
- Cys303 instead of being S-nitrosylated, has a C303P substitution.
- the active site is altered.
- arginase variants having mutagenized first and/or second shell metal ligands; in particular embodiments, S230G and S230C second-shell substitutions may be utilized.
- Variants of arginase may be employed in the compositions of the invention (an example of human arginase is at GenBank® Accession No. CAA31188; GL 1197498, which is incorporated by reference herein). The arginase may be modified as described in U.S. Patent Appl. Publ. No. 2010/0111925.
- arginase in the invention may have at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% sequence identity to wild-type arginase.
- the arginase or arginine depletion agent is provided in a pharmaceutical formulation.
- the concentration of arginase in the formulation is 0.1 ⁇ , 0.2 ⁇ , 0.3 ⁇ , 0.4 ⁇ , 0.5 ⁇ , 0.6 ⁇ , 0.7 ⁇ , 0.8 ⁇ , 0.9 ⁇ , 1 ⁇ , 1.1 ⁇ , 1.2 ⁇ , 1.3 ⁇ , 1.4 ⁇ , 1.5 ⁇ , 1.6 ⁇ , 1.7 ⁇ , 1.8 ⁇ , 1.9 ⁇ , 2 ⁇ , 3 ⁇ , 4 ⁇ , 5 ⁇ , 6 ⁇ , 7 ⁇ , 8 ⁇ , 9 ⁇ , or 10 ⁇ .
- the arginase or arginine depletion agent is in the formulation at a concentration of at least 0.1 ⁇ , 0.2 ⁇ , 0.3 ⁇ , 0.4 ⁇ , 0.5 ⁇ , 0.6 ⁇ , 0.7 ⁇ , 0.8 ⁇ , 0.9 ⁇ , 1 ⁇ , 1.1 ⁇ , 1.2 ⁇ , 1.3 ⁇ , 1.4 ⁇ , 1.5 ⁇ , 1.6 ⁇ , 1.7 ⁇ , 1.8 ⁇ , 1.9 ⁇ , 2 ⁇ , 3 ⁇ , 4 ⁇ , 5 ⁇ ,
- the arginase or arginine depletion agent may be provided as a concentration within a particular but exemplary range, such as from 0.1 ⁇ -10 ⁇ , 0.1 ⁇ -9 ⁇ , 0.1 ⁇ -8 ⁇ , 0.1 ⁇ -7 ⁇ , 0.1 ⁇ -6 ⁇ , 0.1 ⁇ -5 ⁇ , 0.1 ⁇ -4 ⁇ , 0.1 ⁇ -3 ⁇ , 0.1 ⁇ -2 ⁇ , 0.1 ⁇ -1 ⁇ , 0.1 ⁇ -0.5 ⁇ , 0.2 ⁇ -10 ⁇ , 0.2 ⁇ -9 ⁇ , 0.2 ⁇ -8 ⁇ , 0.2 ⁇ -7 ⁇ , 0.2 ⁇ -6 ⁇ , 0.2 ⁇ -5 ⁇ , 0.2 ⁇ -4 ⁇ , 0.2 ⁇ -3 ⁇ , 0.2 ⁇ -2 ⁇ , 0.2 ⁇ -1 ⁇ , 0.2 ⁇ -0.5 ⁇ , 0.2 ⁇ -10 ⁇ , 0.2 ⁇ -9 ⁇ , 0.2 ⁇ -8 ⁇ , 0.2 ⁇ -7 ⁇ , 0.2 ⁇ -6 ⁇ , 0.2 ⁇ -5
- arginase and or an arginine depletion agent are used in the invention.
- the arginase or arginine depletion agent is isolated, purified, or recombinant.
- the composition may be isolated from natural sources, for example.
- the composition may be generated in vivo, such as in a prokaryote, and purified by a modification of the composition, such as a His tag, by size exclusion and/or by ion exchange chromatography.
- the arginase or arginine depletion agent is recombinant, such as generated with standard molecular biological methods known in the art, including gene expression methods.
- arginase may be performed by any suitable method so long as it catabolizes arginine, but in some embodiments the arginase may be modified from its natural form.
- arginase may be generated by the methods of U.S. Pat. Appl. Publ. Nos. 2005/0244398, 2009/0238813, or 2010/0111925 (each of which is incorporated by reference herein in its entirety).
- recombinant human arginase is produced as a His-tagged enzyme in a bacteria, such as B. subtilis, and purified by the His tag.
- Arginase may be conjugated with PEG, for example, mPEG-SPA of MW 5,000 may be covalently attached to arginase by the method of Tsui et al. (2009) or Ensor et al. (2002).
- the arginase composition comprises arginase that is linked to polyethylene glycol (PEG), for example linked to PEG5000.
- PEG polyethylene glycol
- one to forty PEG molecules are linked to arginase.
- Citrulline analogs may be employed in the invention as an alternative or in addition to citrulline.
- Exemplary citrulline analogs include but are not limited to 4-amino-l- carbamoylpiperidine-4-carboxylic acid (CPA), Homocitrulline, N 5 -acetyl-l-ornithine, and substituted citrulline molecules.
- CPA 4-amino-l- carbamoylpiperidine-4-carboxylic acid
- Homocitrulline Homocitrulline
- N 5 -acetyl-l-ornithine and substituted citrulline molecules.
- Citrulline may be employed in any suitable form and/or amount that is therapeutically effective.
- therapeutically effective amount of citrulline concerns an amount that reduces toxic effects of cancer therapy on normal cells, including an amount that reduces the number of normal cells that are killed with the cancer therapy.
- the citrulline is provided in a pharmaceutical formulation.
- the citrulline is L-citrulline, although in some cases the citrulline is D-citrulline.
- Citrulline may be obtained commercially, for example, from the website of Puritan's Pride.
- the concentration of citrulline in the formulation is aboutlOO ⁇ , 125 ⁇ , 150 ⁇ , 175 ⁇ , 200 ⁇ , 225 ⁇ , 250 ⁇ , 275 ⁇ , 300 ⁇ , 325 ⁇ , 350 ⁇ , 360 ⁇ , 370 ⁇ , 375 ⁇ , 380 ⁇ , 390 ⁇ , 400 ⁇ , 410 ⁇ , 420 ⁇ , 430 ⁇ , 440 ⁇ , 450 ⁇ , 460 ⁇ , 475 ⁇ , 480 ⁇ , 490 ⁇ , 500 ⁇ , 525 ⁇ , 550 ⁇ , 575 ⁇ , 600 ⁇ , 650 ⁇ , 700 ⁇ , 800 ⁇ , or 900 ⁇ .
- the citrulline is in the formulation at a concentration of at least 100 ⁇ , 125 ⁇ , 150 ⁇ , 175 ⁇ , 200 ⁇ , 225 ⁇ , 250 ⁇ , 275 ⁇ , 300 ⁇ , 325 ⁇ , 350 ⁇ , 360 ⁇ , 370 ⁇ , 375 ⁇ , 380 ⁇ , 390 ⁇ , or at least 400 ⁇ .
- the citrulline may be provided as a concentration within a particular but exemplary range, such as from about 100 ⁇ - about 900 ⁇ , about 100 ⁇ - about 800 ⁇ , about 100 ⁇ - about 700 ⁇ , about 100 ⁇ - about 600 ⁇ , about 100 ⁇ - about 500 ⁇ , about 100 ⁇ - about 400 ⁇ , about 100 ⁇ -about 300 ⁇ , about 100 ⁇ - about 200 ⁇ , about 200 ⁇ - about 900 ⁇ , about 200 ⁇ - about 800 ⁇ , about 200 ⁇ - about 700 ⁇ , about 200 ⁇ - about 600 ⁇ , about 200 ⁇ - about 500 ⁇ , about 200 ⁇ - about 400 ⁇ , about 200 ⁇ - about 300 ⁇ , about 300 ⁇ - about 900 ⁇ , about 300 ⁇ - about 800 ⁇ , about 300 ⁇ - about 700 ⁇ , about 300 ⁇ - about 600 ⁇ , about 300 ⁇ - about 500 ⁇ , about 300 ⁇ - about 400 ⁇ , about 400 ⁇ - about 900 ⁇ , about 300 ⁇ - about 800
- Administration of the citrulline may be once, twice, three, or four or more times a day or week or month.
- the citrulline may be delivered by any suitable means, although in specific embodiments it is delivered as a pharmaceutical formulation orally, intravenously, intramuscularly, parenterally, and so forth.
- the citrulline composition may be prepared immediately prior to administration to the individual or may be prepared well in advance of its administration.
- citrulline is employed to reduce the toxicity of arginase in cancer therapy.
- the citrulline and arginase may be delivered to the individual in need thereof at the same administration or in separate administrations.
- the citrulline and arginase may be delivered in the same composition or in separate compositions.
- arginase is delivered prior to citrulline, and the citrulline may be delivered before or after any toxicities with arginase are detected.
- the citrulline is delivered before arginase and completely prevents or delays onset of any toxicities from arginase, for example.
- the citrulline and arginase compositions may be delivered via different routes whether at the same or different times.
- arginase may be delivered by intramuscular or intravenous routes
- citrulline may be delivered by oral administration, in particular embodiments.
- the citrulline and arginase compositions are delivered via the same delivery route but at the same or different times.
- the citrulline and/or arginase compositions may be delivered to the individual only once. However, in cases wherein either citrulline or arginase compositions are delivered more than once, the respective other composition may also be delivered more than once, although in some cases the citrulline or arginase composition is delivered more than once and the respective other composition is only delivered once. When the citrulline or arginase compositions are not delivered at the same time, the compositions may be delivered at different duration of times therebetween, so long as citrulline is able to reduce at least some of the toxicities of arginase. The duration between arginase and citrulline delivery may be seconds, minutes, days, weeks, or months.
- the duration between delivery of citrulline and arginase compositions may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 minutes, or it may be 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, 10, 10.25, 10.5, 10.75, 11, 11.25, 11.5, 11.75, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours, or any duration therebetween.
- the duration between delivery of citrulline and arginase compositions is 2.5, 3, 3.5,4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, or 14 days. In certain embodiments, the duration between delivery of citrulline and arginase compositions is 1, 2, 3, 4, 5, or 6 weeks or more, or 1, 2, 3, 4, 5, or 6 months or more.
- an "anti-cancer” agent is capable of negatively affecting cancer in a subject, for example, by killing cancer cells, inducing apoptosis in cancer cells, reducing the growth rate of cancer cells, reducing the incidence or number of metastases, reducing tumor size, inhibiting tumor growth, reducing the blood supply to a tumor or cancer cells, promoting an immune response against cancer cells or a tumor, preventing or inhibiting the progression of cancer, or increasing the lifespan of a subject with cancer.
- these other compositions would be provided in a combined amount effective to kill or inhibit proliferation of the cell.
- This process may involve contacting the cells with the expression construct and the agent(s) or multiple factor(s) at the same time. This may be achieved by contacting the cell with a single composition or pharmacological formulation that includes both agents, or by contacting the cell with two distinct compositions or formulations, at the same time, wherein one composition includes the expression construct and the other includes the second agent(s).
- Tumor cell resistance to chemotherapy and radiotherapy agents represents a major problem in clinical oncology.
- One goal of current cancer research is to find ways to improve the efficacy of chemo- and radiotherapy by combining it with gene therapy.
- herpes simplex-thymidine kinase (HS-tK) gene when delivered to brain tumors by a retroviral vector system, successfully induced susceptibility to the antiviral agent ganciclovir (Culver, et ah, 1992).
- citrulline and/or arginase therapy could be used similarly in conjunction with chemotherapeutic, radiotherapeutic, hormone therapy, gene therapy, or immunotherapeutic intervention.
- the citrulline and arginase therapy may precede or follow the other agent treatment by intervals ranging from minutes to days to weeks to months.
- the other agent and citrulline and/or arginase are applied separately to the cell, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the agent and citrulline and/or arginase would still be able to exert an advantageously combined effect on the cell.
- citrulline and arginase is "A” and the secondary agent, such as radio- or chemotherapy, is "B":
- Administration of the therapeutic citrulline and arginase of the present invention to a patient may follow general protocols for the administration of chemotherapeutics, taking into account toxicity, if any. It is expected that the treatment cycles would be repeated as necessary. It also is contemplated that various standard therapies, as well as surgical intervention, may be applied in combination with the described hyperproliferative cell therapy.
- Cancer therapies also include a variety of combination therapies with both chemical- and radiation-based treatments.
- Combination chemotherapies include, for example, cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP 16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol, gemcitabien, navelbine, farnesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil, vincristin, vinblastin and methotrexate, or any analog or derivative variant of the foregoing.
- CDDP cisplatin
- carboplatin carboplatin
- Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 wk), to single doses of 2000 to 6000 roentgens.
- Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.
- contacted and “exposed,” when applied to a cell are used herein to describe the process by which a therapeutic construct and a chemotherapeutic or radiotherapeutic agent are delivered to a target cell or are placed in direct juxtaposition with the target cell.
- both agents are delivered to a cell in a combined amount effective to kill the cell or prevent it from dividing.
- Immunotherapeutics generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells.
- the immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell.
- the antibody alone may serve as an effector of therapy or it may recruit other cells to actually effect cell killing.
- the antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve merely as a targeting agent.
- the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target.
- Various effector cells include cytotoxic T cells and NK cells.
- Immunotherapy could be used as part of a combined therapy, in conjunction with citrulline and/or arginase therapy.
- the general approach for combined therapy is discussed below.
- the tumor cell must bear some marker that is amenable to targeting, i.e., is not present on the majority of other cells.
- Common tumor markers include carcinoembryonic antigen, prostate specific antigen, urinary tumor associated antigen, fetal antigen, tyrosinase (p97), gp68, TAG-72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B and pi 55.
- the secondary treatment is a secondary gene therapy in which a second therapeutic polynucleotide is administered before, after, or at the same time a first therapeutic polynucleotide encoding all of part of an MDA-7 polypeptide.
- Delivery of a vector encoding either a full length or truncated MDA-7 in conjuction with a second vector encoding one of the following gene products will have a combined anti-hyperproliferative effect on target tissues.
- a single vector encoding both genes may be used.
- a variety of proteins are encompassed within the invention, some of which are described below.
- the proteins that induce cellular proliferation further fall into various categories dependent on function.
- the commonality of all of these proteins is their ability to regulate cellular proliferation.
- a form of PDGF the sis oncogene
- Oncogenes rarely arise from genes encoding growth factors, and at the present, sis is the only known naturally- occurring oncogenic growth factor.
- anti- sense mRNA directed to a particular inducer of cellular proliferation is used to prevent expression of the inducer of cellular proliferation.
- the proteins FMS, ErbA, ErbB and neu are growth factor receptors. Mutations to these receptors result in loss of regulatable function. For example, a point mutation affecting the transmembrane domain of the Neu receptor protein results in the neu oncogene.
- the erbA oncogene is derived from the intracellular receptor for thyroid hormone. The modified oncogenic ErbA receptor is believed to compete with the endogenous thyroid hormone receptor, causing uncontrolled growth.
- the largest class of oncogenes includes the signal transducing proteins (e.g., Src, Abl and Ras).
- Src is a cytoplasmic protein-tyrosine kinase, and its transformation from proto-oncogene to oncogene in some cases, results via mutations at tyrosine residue 527.
- transformation of GTPase protein ras from proto-oncogene to oncogene results from a valine to glycine mutation at amino acid 12 in the sequence, reducing ras GTPase activity.
- Jun, Fos and Myc are proteins that directly exert their effects on nuclear functions as transcription factors.
- the tumor suppressor oncogenes function to inhibit excessive cellular proliferation.
- the inactivation of these genes destroys their inhibitory activity, resulting in unregulated proliferation.
- the tumor suppressors p53, pl6 and C-CAM are described below.
- mutant p53 has been found in many cells transformed by chemical carcinogenesis, ultraviolet radiation, and several viruses.
- the p53 gene is a frequent target of mutational inactivation in a wide variety of human tumors and is already documented to be the most frequently mutated gene in common human cancers. It is mutated in over 50% of human NSCLC (Hollstein et al., 1991) and in a wide spectrum of other tumors.
- the p53 gene encodes a 393-amino acid phosphoprotein that can form complexes with host proteins such as large-T antigen and E1B.
- the protein is found in normal tissues and cells, but at concentrations which are minute by comparison with transformed cells or tumor tissue
- Wild-type p53 is recognized as an important growth regulator in many cell types. Missense mutations are common for the p53 gene and are essential for the transforming ability of the oncogene. A single genetic change prompted by point mutations can create carcinogenic p53. Unlike other oncogenes, however, p53 point mutations are known to occur in at least 30 distinct codons, often creating dominant alleles that produce shifts in cell phenotype without a reduction to homozygosity. Additionally, many of these dominant negative alleles appear to be tolerated in the organism and passed on in the germ line. Various mutant alleles appear to range from minimally dysfunctional to strongly penetrant, dominant negative alleles (Weinberg, 1991).
- CDK cyclin-dependent kinases
- CDK4 cyclin-dependent kinase 4
- the activity of CDK4 is controlled by an activating subunit, D- type cyclin, and by an inhibitory subunit, the pl6INK4 has been biochemically characterized as a protein that specifically binds to and inhibits CDK4, and thus may regulate Rb phosphorylation (Serrano et al, 1993; Serrano et al, 1995).
- pl6INK4 Since the pl6INK4 protein is a CDK4 inhibitor (Serrano, 1993), deletion of this gene may increase the activity of CDK4, resulting in hyperphosphorylation of the Rb protein. pl6 also is known to regulate the function of CDK6.
- pl6INK4 belongs to a newly described class of CDK- inhibitory proteins that also includes pl6B, pl9, p21WAFl, and p27KIPl.
- the pl6INK4 gene maps to 9p21, a chromosome region frequently deleted in many tumor types. Homozygous deletions and mutations of the pl6INK4 gene are frequent in human tumor cell lines. This evidence suggests that the pl6INK4 gene is a tumor suppressor gene.
- genes that may be employed according to the present invention include Rb, APC, DCC, NF-1, NF-2, WT-1, MEN-I, MEN-II, zacl, p73, VHL, MMAC1 / PTEN, DBCCR-1, FCC, rsk-3, p27, p27/pl6 fusions, p21/p27 fusions, anti-thrombotic genes (e.g., COX-1, TFPI), PGS, Dp, E2F, ras, myc, neu, raf, erb, fms, trk, ret, gsp, hst, abl, E1A, p300, genes involved in angiogenesis (e.g., VEGF, FGF, thrombospondin, BAI-1, GDAIF, or their receptors) and MCC.
- angiogenesis e.g., VEGF, FGF, thrombospondin,
- Apoptosis or programmed cell death, is an essential process for normal embryonic development, maintaining homeostasis in adult tissues, and suppressing carcinogenesis (Kerr et al, 1972).
- the Bcl-2 family of proteins and ICE-like proteases have been demonstrated to be important regulators and effectors of apoptosis in other systems.
- the Bel 2 protein discovered in association with follicular lymphoma, plays a prominent role in controlling apoptosis and enhancing cell survival in response to diverse apoptotic stimuli (Bakhshi et al, 1985; Cleary and Sklar, 1985; Cleary et al, 1986; Tsujimoto et al, 1985; Tsujimoto and Croce, 1986).
- the evolutionarily conserved Bel 2 protein now is recognized to be a member of a family of related proteins, which can be categorized as death agonists or death antagonists.
- Bel 2 acts to suppress cell death triggered by a variety of stimuli. Also, it now is apparent that there is a family of Bel 2 cell death regulatory proteins which share in common structural and sequence homologies. These different family members have been shown to either possess similar functions to Bel 2 (e.g., BclXL, BclW, BclS, Mcl-1, Al, Bfl-1) or counteract Bel 2 function and promote cell death (e.g., Bax, Bak, Bik, Bim, Bid, Bad, Harakiri). E. Surgery
- Curative surgery is a cancer treatment that may be used in conjunction with other therapies, such as the treatment of the present invention, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy and/or alternative therapies.
- Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed.
- Tumor resection refers to physical removal of at least part of a tumor.
- treatment by surgery includes laser surgery, cryosurgery, electro surgery, and miscopically controlled surgery (Mohs' surgery). It is further contemplated that the present invention may be used in conjunction with removal of superficial cancers, precancers, or incidental amounts of normal tissue.
- a cavity may be formed in the body.
- Treatment may be accomplished by perfusion, direct injection or local application of the area with an additional anti-cancer therapy.
- Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
- These treatments may be of varying dosages as well.
- agents may be used in combination with the present invention to improve the therapeutic efficacy of treatment.
- additional agents include immunomodulatory agents, agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adehesion, or agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers.
- Immunomodulatory agents include tumor necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; F42K and other cytokine analogs; or MIP-1, MIP-lbeta, MCP-1, RANTES, and other chemokines.
- cell surface receptors or their ligands such as Fas / Fas ligand, DR4 or DR5 / TRAIL would potentiate the apoptotic inducing abililties of the present invention by establishment of an autocrine or paracrine effect on hyperproliferative cells. Increases intercellular signaling by elevating the number of GAP junctions would increase the anti-hyperproliferative effects on the neighboring hyperproliferative cell population.
- cytostatic or differentiation agents can be used in combination with the present invention to improve the anti-hyerproliferative efficacy of the treatments. Inhibitors of cell adehesion are contemplated to improve the efficacy of the present invention.
- cell adhesion inhibitors are focal adhesion kinase (FAKs) inhibitors and Lovastatin. It is further contemplated that other agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such as the antibody c225, could be used in combination with the present invention to improve the treatment efficacy.
- FAKs focal adhesion kinase
- Lovastatin Lovastatin
- Hormonal therapy may also be used in conjunction with the present invention or in combination with any other cancer therapy previously described.
- the use of hormones may be employed in the treatment of certain cancers such as breast, prostate, ovarian, or cervical cancer to lower the level or block the effects of certain hormones such as testosterone or estrogen. This treatment is often used in combination with at least one other cancer therapy as a treatment option or to reduce the risk of metastases.
- compositions of the present invention comprise an effective amount of one or more compositions of the invention, including citrulline and/or arginase, dissolved or dispersed in a pharmaceutically acceptable carrier.
- pharmaceutically acceptable refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.
- the preparation of an pharmaceutical composition that contains at least one citrulline and/or arginase or additional active ingredient will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, incorporated herein by reference.
- preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference).
- preservatives e.g., antibacterial agents, antifungal agents
- isotonic agents e.g., absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like
- the pharmaceutical composition may comprise different types of carriers depending on whether it is to be administered in solid, liquid or aerosol form, and whether it need to be sterile for such routes of administration as injection.
- the present invention can be administered intravenously, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, topically, intramuscularly, subcutaneously, mucosally, orally, topically, locally, inhalation (e.g., aerosol inhalation), injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, via a lavage, in cremes, in lipid compositions (e.g., liposomes), or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, incorporated herein by reference).
- inhalation e.g., aerosol inhalation
- the citrulline and/or arginase may be formulated into a composition in a free base, neutral or salt form.
- Pharmaceutically acceptable salts include the acid addition salts, e.g., those formed with the free amino groups of a proteinaceous composition, or which are formed with inorganic acids such as for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric or mandelic acid. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as for example, sodium, potassium, ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine, trimethylamine, histidine or procaine.
- solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
- the formulations are easily administered in a variety of dosage forms such as formulated for parenteral administrations such as injectable solutions, or aerosols for delivery to the lungs, or formulated for alimentary administrations such as drug release capsules and the like.
- the composition of the present invention suitable for administration is provided in a pharmaceutically acceptable carrier with or without an inert diluent.
- the carrier should be assimilable and includes liquid, semi-solid, i.e., pastes, or solid carriers. Except insofar as any conventional media, agent, diluent or carrier is detrimental to the recipient or to the therapeutic effectiveness of a the composition contained therein, its use in administrable composition for use in practicing the methods of the present invention is appropriate.
- carriers or diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, binders, fillers and the like, or combinations thereof.
- composition may also comprise various antioxidants to retard oxidation of one or more component. Additionally, the prevention of the action of microorganisms can be brought about by preservatives such as various antibacterial and antifungal agents, including but not limited to parabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.
- parabens e.g., methylparabens, propylparabens
- chlorobutanol phenol
- sorbic acid thimerosal or combinations thereof.
- the composition is combined with the carrier in any convenient and practical manner, i.e., by solution, suspension, emulsification, admixture, encapsulation, absorption and the like. Such procedures are routine for those skilled in the art.
- the composition is combined or mixed thoroughly with a semi-solid or solid carrier.
- the mixing can be carried out in any convenient manner such as grinding.
- Stabilizing agents can be also added in the mixing process in order to protect the composition from loss of therapeutic activity, i.e., denaturation in the stomach.
- stabilizers for use in an the composition include buffers, amino acids such as glycine and lysine, carbohydrates such as dextrose, mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc.
- the present invention may concern the use of a pharmaceutical lipid vehicle compositions that include citrulline and/or arginase, one or more lipids, and an aqueous solvent.
- lipid will be defined to include any of a broad range of substances that is characteristically insoluble in water and extractable with an organic solvent. This broad class of compounds are well known to those of skill in the art, and as the term "lipid” is used herein, it is not limited to any particular structure. Examples include compounds which contain long-chain aliphatic hydrocarbons and their derivatives. A lipid may be naturally occurring or synthetic (i.e., designed or produced by man). However, a lipid is usually a biological substance.
- Biological lipids are well known in the art, and include for example, neutral fats, phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, glycosphingolipids, glycolipids, sulphatides, lipids with ether and ester-linked fatty acids and polymerizable lipids, and combinations thereof.
- neutral fats phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, glycosphingolipids, glycolipids, sulphatides, lipids with ether and ester-linked fatty acids and polymerizable lipids, and combinations thereof.
- lipids are also encompassed by the compositions and methods of the present invention.
- the citrulline and/or arginase may be dispersed in a solution containing a lipid, dissolved with a lipid, emulsified with a lipid, mixed with a lipid, combined with a lipid, covalently bonded to a lipid, contained as a suspension in a lipid, contained or complexed with a micelle or liposome, or otherwise associated with a lipid or lipid structure by any means known to those of ordinary skill in the art.
- the dispersion may or may not result in the formation of liposomes.
- the actual dosage amount of a composition of the present invention administered to an animal patient can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and/or an effective amount may vary according to the response of the subject. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
- compositions may comprise, for example, at least about 0.1% of an active compound.
- the an active compound may comprise between about 2% to about 75% of the weight of the unit, or between about 25% to about 60%, for example, and any range derivable therein.
- the amount of active compound(s) in each therapeutically useful composition may be prepared is such a way that a suitable dosage will be obtained in any given unit dose of the compound. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable.
- a dose may also comprise from about 1 microgram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein.
- a range of about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500 milligram/kg/body weight, etc. can be administered, based on the numbers described above.
- the citrulline and/or arginase are formulated to be administered via an alimentary route.
- Alimentary routes include all possible routes of administration in which the composition is in direct contact with the alimentary tract.
- the pharmaceutical compositions disclosed herein may be administered orally, buccally, rectally, or sublingually.
- these compositions may be formulated with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard- or soft- shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
- the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like (for example, see U.S. Pat. Nos. 5,641,515; 5,580,579 and 5,792, 451, each specifically incorporated herein by reference in its entirety).
- the tablets, troches, pills, capsules and the like may also contain the following: a binder, such as, for example, gum tragacanth, acacia, cornstarch, gelatin or combinations thereof; an excipient, such as, for example, dicalcium phosphate, mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate or combinations thereof; a disintegrating agent, such as, for example, corn starch, potato starch, alginic acid or combinations thereof; a lubricant, such as, for example, magnesium stearate; a sweetening agent, such as, for example, sucrose, lactose, saccharin or combinations thereof; a flavoring agent, such as, for example peppermint, oil of wintergreen, cherry flavoring, orange flavoring, etc.
- a binder such as, for example, gum tragacanth, acacia, cornstarch, gelatin or combinations thereof
- an excipient such as, for
- the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. When the dosage form is a capsule, it may contain, in addition to materials of the above type, carriers such as a liquid carrier. Gelatin capsules, tablets, or pills may be enterically coated. Enteric coatings prevent denaturation of the composition in the stomach or upper bowel where the pH is acidic. See, e.g., U.S. Pat. No. 5,629,001.
- the basic pH therein dissolves the coating and permits the composition to be released and absorbed by specialized cells, e.g., epithelial enterocytes and Peyer's patch M cells.
- a syrup of elixir may contain the active compound sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor.
- any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
- the active compounds may be incorporated into sustained-release preparation and formulations.
- compositions of the present invention may alternatively be incorporated with one or more excipients in the form of a mouthwash, dentifrice, buccal tablet, oral spray, or sublingual orally- administered formulation.
- a mouthwash may be prepared incorporating the active ingredient in the required amount in an appropriate solvent, such as a sodium borate solution (Dobell's Solution).
- the active ingredient may be incorporated into an oral solution such as one containing sodium borate, glycerin and potassium bicarbonate, or dispersed in a dentifrice, or added in a therapeutically- effective amount to a composition that may include water, binders, abrasives, flavoring agents, foaming agents, and humectants.
- the compositions may be fashioned into a tablet or solution form that may be placed under the tongue or otherwise dissolved in the mouth.
- suppositories are solid dosage forms of various weights and shapes, usually medicated, for insertion into the rectum. After insertion, suppositories soften, melt or dissolve in the cavity fluids.
- traditional carriers may include, for example, polyalkylene glycols, triglycerides or combinations thereof.
- suppositories may be formed from mixtures containing, for example, the active ingredient in the range of about 0.5% to about 10%, and preferably about 1% to about 2%.
- the citrulline and/or arginase may be administered via a parenteral route.
- parenteral includes routes that bypass the alimentary tract.
- the pharmaceutical compositions disclosed herein may be administered for example, but not limited to intravenously, intradermally, intramuscularly, intraarterially, intrathecally, subcutaneous, or intraperitoneally U.S. Pat. Nos. 6,7537,514, 6,613,308, 5,466,468, 5,543,158; 5,641,515; and 5,399,363 (each specifically incorporated herein by reference in its entirety).
- Solutions of the active compounds as free base or pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (U.S. Patent 5,466,468, specifically incorporated herein by reference in its entirety). In all cases the form must be sterile and must be fluid to the extent that easy injectability exists.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (i.e., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils.
- polyol i.e., glycerol, propylene glycol, and liquid polyethylene glycol, and the like
- suitable mixtures thereof and/or vegetable oils.
- Proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars or sodium chloride.
- Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
- aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
- aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration.
- sterile aqueous media that can be employed will be known to those of skill in the art in light of the present disclosure.
- one dosage may be dissolved in isotonic NaCl solution and either added hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences” 15th Edition, pages 1035-1038 and 1570-1580).
- Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- a powdered composition is combined with a liquid carrier such as, e.g., water or a saline solution, with or without a stabilizing agent.
- the active compound citrulline and/or arginase may be formulated for administration via various miscellaneous routes, for example, topical (i.e., transdermal) administration, mucosal administration (intranasal, vaginal, etc.) and/or inhalation.
- topical i.e., transdermal
- mucosal administration intranasal, vaginal, etc.
- inhalation inhalation
- compositions for topical administration may include the active compound formulated for a medicated application such as an ointment, paste, cream or powder.
- Ointments include all oleaginous, adsorption, emulsion and water-solubly based compositions for topical application, while creams and lotions are those compositions that include an emulsion base only.
- Topically administered medications may contain a penetration enhancer to facilitate adsorption of the active ingredients through the skin. Suitable penetration enhancers include glycerin, alcohols, alkyl methyl sulfoxides, pyrrolidones and luarocapram.
- compositions for topical application include polyethylene glycol, lanolin, cold cream and petrolatum as well as any other suitable absorption, emulsion or water-soluble ointment base.
- Topical preparations may also include emulsifiers, gelling agents, and antimicrobial preservatives as necessary to preserve the active ingredient and provide for a homogenous mixture.
- Transdermal administration of the present invention may also comprise the use of a "patch".
- the patch may supply one or more active substances at a predetermined rate and in a continuous manner over a fixed period of time.
- the pharmaceutical compositions may be delivered by eye drops, intranasal sprays, inhalation, and/or other aerosol delivery vehicles.
- Methods for delivering compositions directly to the lungs via nasal aerosol sprays has been described e.g., in U.S. Pat. Nos. 5,756,353 and 5,804,212 (each specifically incorporated herein by reference in its entirety).
- the delivery of drugs using intranasal microparticle resins Takenaga et ah, 1998) and lysophosphatidyl-glycerol compounds (U.S. Pat. No. 5,725, 871, specifically incorporated herein by reference in its entirety) are also well-known in the pharmaceutical arts.
- transmucosal drug delivery in the form of a polytetrafluoroetheylene support matrix is described in U.S. Pat. No. 5,780,045 (specifically incorporated herein by reference in its entirety).
- aerosol refers to a colloidal system of finely divided solid of liquid particles dispersed in a liquefied or pressurized gas propellant.
- the typical aerosol of the present invention for inhalation will consist of a suspension of active ingredients in liquid propellant or a mixture of liquid propellant and a suitable solvent.
- Suitable propellants include hydrocarbons and hydrocarbon ethers.
- Suitable containers will vary according to the pressure requirements of the propellant.
- Administration of the aerosol will vary according to subject's age, weight and the severity and response of the symptoms.
- compositions described herein may be comprised in a kit.
- citrulline and/or an anticancer agent including an arginine-depleting agent such as arginase
- suitable container means in a kit may be comprised in suitable container means in a kit.
- the components of the kits may be packaged either in aqueous media (including sterile aqeous solution, for example) or in lyophilized form.
- the container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which a component may be placed, and preferably, suitably aliquoted.
- kits of the present invention also will typically contain a means for containing the citrulline and/or arginase and any other reagent containers in close confinement for commercial sale. Such containers may include injection or blow molded plastic containers into which the desired vials are retained.
- the kit comprises a pharmaceutically effective amount of citrulline and a pharmaceutically effective amount of an anticancer agent, such as arginase, and in specific aspects they are in one or more sealed vials or bottles, for example.
- the citrulline and arginase are in separate vials, although in certain cases the citrulline and arginase are in the same vials.
- the liquid solution may be an aqueous solution, including a sterile aqueous solution, for example.
- the composition(s) may also be formulated into a syringeable composition.
- the container means may itself be a syringe, pipette, and/or other such like apparatus, from which the formulation may be applied to an affected area of the body, injected into an animal, and/or even applied to and/or mixed with the other components of the kit.
- kits may be provided as dried powder(s).
- the powder can be reconstituted by the addition of a suitable solvent.
- the solvent may also be provided in another container means.
- kits may also comprise a second container means for containing a sterile, pharmaceutically acceptable buffer and/or other diluent.
- kits of the invention may also comprise, and/or be packaged with, an instrument for assisting with the injection/administration and/or placement of the ultimate composition within the body of an animal.
- an instrument may be a syringe, pipette, forceps, and/or any such medically approved delivery vehicle.
- the present example concerns exemplary methods and reagents for practicing embodiments of the invention.
- Cytotoxicity Assays 5,000 cells were plated in 96-well float bottom plates and labeled with different dilutions of HuArg(Co)PEG500 + 400uM citrulline. Drug concentrations were varied from 10 "12 to 10 "6 M. After 54hr at 37°C/5%C0 2 , luCi of 3 H-thymidine or leucine was added, and the mixture was incubated for 18 hrs more. The plates were frozen and thawed, and H was harvested with a cell harvester and glass fiber mats. Liquid scintillation fluid was added, and H cpm were counted on a betaplate reader. IC50 concentrations of drug producing 50% inhibition of thymidine or leucine incorporation were calculated. Maximal percent cell kill was at luM drug.
- FIG. 1 shows a summary table of cell lines treated with HuArg(Co)PEG500 in vitro.
- the IC50s are all essentially the same and suggest that HuArg(Co)PEG500 is toxic to all cells.
- FIG. 2 shows a summary table of cell lines treated with HuArg(Co)PEG500 + 400uM citrulline. In the presence of citrulline, HuArg(Co)PEG500 is no longer toxic to all cell types. ;
- FIG. 3 A is a Western blot analysis of representative tumor cell lines tested in FIGS. 1-2.
- FIG. 3B shows a Ratio of ASS to beta actin for particular exemplary tumor cell lines.
- FIG. 4 shows that tumor ASS level predicts recombinant human arginase response. Combining the data from FIGS. 2 and 3, one recognizes that tumor ASS level predicts whether or not tumor cell lines will respond to HuArg(Co)PEG500. Tumor cells with essentially zero ASS cannot synthesize arginine from citrulline. HuArg(Co)PEG500 is toxic in these cells. However, cells that do contain ASS are able to synthesize arginine from citrulline and are therefore not sensitive to HuArg(Co)PEG500 treatment.
- FIG. 5 shows co-arginaseI-PEG5000 cell cytotoxicity.
- HuArg(Co)PEG500 is toxic for all exemplary cell lines in vitro.
- the studies demonstrate that arginine is, indeed, an essential amino acid, but in the presence of citrulline, only ASS-negative tumor types are killed by HuArg(Co)PEG500.
- HuArg(Co)PEG500 treatment alone in humans is useful but likely not for sustained long periods of time without serious side effects.
- Co-treatment with HuArg(Co)PEG500 and citrulline can be used to target ASS-negative tumors that will drastically decrease potential side effects.
- Arginine is a nonessential amino acid for humans. Arginine is synthesized by normal human tissues using the urea cycle enzymes, ornithine transcarbamylase, arginino succinate synthetase and arginino succinate lyase. Certain tumors are arginine auxotrophs due to deficiency of arginino succinate synthetase (ASS).
- a recombinant human enzyme, hArg(Co)- PEG5000 depletes blood levels of arginine and inhibits tumor growth in tissue culture and animal models.
- this enzyme converts arginine to ornithine and urea, there are normal tissue toxicities to cells lacking ornithine transcarbamylase, in particular aspects. To overcome this toxicity, in certain aspects one administers citrulline orally and thus limits toxicity to ASS- deficient tumor cells.
- an individual with diagnosed cancer such as melanoma, breast, colon, lung, prostate, cervical, liver, mesothelioma, pancreatic cancer, acute lymphoblastic leukemia, or acute myelogenous leukemia
- a combination of arginase and citrulline is administered a combination of arginase and citrulline.
- the concentration of arginase is about 0.5 ⁇ -5 ⁇ , such as about 1 ⁇
- the concentration of citrulline is about 100 ⁇ -800 ⁇ , such as about 400 ⁇ .
- the arginase is delivered via intramuscular or intravenous administration, and the citrulline is delivered orally.
- the individual is able to be administered arginase with citrulline longer than if arginase were administered to the individual alone.
- BALB/c mice are given various doses of hArg(Co)- PEG5000 (0, 1, 5 or 10 mg/kg twice a week for 4 weeks) to evaluate its potential for toxicity and its ability to reduce arginine levels.
- a second group of mice are given hArg(Co)-PEG5000 at various doses (0, 1, 5 or 10 mg/kg twice a week for 4 weeks), and in addition to Citrulline (10 mg/mL in drinking water) orally, to characterize protective properties.
- animals are humanely euthanized and tissues are collected for further analysis.
- the toxicity of the drug is determined in mice over a month period, for example.
- the protective role of supplemental citruUine is assessed. Measurements include day 7 and 28 serum arginine and citruUine, weight loss twice weekly, survival at day 28, and organ pathologies at day 28, for example.
- Human recombinant arginase I cobalt coupled to polyethylene glycol 5000 Human recombinant arginase I cobalt coupled to polyethylene glycol 5000 (HuArg I [Co]-PEG5000) was produced from purified human recombinant arginase I (HuArg I) expressed in Escherichia coli (Glaser et al., 2011). Briefly, enzyme in lOOmM sodium phosphate pH 8.3 was reacted with a 40-fold excess of methoxy polyethylene glycol (PEG) succinidmidyl carboxymethyl ester 5000 MW (JemKem Technology, Allen, TX) for 1 h at 25°C.
- PEG methoxy polyethylene glycol
- mice Animals. 6-8 wk old female Balb/c mice were purchased from Jackson Laboratories (Bar Harbor, ME) and housed in ventilated cages equipped with municipal water and standard rodent chow containing 1.4% arginine (Purina LabDiet 5001). Animals were weighed daily and examined twice daily for activity, eating, posture and coat condition. Mice received lmL Dulbecco's phosphate buffered saline (PBS) sq daily for weight loss exceeding 10%. Additionally, supplemental nutrition with DietGel, water gels, and dry cereal mix was provided. Moribund animals or animals losing >25% body weight were euthanized by CO 2 asphyxiation, and cardiac puncture was performed to collect blood.
- PBS Dulbecco's phosphate buffered saline
- HuArg I rCo1-PEG5000 dose studies Cohorts of 10 - 20 mice received lmg/kg, 5mg/kg or lOmg/kg HuArg I [Co]-PEG5000 twice weekly for up to 4 weeks. Animals were monitored for weight, overall condition and survival. ⁇ blood was collected from facial vein of surviving animals on day 7 and 28. Blood was mixed with equal volume 0.1M citrate buffer pH 6.6, plasma separated and stored at -80°C. Moribund animals and animals completing the study were assayed for tissue histology and blood counts and chemistries as described above.
- Serum Arginine Concentrations Freshly obtained or thawed plasma was mixed with perchloric acid, neutralized with potassium carbonate, and centrifuged. Supernatants were reacted with 30mM ophthalaldehyde (OPA), 50mM 2-mercaptoethanol, 40mM sodium borate and 3.1% Brij-35 pH 9.5. Samples and standards (Sigma-Aldrich) were run immediately on a Supelcosil LC-18 (Sigma-Aldrich) HPLC (Shimadzu, Tokyo, Japan) with gradient of 86% 0.1M sodium acetate pH 7.2/14% methanol to 100% methanol as described by Wu (Wu et al., 2008). Fluorescence is monitored at excitation and emission wavelengths of 340 and 455nm, respectively. Area under the curve (AUC) was calculated and correlated with standards. The assay range was 4 - ⁇ arginine.
- HuArg I rCol-PEG5000 mouse toxicity The MTD of HuArg I [Co]-PEG5000 administered ip twice weekly to Balb/c mice was 5mg/kg. As shown in FIG. 6, control and lmg/kg protein yielded 100% survival; 5mg/kg produced 90% survival, and lOmg/kg led to 10% survival. Lethality occurred within ten days of treatment initiation. The difference in survival between the control, lmg/kg and 5mg/kg were not significant; the differences in survival between control and lOmg/kg and between the 5mg/kg and lOmg/kg dose levels were significant (p ⁇ 0.001) as determine by log rank tests. The DLT was extreme weight loss (FIG.
- Plasma arginine concentrations Control mouse plasma arginine levels averaged 61 + 19 ⁇ and 44 + 15 ⁇ on day 7 and 28 of the experiment, respectively (Table 3).
- HuArg I [Co]-PEG5000 lmg/kg treated animals yielded arginine concentrations of 32 + 30 ⁇ and 54 + 22 ⁇ at day 7 and 28, respectively.
- HuArg I [Co]-PEG5000 5mg/kg gave 7 + 2 ⁇ and 18 + 20 ⁇ at day 7 and 28, respectively;
- HuArg I [Co]-PEG5000 lOmg/kg produced 6 + 2 ⁇ arginine levels at day 7. There were no surviving mice at this dose at day 28.
- L-citrulline protection Because all deaths from HuArg I [Co]-PEG5000 occurred within 10 days, the protection study to designed to last two weeks. L-citrulline was given either as lOOmg (5g/kg) bolus sq injection daily or twice daily or at lOOmg/mL in drinking water to HuArg I [Co]-PEG5000 lOmg/kg treated animals for two weeks. L-citrulline supplementation ameliorated the HuArg I [Co]-PEG5000 toxicities in all treated cohorts. Animals treated with either daily or twice daily subcutaneous L-citrulline survived the entire 2 weeks (FIG. 8).
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Abstract
La présente invention concerne des procédés et des compositions pour la réduction de la toxicité d'un agent anticancéreux qui met en jeu la citrulline ou un analogue de celle-ci. Des exemples non limitants d'agents anticancéreux comprennent des agents de déplétion de l'arginine.
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RU2771313C2 (ru) * | 2016-08-08 | 2022-04-29 | Эйрэйз, Инк. | Композиции и способы для лечения рака с истощающими аргинин и иммуноонкологическими агентами |
US11717562B2 (en) | 2017-12-05 | 2023-08-08 | Aerase, Inc. | Method and composition for treating arginase 1 deficiency |
WO2021041904A1 (fr) * | 2019-08-30 | 2021-03-04 | Aeglea Biotherapeutics, Inc. | Procédés de production d'arginase 1 de recombinaison humaine et utilisations associées |
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