US20120276126A1 - Lactoferrin in the treatment of malignant neoplasms and other hyperproliferative diseases - Google Patents
Lactoferrin in the treatment of malignant neoplasms and other hyperproliferative diseases Download PDFInfo
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- US20120276126A1 US20120276126A1 US13/546,208 US201213546208A US2012276126A1 US 20120276126 A1 US20120276126 A1 US 20120276126A1 US 201213546208 A US201213546208 A US 201213546208A US 2012276126 A1 US2012276126 A1 US 2012276126A1
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- Prior art keywords
- lactoferrin
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- composition
- cells
- hyperproliferative disease
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Definitions
- the present invention relates to methods of treating a hyperproliferative disease by administering a composition of lactoferrin alone or in combination with standard anti-cancer therapies.
- the lactoferrin composition may be administered orally, intravenously, intratumorally, or topically.
- Radiotherapy chemotherapy, biotherapy and immunotherapy are alternatives to surgical treatment of cancer (Mayer, 1998; Ohara, 1998; Ho et al., 1998).
- the disadvantage of many of the alternative therapies are the side effects, which can include myelosuppression, skin irritation, difficulty swallowing, dry mouth, nausea, diarrhea, hair loss, weight loss, and loss of energy (Curran, 1998; Brizel, 1998).
- Lactoferrin is a single chain metal binding glycoprotein. Many cells types, such as monocytes, macrophages, lymphocytes, and intestinal brush-border cells, are known to have lactoferrin receptors. In addition to lactoferrin being an essential growth factor for both B and T lymphocytes, lactoferrin has a wide array of functions related to host primary defense mechanisms. For example, lactoferrin has been reported to activate natural killer (NK) cells, induce colony stimulating activity, activate polymorphonuclear neutrophils (PMN), regulate granulopoeisis, enhance antibody-dependent cell cytotoxicity, stimulate lymphokine-activated killer (LAK) cell activity, and potentiate macrophage toxicity.
- NK natural killer
- PMN polymorphonuclear neutrophils
- LAK stimulate lymphokine-activated killer
- bovine lactoferrin (bLF) was used as a prophylaxis for tumor formation and/or established tumors.
- the present invention is the first to use lactoferrin as a treatment, not a prophylaxis, for established tumors.
- the present invention is directed to a method for treating a hyperproliferative disease.
- the method of treatment involves oral, intravenous, topical and/or intratumoral administration of lactoferrin.
- a specific embodiment of the present invention is a method of treating a hyperproliferative disease comprising the step of administering orally to a subject a human lactoferrin composition in an amount sufficient to provide an improvement in the hyperproliferative disease in the subject. More specifically, the amount of the composition that is administered is about 1 mg to about 100 g per day, more preferabley 20 mg to about 10 g per day. A further embodiment includes administering an antacid in conjunction with the human lactoferrin composition.
- the human lactoferrin composition is dispersed in a pharmaceutically acceptable carrier. More specifically, the human lactoferrin is recombinant human lactoferrin.
- the hyperproliferative disease is further defined as cancer, in which the cancer comprises a neoplasm.
- the neoplasm is selected from the group consisting of melanoma, non-small cell lung, small-cell lung, lung hepatocarcinoma, retinoblastoma, astrocytoma, gliobastoma, leukemia, neuroblastoma, squamous cell, head, neck, gum, tongue, breast, pancreatic, prostate, renal, bone, testicular, ovarian, mesothelioma, sarcoma, cervical, gastrointestinal, lymphoma, brain, colon, and bladder.
- the neoplasm is a hematopoietic neoplasm.
- the hematopoietic neoplasm is selected from the group consisting of acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, juvenile myelomonocyte leukemia, multiple myeloma, and chronic lymphocytic leukemia.
- the hyperproliferative disease is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, leiomyomas, adenomas, lipomas, hemangiomas, fibromas, vascular occlusion, restenosis, atherosclerosis, pre-neoplastic lesions, carcinoma in situ, oral hairy leukoplakia, and psoriasis.
- Another embodiment is a method of treating a hyperproliferative disease comprising the step of supplementing the mucosal immune system in a subject by increasing the amount of human lactoferrin in the gastrointestinal tract.
- the human lactoferrin is administered orally and stimulates the production of interleukin-18 and Granulocyte Macrophage Colony Stimulating Factor (GM-CSF).
- GM-CSF Granulocyte Macrophage Colony Stimulating Factor
- another embodiment is a method of enhancing a mucosal immune response in the gastrointestinal tract in a subject comprising the step of administering orally to the subject a human lactoferrin.
- the human lactoferrin stimulates interleukin-18 and CM-CSF in the gastrointestinal tract.
- IL-18 stimulates the production, maturation, migration or activity of immune cells, e.g., T lymphocytes or natural killer cells.
- T lymphocytes are selected from the group consisting of CD4+, CD8+ and CD3+ cells.
- GM-CSF also stimulates the production, maturation, migration or activity of immune cells, e.g. dendritic cells and other antigen presenting cells.
- a further embodiment includes treating a hyperproliferative disease comprising administering orally to a subject a human lactoferrin composition in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy.
- the chemotherapy is a platinum based chemotherapy such as cisplatin or a taxane based chemotherapy such as docetaxel.
- Another embodiment is a method of reducing growth of a neoplasm in a subject comprising the step of administering orally to the subject a human lactoferrin composition in an amount sufficient to reduce the growth of the neoplasm in the subject.
- the lactoferrin composition may be administered in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy.
- another embodiment is a method of treating a hyperproliferative disease comprising the step of administering intravenously to a subject a lactoferrin composition in an amount sufficient to provide an improvement in the hyperproliferative disease.
- the amount of the composition that is administered is about 0.1 ⁇ g to about 10 g per day.
- the lactoferrin is mammalian lactoferrin, for example, human or bovine, and the lactoferrin can be recombinant lactoferrin.
- Another embodiment comprises a method of treating a hyperproliferative disease comprising the step of supplementing a systemic immune system in a subject by increasing the amount of lactoferrin in the systemic circulation.
- the lactoferrin is administered intravenously.
- the lactoferrin composition is administered in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy.
- another embodiment is a method of enhancing a systemic immune response following the step of administering intravenously to the subject a lactoferrin composition.
- the lactoferrin stimulates interleukin-18 and GM-CSF. It is envisioned that interleukin-18 stimulates the production or activity of immune cells, for example T lymphocytes or natural killer cells and CM-CSF promotes the migration and maturation of immune cells including dendritic and other antigen presenting cells
- another embodiment is a method of treating a hyperproliferative disease comprising the step of administering topically to a subject a lactoferrin composition in an amount sufficient to provide an improvement in the hyperproliferative disease.
- the amount of the composition that is administered is about 0.1 ⁇ g to about 10 g per day.
- the composition may be a topical gel, a solution, capsule or a tablet having a lactoferrin concentration of about 0.01% to about 20%. More particularly, the lactoferrin is mammalian lactoferrin, for example, human or bovine, and the lactoferrin can be recombinant lactoferrin.
- Another embodiment is a method of treating a hyperproliferative disease by topically administering a lactoferrin composition in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy.
- another embodiment is a method of enhancing a local or systemic immune response following the step of administering topically to the subject a lactoferrin composition.
- the lactoferrin stimulates production of interleukin-18 and/or GM-CSF by the keratinocytes. It is envisioned that interleukin-18 stimulates the production or activity of immune cells, for example T lymphocytes or natural killer cells and GM-CSF promotes the migration and maturation of immune cells including dendritic and other antigen presenting cells.
- another embodiment of the present invention is a method of stimulating, enhancing or up-regulating interleukin-18 and/or GM-CSF by administering a lactoferrin composition to a subject.
- FIG. 1 shows squamous cell tumor growth with and without oral, intravenous and intratumoral administration of recombinant human lactoferrin.
- FIG. 2 shows percent tumor growth inhibition in animals receiving lactoferrin, cisplatin and lactoferrin in combination with cisplatin.
- FIG. 3 shows the percent tumor growth inhibition with lactoferrin in combination with various doses of cisplatin.
- FIG. 4 shows the NK activity after treatment with lactoferrin.
- FIG. 5 shows squamous cell tumor growth with and without intratumoral administration of recombinant lactoferrin once or twice a day.
- hyperproliferative disease refers to any disease or disorder in which the cells proliferate more rapidly than normal tissue growth.
- a hyperproliferating cell is a cell that is proliferating more rapidly than normal cells.
- parenteral administration includes any form of administration in which the compound is absorbed into the subject without involving absorption via the intestines.
- exemplary parenteral administrations that are used in the present invention include, but are not limited to intramuscular, intravenous, intraperitoneal, intratumoral, intraocular, or intraarticular administration.
- intravenous administration includes all techniques to deliver a lactoferrin composition to the systemic circulation via an intravenous injection or infusion.
- intramoral administration includes all techniques to deliver a lactoferrin composition to the site of a tumor including injection, electroporation, creams, lotions or other forms of administration.
- oral administration includes oral, buccal, enteral or intragastric administration.
- topical administration includes application to a dermal, epidermal, subcutaneous or mucosal surface.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- the use of such media and agents for pharmaceutically active substances is well know in the art. Except insofar as any conventional media or agent is incompatible with the vectors or cells of the present invention, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.
- lactoferrin or “LF” as used herein refers to native or recombinant lactoferrin.
- Native lactoferrin can be obtained by purification from mammalian milk or colostrum or from other natural sources.
- Recombinant lactoferrin (rLF) can be made by recombinant expression or direct production in genetically altered animals, plants, fungi, bacteria, or other prokaryotic or eukaryotic species, or through chemical synthesis.
- subject as used herein, is taken to mean any mammalian subject to which the lactoferrin composition is administered according to the methods described herein.
- the methods of the present invention are employed to treat a human subject.
- Another embodiment includes treating a human subject suffering from a hyperproliferative disease.
- terapéuticaally effective amount refers to an amount that results in an improvement or remediation of the symptoms of the disease or condition.
- treating refers to administering to a subject a therapeutically effective amount of a lactoferrin composition so that the subject has an improvement in the disease.
- the improvement is any improvement or remediation of the symptoms.
- the improvement is an observable or measurable improvement.
- a treatment may improve the disease condition, but may not be a complete cure for the disease.
- improvements in patients with cancer may include tumor stabilization, tumor shrinkage, increased time to progression, increased survival or improvements in the quality of life.
- Beneficial effect may also be reflected in an improvement of the patient's immune system as measured by the number and activity of circulating immune cells such as CD4+ cells, CD8+ cells, NK cells and CD40+ cells.
- Vicinity refers to in or around the area or site of the tumor and/or hyperproliferative disease.
- “vicinity of a tumor” may refer to the area in or around the tumor or margins of the tumor. Vicinity includes the area adjacent to the tumor, the area over the tumor, the area under the tumor, the margin area around the tumor, or the area adjacent the tumor margin area.
- the lactoferrin used according to the present invention can be obtained through isolation and purification from natural sources, for example, but not limited to mammalian milk.
- the lactoferrin is preferably mammalian lactoferrin, such as bovine or human lactoferrin.
- the lactoferrin is human lactoferrin produced recombinantly using genetic engineering techniques well known and used in the art, such as recombinant expression or direct production in genetically altered animals, plants or eukaryotes, or chemical synthesis. See, i.e., U.S. Pat. Nos. 5,571,896; 5,571,697 and 5,571,691, which are herein incorporated by reference.
- lactoferrin compositions according to the present invention will be via any common route, orally, parenterally, or topically.
- exemplary routes include, but are not limited to oral, nasal, buccal, rectal, vaginal, intramuscular, intraperitoneal, intravenous, intraarterial, intratumoral or dermal.
- Such compositions would normally be administered as pharmaceutically acceptable compositions as described herein.
- compositions of the present invention may be formulated in a neutral or salt form.
- Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. 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, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
- Sterile injectable solutions are prepared by incorporating the lactoferrin 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.
- the inventive composition suitable for oral administration is provided in a pharmaceutically acceptable carrier with or without an inert diluent.
- the carrier should be assimilable or edible 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 lactoferrin preparation contained therein, its use in an orally administrable lactoferrin 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.
- the composition is combined with the carrier in any convenient and practical manner, i.e., by solution, suspension, emulsification, admixture, encapsulation, microencapsulation, absorption and the like. Such procedures are routine for those skilled in the art.
- the composition in powder form 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 through, i.e., denaturation in the stomach.
- stabilizers for use in an orally administrable composition include buffers, antagonists to the secretion of stomach acids, amino acids such as glycine and lysine, carbohydrates such as dextrose, mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc., proteolytic enzyme inhibitors, and the like. More preferably, for an orally administered composition, the stabilizer can also include antagonists to the secretion of stomach acids.
- composition for oral administration which is combined with a semi-solid or solid carrier can be further formulated into hard or soft shell gelatin capsules, tablets, or pills. More preferably, gelatin capsules, tablets, or pills are enterically coated. Enteric coatings prevent denaturation of the composition in the stomach or upper bowel where the pH is acidic. See, i.e., U.S. Pat. No. 5,629,001. Upon reaching the small intestines, the basic pH therein dissolves the coating and permits the composition to be released and absorbed by specialized cells, i.e., epithelial enterocytes and Peyer's patch M cells.
- specialized cells i.e., epithelial enterocytes and Peyer's patch M cells.
- a powdered composition is combined with a liquid carrier such as, i.e., water or a saline solution, with or without a stabilizing agent.
- a liquid carrier such as, i.e., water or a saline solution
- a specific formulation that may be used in the present invention is a solution of lactoferrin in a hypotonic phosphate based buffer that is free of potassium where the composition of the buffer is as follows: 6 mM sodium phosphate monobasic monohydrate, 9 mM sodium phosphate dibasic heptahydrate, 50 mM sodium chloride, pH 7.0 ⁇ 0.1.
- the concentration of lactoferrin in a hypotonic buffer may range from 10 microgram/ml to 100 milligram/ml.
- This formulation may be administered via any route of administration, for example, but not limited to intratumoral administration.
- a composition for topical administration which is combined with a semi-solid carrier can be further formulated into a gel ointment.
- a preferred carrier for the formation of a gel ointment is a gel polymer.
- Preferred polymers that are used to manufacture a gel composition of the present invention include, but are not limited to carbopol, carboxymethyl-cellulose, and pluronic polymers.
- a powdered lactoferrin composition is combined with an aqueous gel containing an polymerization agent such as Carbopol 980 at strengths between 0.5% and 5% wt/volume for application to the skin for treatment of hyperproliferative disease on or beneath the skin.
- solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective to result in an improvement or remediation of the symptoms.
- the formulations are easily administered in a variety of dosage forms such as ingestible solutions, drug release capsules and the like. Some variation in dosage can occur depending on the condition of the subject being treated. The person responsible for administration can, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations meet sterility, general safety and purity standards as required by FDA Office of Biologics standards.
- a lactoferrin composition provided in any of the above-described pharmaceutical carriers is administered to a subject suspected of or having a hyperproliferative disease.
- One of skill in the art can determine the therapeutically effective amount of human lactoferrin to be administered to a subject based upon several considerations, such absorption, metabolism, method of delivery, age, weight, disease severity and response to the therapy.
- the route of administration will vary, naturally, with the location and nature of the lesion, and include, for example intradermal, transdermal, parenteral, intravenous, intramuscular, intranasal, subcutaneous, percutaneous, intratracheal, intraperitoneal, intratumoral, perfusion, lavage, direct injection, and oral administration.
- Oral administration of the lactoferrin composition includes oral, buccal, enteral or intragastric administration. It is also envisioned that the composition may be used as a food additive. For example, the composition is sprinkled on food or added to a liquid prior to ingestion.
- Intratumoral administration of the lactoferrin composition includes intratumoral injection, electroporation, or surgical or endoscopic implantation. Intratumoral injection, or injection into the tumor vasculature is specifically contemplated for discrete, solid, accessible tumors. Local, regional or systemic administration also may be appropriate.
- the hyperproliferative disease includes but is not limited to neoplasms.
- a neoplasm is an abnormal tissue growth, generally forming a distinct mass that grows by cellular proliferation more rapidly than normal tissue growth.
- Neoplasms show partial or total lack of structural organization and functional coordination with normal tissue. These can be broadly classified into three major types. Malignant neoplasms arising from epithelial structures are called carcinomas, malignant neoplasms that originate from connective tissues such as muscle, cartilage, fat or bone are called sarcomas and malignant tumors affecting hematopoietic structures (structures pertaining to the formation of blood cells) including components of the immune system, are called leukemias, lymphomas and myelomas.
- a tumor is the neoplastic growth of the disease cancer.
- a “neoplasm”, also referred to as a “tumor”, is intended to encompass hematopoietic neoplasms as well as solid neoplasms.
- neoplasms include, but are not limited to melanoma, non-small cell lung, small-cell lung, lung, hepatocarcinoma, retinoblastoma, astrocytoma, gliobastoma, gum, tongue, leukemia, neuroblastoma, head, neck, breast, pancreatic, prostate, renal, bone, testicular, ovarian, mesothelioma, sarcoma, cervical, gastrointestinal, lymphoma, brain, colon, bladder, myeloma, or other malignant or benign neoplasms.
- hyperproliferative diseases include, but are not limited to neurofibromatosis, rheumatoid arthritis, Waginer's granulomatosis, Kawasaki's disease, lupus erathematosis, midline granuloma, inflammatory bowel disease, osteoarthritis, leiomyomas, adenomas, lipomas, hemangiomas, fibromas, vascular occlusion, restenosis, atherosclerosis, pre-neoplastic lesions, carcinoma in situ, oral hairy leukoplakia, or psoriasis, and pre-leukemias, anemia with excess blasts, and myelodysplastic syndrome.
- neoplasms of interest in the present invention include, but are not limited to hematopoietic neoplasms.
- a hematopoietic neoplasm may include acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, juvenile myelomonocyte leukemia, multiple myeloma, chronic lymphocytic leukemia or other malignancy of hematologic origin.
- the lactoferrin compositions are administered in an effective amount to decrease, reduce, inhibit or abrogate the growth of a tumor.
- the amount may vary from about 0.1 ⁇ g to about 100 g of the lactoferrin composition.
- the lactoferrin composition is orally administered in the range of 1mg to 100 g per day, more preferably about 20 mg to about 10 g per day with the most preferred dose being 4.5 g per day.
- Intravenously administered lactoferrin can be in the range of 0.1 ⁇ g to about to 10 g per day, more preferably about 0.1 ⁇ g to about 1 mg with the most preferred dose being 250 mg per day.
- a lactoferrin composition is intratumorally administered in the range of 0.1 ⁇ g to 10 g per day with the most preferred dose being 100 ⁇ g per day.
- the amount of lactoferrin may vary from about 1 ⁇ g to about 100 g of lactoferrin.
- the topical gel, solution, capsule or tablet comprises a lactoferrin concentration of about 0.01% to about 20%. More preferably, the topical gel, solution, capsule or tablet may comprise a lactoferrin concentration of about 1% to about 8.5%.
- Treatment regimens may vary as well, and often depend on tumor type, tumor location, disease progression, and health and age of the patient. Obviously, certain types of tumor will require more aggressive treatment, while at the same time, certain patients cannot tolerate more taxing protocols. The clinician will be best suited to make such decisions based on the known efficacy and toxicity (if any) of the therapeutic formulations.
- the tumor being treated may not, at least initially, be resectable.
- Treatments with the lactoferrin composition may increase the resectability of the tumor due to shrinkage at the margins or by elimination of certain particularly invasive portions. Following treatments, resection may be possible. Additional treatments subsequent to resection will serve to eliminate microscopic residual disease at the tumor site.
- the present invention may be used at the time of surgery, and/or thereafter, to treat residual or metastatic disease.
- a resected tumor bed may be injected or perfused with a formulation comprising the lactoferrin composition.
- the perfusion may be continued post-resection, for example, by leaving a catheter implanted at the site of the surgery. Periodic post-surgical treatment is also envisioned.
- Continuous administration also may be applied where appropriate, for example, where a tumor is excised and the tumor bed is treated to eliminate residual, microscopic disease. Delivery via syringe or catherization is preferred. Such continuous perfusion may take place for a period from about 1-2 hours, to about 6-12 hours, to about 12-24 hours, to about 1-2 days, to about 1-2 weeks or longer following the initiation of treatment. Generally, the dose of the therapeutic composition via continuous perfusion will be equivalent to that given by a single or multiple injections, adjusted over a period of time during which the perfusion occurs. It was further contemplated that limb perfusion may be used to administer therapeutic compositions of the present invention, particularly in the treatment of melanomas and sarcomas.
- the lactoferrin composition is given in a single dose or multiple doses.
- the single dose may be administered daily, or multiple times a day, or multiple times a week, or monthly or multiple times a month.
- the lactoferrin composition is given in a series of doses. The series of doses may be administered daily, or multiple times a day, weekly, or multiple times a week, or monthly, or multiple times a month.
- a further embodiment of the present invention is a method of treating a hyperproliferative disease comprising the step of supplementing a mucosal immune system by increasing the amount of lactoferrin in the gastrointestinal tract.
- the lactoferrin is administered orally.
- a further embodiment is a method of enhancing a mucosal immune response in the gastrointestinal tract in a subject comprising the step of administering orally to said subject a lactoferrin composition, preferably human lactoferrin.
- lactoferrin stimulates interleukin-18 and GM-CSF in the gastrointestinal tract, which enhance immune cells.
- interleukin-18 enhances T lymphocytes or natural killer cells and GM-CSF promotes maturation and migration of immune cells including dendritic and other antigen presenting cells.
- interleukin-18 IL-18 enhances CD4+, CD8+ and CD3+ cells.
- IL-18 is a Thi cytokine that acts in synergy with interleukin-12 and interleukin-2 in the stimulation of lymphocyte IFN-gamma production.
- Other cytokines may also be enhanced for example, but not limited to IL-1b or, IL-12 or IFN-gamma.
- lactoferrin stimulates interleukin-18 following oral administration, which inhibits angiogenesis and thereby has activity against tumor cells which are dependent on neovascularization.
- a further embodiment of the present invention is a method of treating a hyperproliferative disease comprising the step of supplementing the systemic immune system by increasing the amount of lactoferrin in the systemic circulation.
- the lactoferrin composition is administered intravenously.
- lactoferrin stimulates interleukin-18 and GM-CSF in the tissue, which enhance immune cells.
- interleukin-18 enhances T lymphocytes or natural killer cells and GM-CSF promotes maturation and migration of immune cells including dendritic and other antigen presenting cells.
- interleukin-18 enhances CD4+, CD8+ and CD3+ cells.
- IL-18 is a Th1 cytokine that acts in synergy with interleukin-12 and interleukin-2 in the stimulation of lymphocyte IFN-gamma production.
- Other cytokines may also be enhanced for example, but not limited to IL-1b or, IL-12 or IFN-gamma.
- lactoferrin stimulates interleukin-18 following intravenous administration, which inhibits angiogenesis and thereby has activity against tumor cells which are dependent on neovascularization.
- a further embodiment of the present invention is a method of treating a hyperproliferative disease comprising the step of supplementing a local or systemic immune system by increasing the amount of lactoferrin in the vicinity of the tumor.
- Vicinity of the tumor refers to the general area of the tumor, for example the lactoferrin can be administered directly into or on the tumor, or in the general area of the tumor, but not directly into the tumor.
- the general area may include the margin area or near or adjacent the margin area of the tumor.
- the lactoferrin composition is administered intratumorally. It is envisioned that lactoferrin stimulates interleukin-18 and GM-CSF in the local tissue, which enhances immune cells.
- interleukin-18 enhances T lymphocytes or natural killer cells and GM-CSF promotes maturation and migration of immune cells including dendritic and other antigen presenting cells.
- interleukin-18 enhances CD4+, CD8+ and CD3+ cells.
- IL-18 is a Th1 cytokine that acts in synergy with interleukin-12 and interleukin-2 in the stimulation of lymphocyte IFN-gamma production.
- Other cytokines may also be enhanced for example, but not limited to IL-1b or, IL-12 or IFN-gamma.
- lactoferrin stimulates interleukin-18 following intratumoral administration, which inhibits angiogenesis and thereby has activity against tumor cells which are dependent on neovascularization.
- a further embodiment of the present invention is a method of treating a hyperproliferative disease comprising the step of supplementing a local or systemic immune system by increasing the amount of lactoferrin in the skin in the vicinity of the tumor.
- the lactoferrin composition is administered topically.
- administration in the vicinity of the tumor includes administration near or adjacent to the margins of the tumor or directly in the margin area of the tumor. It is envisioned that lactoferrin stimulates interleukin-18 and GM-CSF in the local tissue (e.g., keratinocytes), which enhances immune cells.
- interleukin-18 enhances T lymphocytes or natural killer cells and GM-CSF promotes maturation and migration of immune cells including dendritic and other antigen presenting cells.
- interleukin-18 enhances CD4+, CD8+ and CD3+ cells.
- IL-18 is a Th1 cytokine that acts in synergy with interleukin-12 and interleukin-2 in the stimulation of lymphocyte IFN-gamma production.
- Other cytokines may also be enhanced for example, but not limited to IL-1b or, IL-12 or IFN-gamma.
- lactoferrin stimulates interleukin-18 following intratumoral administration, which inhibits angiogenesis and thereby has activity against tumor cells which are dependent on neovascularization.
- 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 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.
- Anti-cancer agents include biological agents (biotherapy), chemotherapy agents, and radiotherapy agents. More generally, these other compositions would be provided in a combined amount effective to kill or inhibit proliferation of the cell.
- This process may involve administering the human lactoferrin composition of the present invention and the agent(s) or multiple factor(s) at the same time. This may be achieved by administering a single composition or pharmacological formulation that includes both agents, or by administering two distinct compositions or formulations, at the same time, or at times close enough so as to result in an overlap of this effect, wherein one composition includes the human lactoferrin composition and the other includes the second agent(s).
- the lactoferrin composition of the present invention may precede or follow the other anti-cancer agent treatment by intervals ranging from minutes to weeks.
- the other anti-cancer agent and lactoferrin composition are administered or 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 lactoferrin composition would still be able to exert an advantageously combined effect on the cell.
- Cancer therapies also include a variety of chemical based treatments.
- chemotherapeutic agents include without limitation antibiotic chemotherapeutics such as Doxorubicin, Daunorubicin, Adriamycin, Mitomycin (also known as mutamycin and/or mitomycin-C), Actinomycin D (Dactinomycin), Bleomycin, Plicomycin, plant alkaloids such as Taxol, Vincristine, Vinblastine, miscellaneous agents such as platinum based agents (e.g., Cisplatin (CDDP)), etoposide (VP16), Tumor Necrosis Factor, and alkylating agents such as, Carmustine, Melphalan (also known as alkeran, L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, (a phenylalanine derivative of nitrogen mustard), Cyclophosphamide, Chlorambucil, Busulfan (also known as myleran), taxane based
- agents include, but are not limited to, Carboplatin, Procarbazine, Mechlorethamine, Irinotecan, Topotecan, Ifosfamide, Nitrosurea, Etoposide (VP16), Tamoxifen, Raloxifene, Toremifene, Idoxifene, Droloxifene, TAT-59, Zindoxifene, Trioxifene, ICI 182,780, EM-800, Estrogen Receptor Binding Agents, Gemcitabinen, Navelbine, Farnesyl-protein transferase inhibitors, Transplatinum, 5-Fluorouracil, hydrogen peroxide, and Methotrexate, Temazolomide (an aqueous form of DTIC), Mylotarg, Dolastatin-10, Bryostatin, or any analog or derivative variant of the foregoing.
- Radiotherapeutic agents and factors include radiation and waves that induce DNA damage for example, 7-irradiation, X-rays, UV-irradiation, microwaves, electronic emissions, radioisotopes, and the like. Therapy may be achieved by irradiating the localized tumor site with the above described forms of radiations. It is most likely that all of these factors effect a broad range of damage to DNA, the precursors of DNA, the replication and repair of DNA, and the assembly and maintenance of chromosomes.
- Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 weeks), 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.
- 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, electrosurgery, 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.
- additional agents include, without limitation, agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers, or other biological agents, as well as biotherapy such as for example, hyperthermia.
- Hyperthermia is a procedure in which a patient's tissue is exposed to high temperatures (up to 106° F.). External or internal heating devices may be involved in the application of local, regional, or whole-body hyperthermia. Local hyperthermia involves the application of heat to a small area, such as a tumor. Heat may be generated externally with high-frequency waves targeting a tumor from a device outside the body. Internal heat may involve a sterile probe, including thin, heated wires or hollow tubes filled with warm water, implanted microwave antennae, or radiofrequency electrodes.
- a patient's organ or a limb is heated for regional therapy, which is accomplished using devices that produce high energy, such as magnets.
- some of the patient's blood may be removed and heated before being perfused into an area that will be internally heated.
- Whole-body heating may also be implemented in cases where cancer has spread throughout the body. Warm-water blankets, hot wax, inductive coils, and thermal chambers may be used for this purpose.
- Hormonal therapy may also be used in conjunction with the present invention.
- 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 and this often reduces the risk of metastases.
- Adjuvant therapy may also be used in conjunction with the present invention.
- adjuvants or immunomodulatory agents include, but are not limited to tumor necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; F42K and other cytokine analogs; or MIP-1, MIP-1beta, MCP-1, RANTES, and other chemokines.
- 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.
- vaccines that are used to treat cancer may be used in combination with the present invention to improve the therapeutic efficacy of the treatment.
- Such vaccines include peptide vaccines or dendritic cell vaccines.
- Peptide vaccines may include any tumor-specific antigen that is recognized by cytolytic T lymphocytes.
- dendritic cell vaccination comprises dendritic cells that are pulsed with a peptide or antigen and the pulsed dendritic cells are administered to the patient.
- tumor-specific antigens that are being used as vaccines in melanoma include, but are not limited to gp100 or MAGE-3. These antigens are being administered as peptide vaccines and/or as dendritic cell vaccines.
- Human squamous cell carcinoma (O12) was used. The cells were injected into the right flank of athymic nude mice. rhLF was administered either intratumorally (49 animals, 7 doses ranging from 0.05 ⁇ g to 125 ⁇ g per dose), intravenously (7 animals, 125 ug/dose) or orally (7 animals 20 mg/dose). Control animals were treated with only the vehicle; no rhLF was administered to the control animals. rhLF was administered twice a day for either five days (intravenous group) or eight days (all other groups) starting 11 days after inoculation with tumor cells to allow formation of established tumors.
- treatment with rhLF reduced rates of tumor growth relative to the control by 46% to 80%.
- Tumor cells from a broad range of tumor types are injected into the right flank of athymic nude mice.
- Animals are administered either rhLF, native hLF or bovine LF orally.
- Control animals are treated with only the vehicle, no rhLF is administered to the control animals.
- rhLF is administered either once or twice a day for either one, five, seven or fourteen days or eight days starting approximately eleven days after inoculation with tumor cells to allow formation of established tumors or at such other time as is generally done with standard or published regimens.
- the efficacy of treatment is evaluated by measuring the solid tumor size during and at the end of the experiment; the body weights are also determined at the time of tumor measurements.
- the immune response is measured by measuring the amount of cytokines, T-cells and NK cells in circulation and in the intestine.
- mice were treated for three days daily with 65 mg/kg/day of rhLF, 300 mg/kg/day of rhLF or 300 mg/kg/day of bLF.
- mice were only administered the pharmaceutical carrier. Twenty-four hours following administration of the LF or control for 3 days, animals were weighed and blood and serum were collected. Serum was used for cytokine ELISA assays.
- Small intestinal epithelium was homogenized using a lysis buffer consisting of PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulphate containing 10 ⁇ g/ml PhenylMetheylsulfonyl fluoride. Homogenate was centrifuged at 15,000 rpm for 10 minutes and the supernatant stored at ⁇ 80 C till it was tested for IL-18 levels.
- mice were treated orally with rhLF or placebo once a day for 3 days (see Table 4).
- mice were sacrificed and spleens were collected.
- NK cells were separated using a magnetic bead cell sorting assay (MACS anti-NK—DX5) and counted. Cells were then tested in vitro for NK-activity against YAC targets using a lactate dehydrogenase (LDH) release test.
- LLC lactate dehydrogenase
- Table 5 shows that oral rhLF treatment resulted in a significant increase of NK activity ex-vivo against YAC-target cells (10% @ 30:1 versus 2.8% of ctrl group). No significant change in NK activity was observed in placebo treated mice.
- Recombinant human lactoferrin or placebo were orally administered to mice, and the production of GM-CSF in the small intestine was measured.
- mice (5 animals per group) were treated for three days daily with 300 mg/kg/day of rhLF. For a control, mice were only administered the pharmaceutical carrier. Twenty-four hours following administration of the LF or placebo for 3 days, animals were and the small intestinal tissue was removed for further analysis. Small intestinal epithelium was homogenized using a lysis buffer consisting of PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulphate containing 10 ⁇ g/ml PhenylMetheylsulfonyl fluoride. Homogenate was centrifuged at 15,000 rpm for 10 minutes and the supernatant stored at ⁇ 80 C till it was tested for GM-CSF levels using an ELISA kit.
- a lysis buffer consisting of PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulphate containing 10 ⁇ g/ml PhenylMetheylsulfon
- a murine squamous carcinoma cell line (SCCVII) was injected into the floor of the mouth through the neck skin of immunocompetent C3H mice (Day 0). Five days after tumor cell implantation (Day 5), a skin incision was made in the lower neck and surgical dissection revealed the established tumors. Tumors were measured in three dimensions with calipers.
- RhLF 4 mg; 200 mg/Kg
- Cisplatin was administered as a single dose of 5 mg/Kg given intraperitoneally either at the start of rhLF (day 5), in the middle (day 8) or at the end (day 12) of rhLF therapy. Animals were sacrificed on day 12 post-implantation and the residual tumor masses were measured and processed for later additional analyses.
- RhLF mg/kg Cisplatin Group A Placebo 5 0 (Placebo) 0 Group B RhLF Alone 5 200 mg/kg 0 Group C CP Day 5 5 0 5 mg/kg on day 5* Group D CP Day 8 5 0 5 mg/kg on day 8* Group E CP Day 12 4 0 5 mg/kg on day 12 Group F RhLF/CP-5 5 200 mg/kg 5 mg/kg on day 5* Group G RhLF/CP-8 5 200 mg/kg 5 mg/kg on day 8* Group H RhLF/CP-12 5 200 mg/kg 5 mg/kg on day 12*
- TGI tumor growth inhibition
- mice receiving rhLF+cisplatin showed a TGI relative to the relevant group receiving cisplatin alone.
- animals receiving rhLF+cisplatin showed a 77% TGI relative to the placebo animals (P ⁇ 0.0001), a 66% TGI relative to rhLF alone (P ⁇ 0.01) and a 63% TGI relative to cisplatin alone (P ⁇ 0.01).
- Cisplatin dosing immediately prior to the start of rhLF (RhLF+CP-5) or during the period of rhLF administration (RhLF+CP-8) provided greater incremental benefit than when cisplatin was administered following completion of rhLF therapy (RhLF+CP-12).
- RhLF+CP-8 only the straddling regimen (RhLF+CP-8) provided a statistically significant improvement (P ⁇ 0.01) TGI of 77% over cisplatin alone (CP Day 8).
- TGI Tumor Growth Inhibition
- SEM Treatment Group Growth Relative to Placebo* Group
- TGI TGI (%) P-value A (Placebo) 741 (79) — — B (RhLF alone) 496 (155) 33% 0.0989 C (CP Day 5) 240 (137) 68% 0.0066 D (CP Day 8) 693 (146) 6% 0.3898 E (CP Day 12) 433 (175) 42% 0.0634 F (RhLF + CP-5) 14 (5) 98% ⁇ 0.0001 G (RhLF + CP-8) 159 (48) 79% 0.0001 H (RhLF + CP-12) 331 (47) 55% 0.0011 C to E (All CP) 457 (96) 38% 0.0564 F to H (All 168 (40) 77% ⁇ 0.0001 rhLF/CP) *Inhibition and 1-tailed P-value relative to the placebo group **Inhibition and 1-tailed P-value compared to the respective Cisplatin groups
- a murine squamous carcinoma cell line (SCCVII) was injected into the floor of the mouth through the neck skin of immunocompetent C3H mice (Day 0) as described in Example 6.
- tumors were measured for the baseline, then treated with either cisplatin (Day 8, i.p., 5 mg/kg) alone or cisplatin plus three doses of oral rhLF (daily by gavage for 7-8 days on days 5 through 11/12). Animals were sacrificed on Day 11/12 and tumors measured. There was a dose dependent inhibition of tumor growth in the animals receiving both rhLF and cisplatin as compared to the animals receiving cisplatin alone as shown in FIG. 3 .
- a murine squamous carcinoma cell line (SCCVII) was injected into the floor of the mouth through the neck skin of immunocompetent C3H mice (Day 0) as described in Example 7.
- tumors were measured for the baseline, then treated with either oral placebo alone (once daily from days 5 to 12; 6 animals), placebo and docetaxel (i.v. bolus of 31.3 mg/kg docetaxel on Day 8; 9 animals), or docetaxel plus oral rhLF (200 mg/kg, administered once daily by gavage from days 5 to 12; 9 animals). Animals were sacrificed on Day 14 and tumors measured.
- Docetaxel alone caused an inhibition of tumor growth relative to placebo and the combination of rhLF and docetaxel induced a further growth inhibition. Inhibition and p-values (1-tailed) are shown in Table 9.
- TGI Tumor Growth Inhibition
- a murine squamous carcinoma cell line (SCCVII) was injected into the floor of mouth through the neck skin of immunocompetent C3H mice (Day 0). Five days after tumor cell implantation (Day 5), a skin incision was made in the lower neck and surgical dissection revealed the established tumors. Tumors were measured in three dimensions with calipers.
- RhLF 200 mg/Kg
- Radiotherapy was administered as single dose of 2 Gray given at the beginning (day 5) or at during (day 8) rhLF-therapy. Animals were sacrificed on day 14 post-treatment and the residual tumor masses were measured and processed for later additional analyses.
- mice receiving rhLF alone, radiotherapy alone, or combination therapy showed a significant tumor growth inhibition (TGI) relative to placebo treated mice.
- TGI tumor growth inhibition
- TGI Tumor Growth Inhibition
- SEM Stimultion* P-value* A (Placebo) 2348 (395) — B (rhLF alone) 1074 (163) 54% 0.0040 C (Radiation Day 5) 827 (105) 65% 0.0021 D (rhLF/Rad 5) 750 (125) 68% 0.0006 E (Radiation Day 8) 977 (112) 58% 0.0018 F (rhLF/Rad 8) 797 (119) 66% 0.0007 C/E (Both Radiation) 911 (78) 61% ⁇ 0.0001 D/F (Both rhLF/Rad) 774 (84) 67% ⁇ 0.0001 *Inhibition and 1-tailed P-value compared to the placebo group
- lactoferrin stimulated the immune system. Still further, lactoferrin in combination with cisplatin, docetaxel and/or radiation resulted in inhibition of tumor growth.
- RhLF Recombinant human lactoferrin was orally administered to human patients with a range of metastatic cancer types that had failed standard chemotherapy in two different studies conducted in multiple centers in four countries (Argentina, Brazil, Chile, U.S.) RhLF was administered at doses of 1.5 to 9 grams daily in two divided doses in cycles of 14 each with a 14 day gap.
- Tumor size progression was monitored through CT scans and tumor markers where available.
- CT scans were performed at baseline and after each 8-week period once treatment was initiated, and also compared with a pre-baseline scan conducted prior to enrollment in the study. Tumor markers are measured every 4 weeks.
- Blood samples were collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples were collected to measure circulating IL-18, IL-1, IL-2, and IL-4, IL-5, IL-10, IL-12 and IFN- ⁇ .
- Table 12 shows the tumor response of five individual patients with different tumor types. In all cases, the percent growth of the tumor size prior to treatment of rhLF (the relevant duration of time is shown in parentheses) and the growth of the tumor in the ensuing two time periods, as measured by CT, showed a diminution in their rate of tumor growth or an actual shrinkage.
- Recombinant human lactoferrin is orally administered to human patients to inhibit tumor growth either alone or in combination with standard anti-cancer regimens.
- rhLF is administered using the optimum regimen and doses identified in Example 10 and the standard anti-cancer regimen(s) for the selected tumor type is used as part of the combination therapy.
- the route of administration and regimen of the additional anti-cancer therapy is as approved by the FDA for that indication or as described in a peer reviewed publication.
- Tumor size progression is monitored through CT scans and tumor markers where available.
- CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks once treatment is initiated.
- Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, and IL-12 and IFN- ⁇ .
- mice Balb/c na ⁇ ve mice were treated orally with rhLF or placebo once a day for 3 days. One day later (day 4), mice were sacrificed and spleens collected. NK cells were separated using a magnetic bead cell sorting assay (MACS anti-NK—DX5) and counted. Cells were then tested in vitro for NK-activity against YAC targets using a lactate dehydrogenase (LDH) release test.
- LLC anti-NK—DX5 magnetic bead cell sorting assay
- oral rhLF treatment resulted in a significant increase of NK activity ex-vivo against YAC-target cells.
- E:T ratio rhLF administration resulted in a 243% relative increase over placebo-treated animals (from 2.86% to 9.81%; p ⁇ 0.05).
- Recombinant lactoferrin, bovine lactoferrin and native lactoferrin are intravenously administered to animals, preferably rats, and the production of IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-gamma in the plasma, serum and blood packed cells are measured.
- rats are treated for fourteen consecutive days with 0.05 ⁇ g to 1000 ⁇ g per dose.
- rats are only administered the pharmaceutical carrier.
- animals are weighed and blood and serum are collected.
- the levels of CD4+, CD8+ and NK cells are counted from the blood that was collected.
- Plasma, serum and an extract of the blood cells are used for cytokine ELISA assays.
- tissues are removed for further analysis. Tissues are homogenized using a lysis buffer consisting of PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulphate containing 10 ⁇ g/ml PhenylMetheylsulfonyl fluoride. Homogenate is centrifuged at 15,000 rpm for 10 minutes and the supernatant stored at ⁇ 80 C till it is tested for the cytokines IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-gamma.
- a lysis buffer consisting of PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulphate containing 10 ⁇ g/ml PhenylMetheylsulfonyl fluoride. Homogenate is centrifuged at 15,000 rpm for 10 minutes and the supernatant stored at ⁇ 80
- Tumor cells to be tested are injected into the right flank of athymic nude mice. Animals are administered rhLF intravenously alone and in combination with other anti-cancer regimens as described in Example 13. Control animals are treated with only the vehicle; no rhLF is administered to the control animals. rhLF is administered using regimens identified as being optimal in the trials described in Example 13. Anti-cancer therapy is administered using standard or published regimens. Therapy starts approximately 11 days after inoculation with tumor cells to allow formation of established tumors or at such other time as is generally done with standard or published regimens.
- the efficacy of individual and combination treatments are evaluated by measuring the solid tumor size during and at the end of the experiment; the body weights are also determined at the time of tumor measurements.
- Recombinant lactoferrin is intravenously administered to patients to inhibit tumor growth.
- rhLF at a dose of 500 mg per day for eight days to patients suffering from unresectable or metastatic cancer.
- rhLF is administered for one to eight days to patients suffering from metastatic cancer in daily doses of 0.1, 1, 10, 100, and 1000 mg.
- the dose is administered intravenously.
- Tumor size progression is monitored through CT scans and tumor markers where available.
- CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks.
- Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN- ⁇ .
- Recombinant lactoferrin is intravenously administered to patients to inhibit tumor growth either alone or in combination with standard anti-cancer regimens.
- rhLF is administered using the optimum regimen and doses identified in Example 15 and the standard anti-cancer regimen(s) for the selected tumor type is used as part of the combination therapy.
- the route of administration and regimen of the additional anti-cancer therapy is as approved by the FDA for that indication or as described in a peer reviewed publication.
- Tumor size progression is monitored through CT scans and tumor markers where available.
- CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks once treatment is initiated.
- Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN- ⁇ .
- O12 human oropharyngeal squamous cell carcinoma tumor cells were injected to the right flank of athymic nude mice.
- Recombinant human lactoferrin and vehicle controls were dosed via intratumoral injection.
- Each animal was administered different concentrations of rhLF in 50 ⁇ L doses consisting of four separate injections of approximately 12.5 ⁇ L of the dose, at different directions and angles (approximately S/N/E/W) to ensure that the dose was distributed evenly throughout the tumor (fanning).
- Table 13 shows the regimen followed for each experimental group and the dose of rhLF per injection for each animal per group.
- rhLF was administered directly into the tumor.
- Each animal was tracked daily for tumor growth by external caliper measurements of the protruding tumor.
- mice Normal C3H/HeJ mice were implanted with one of two mouse tumors following the methodology described in Example 17. Tumors used were SCCVII and RIF mouse tumor cell lines. Following establishment of the tumors in the mice, tumors were injected intratumorally daily for 4 days with 250 or 500 ⁇ g rhLF per dose or with vehicle control. Twenty four hours following the last intratumoral injection, animals were sacrificed and the blood examined for lymphocyte populations. The number of circulating lymphocytes were increased by 34% to 56% relative to the placebo treated control animals (Table 14).
- Tumor cells to be tested are injected into the right flank of athymic nude mice. Animals are administered rhLF intratumorally alone and in combination with other anti-cancer regimens as described in Example 1 or Example 17. Control animals are treated with only the vehicle; no rhLF is administered to the control animals.
- Anti-cancer therapy is administered using standard or published regimens. Therapy starts approximately 11 days after inoculation with tumor cells to allow formation of established tumors or at such other time as is generally done with standard or published regimens.
- the efficacy of individual and combination treatments are evaluated by measuring the solid tumor size during and at the end of the experiment; the body weights are also determined at the time of tumor measurements.
- Recombinant lactoferrin is intratumorally administered to patients to inhibit tumor growth.
- rhLF at a dose of 1000 ⁇ g per day for eight days to patients suffering from unresectable or metastatic cancer.
- rhLF is administered for one to eight days to patients suffering from metastatic cancer in daily doses of 10, 50, 100, 500 and 1000 ⁇ g.
- the dose is administered intratumorally.
- Tumor size progression is monitored through CT scans and tumor markers where available.
- CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks.
- Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN- ⁇ .
- Recombinant lactoferrin is intratumorally administered to patients to inhibit tumor growth either alone or in combination with standard anti-cancer regimens.
- rhLF is administered using the optimum regimen and doses identified in Example 20 and the standard anti-cancer regimen(s) for the selected tumor type is used as part of the combination therapy.
- the route of administration and regimen of the additional anti-cancer therapy is as approved by the FDA for that indication or as described in a peer reviewed publication.
- Tumor size progression is monitored through CT scans and tumor markers where available.
- CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks once treatment is initiated.
- Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN- ⁇ .
- Recombinant lactoferrin in a gel formulation is administered to patients to inhibit tumor growth.
- rhLF gel at strengths of 1%, 2.5% or 8.5% is applied twice a day to a skin or subcutaneous cancerous lesion in a patient with metastatic disease. Application of rhLF gel continues till tumor progression.
- CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks.
- Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN- ⁇ .
- Recombinant lactoferrin in a gel formulation is administered to patients to inhibit tumor growth either alone or in combination with standard anti-cancer regimens.
- rhLF is administered using the optimum regimen and doses identified in Examples 22 and the standard anti-cancer regimen(s) for the selected tumor type is used as part of the combination therapy.
- the route of administration and regimen of the additional anti-cancer therapy is as approved by the FDA for that indication or as described in a peer reviewed publication.
- CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks once treatment is initiated.
- Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN- ⁇ .
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Abstract
The present invention relates to methods of treating a hyperproliferative disease by administering a composition of lactoferrin alone or in combination with standard anti-cancer therapies.
Description
- This application claims priority to U.S. Provisional Application No. 60/379,442 filed on May 10, 2002; U.S. Provisional Application No. 60/379,441 filed on May 10, 2002 and U.S. Provisional Application No. 60/379,474 filed on May 10, 2002, which are incorporated herein by reference in their entirety.
- The present invention relates to methods of treating a hyperproliferative disease by administering a composition of lactoferrin alone or in combination with standard anti-cancer therapies. The lactoferrin composition may be administered orally, intravenously, intratumorally, or topically.
- Currently, there are few effective options for the treatment of many common cancer types. The course of treatment for a given individual depends on the diagnosis, the stage to which the disease has developed, and factors such as age, sex, and general health of the patient. The most conventional options of cancer treatment are surgery, radiation therapy, and chemotherapy. Surgery plays a central role in the diagnosis and treatment of cancer. Typically, a surgical approach is required for biopsy and the removal of cancerous growth. However, if the cancer has metastasized and is widespread, surgery is unlikely to result in a cure, and an alternate approach must be taken. Side effects of surgery include diminished structural or organ function and increased risk of infection, bleeding, or coagulation related complications. Radiation therapy, chemotherapy, biotherapy and immunotherapy are alternatives to surgical treatment of cancer (Mayer, 1998; Ohara, 1998; Ho et al., 1998). The disadvantage of many of the alternative therapies are the side effects, which can include myelosuppression, skin irritation, difficulty swallowing, dry mouth, nausea, diarrhea, hair loss, weight loss, and loss of energy (Curran, 1998; Brizel, 1998).
- Lactoferrin is a single chain metal binding glycoprotein. Many cells types, such as monocytes, macrophages, lymphocytes, and intestinal brush-border cells, are known to have lactoferrin receptors. In addition to lactoferrin being an essential growth factor for both B and T lymphocytes, lactoferrin has a wide array of functions related to host primary defense mechanisms. For example, lactoferrin has been reported to activate natural killer (NK) cells, induce colony stimulating activity, activate polymorphonuclear neutrophils (PMN), regulate granulopoeisis, enhance antibody-dependent cell cytotoxicity, stimulate lymphokine-activated killer (LAK) cell activity, and potentiate macrophage toxicity.
- Recently, bovine lactoferrin (bLF) was used as a prophylaxis for tumor formation and/or established tumors. The present invention is the first to use lactoferrin as a treatment, not a prophylaxis, for established tumors.
- The present invention is directed to a method for treating a hyperproliferative disease. The method of treatment involves oral, intravenous, topical and/or intratumoral administration of lactoferrin.
- A specific embodiment of the present invention is a method of treating a hyperproliferative disease comprising the step of administering orally to a subject a human lactoferrin composition in an amount sufficient to provide an improvement in the hyperproliferative disease in the subject. More specifically, the amount of the composition that is administered is about 1 mg to about 100 g per day, more preferabley 20 mg to about 10 g per day. A further embodiment includes administering an antacid in conjunction with the human lactoferrin composition.
- In specific embodiments, the human lactoferrin composition is dispersed in a pharmaceutically acceptable carrier. More specifically, the human lactoferrin is recombinant human lactoferrin.
- The hyperproliferative disease is further defined as cancer, in which the cancer comprises a neoplasm. The neoplasm is selected from the group consisting of melanoma, non-small cell lung, small-cell lung, lung hepatocarcinoma, retinoblastoma, astrocytoma, gliobastoma, leukemia, neuroblastoma, squamous cell, head, neck, gum, tongue, breast, pancreatic, prostate, renal, bone, testicular, ovarian, mesothelioma, sarcoma, cervical, gastrointestinal, lymphoma, brain, colon, and bladder. More specifically, the neoplasm is a hematopoietic neoplasm. For example, the hematopoietic neoplasm is selected from the group consisting of acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, juvenile myelomonocyte leukemia, multiple myeloma, and chronic lymphocytic leukemia.
- In further embodiments, the hyperproliferative disease is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, leiomyomas, adenomas, lipomas, hemangiomas, fibromas, vascular occlusion, restenosis, atherosclerosis, pre-neoplastic lesions, carcinoma in situ, oral hairy leukoplakia, and psoriasis.
- Another embodiment is a method of treating a hyperproliferative disease comprising the step of supplementing the mucosal immune system in a subject by increasing the amount of human lactoferrin in the gastrointestinal tract. The human lactoferrin is administered orally and stimulates the production of interleukin-18 and Granulocyte Macrophage Colony Stimulating Factor (GM-CSF).
- Still further, another embodiment is a method of enhancing a mucosal immune response in the gastrointestinal tract in a subject comprising the step of administering orally to the subject a human lactoferrin. The human lactoferrin stimulates interleukin-18 and CM-CSF in the gastrointestinal tract. IL-18 stimulates the production, maturation, migration or activity of immune cells, e.g., T lymphocytes or natural killer cells. T lymphocytes are selected from the group consisting of CD4+, CD8+ and CD3+ cells. GM-CSF also stimulates the production, maturation, migration or activity of immune cells, e.g. dendritic cells and other antigen presenting cells. A further embodiment includes treating a hyperproliferative disease comprising administering orally to a subject a human lactoferrin composition in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy. More particularly, the chemotherapy is a platinum based chemotherapy such as cisplatin or a taxane based chemotherapy such as docetaxel.
- Another embodiment is a method of reducing growth of a neoplasm in a subject comprising the step of administering orally to the subject a human lactoferrin composition in an amount sufficient to reduce the growth of the neoplasm in the subject. Still further, the lactoferrin composition may be administered in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy.
- Still further, another embodiment is a method of treating a hyperproliferative disease comprising the step of administering intravenously to a subject a lactoferrin composition in an amount sufficient to provide an improvement in the hyperproliferative disease. The amount of the composition that is administered is about 0.1 μg to about 10 g per day. More particularly, the lactoferrin is mammalian lactoferrin, for example, human or bovine, and the lactoferrin can be recombinant lactoferrin.
- Another embodiment comprises a method of treating a hyperproliferative disease comprising the step of supplementing a systemic immune system in a subject by increasing the amount of lactoferrin in the systemic circulation. The lactoferrin is administered intravenously. Still further, the lactoferrin composition is administered in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy.
- Still further, another embodiment is a method of enhancing a systemic immune response following the step of administering intravenously to the subject a lactoferrin composition. The lactoferrin stimulates interleukin-18 and GM-CSF. It is envisioned that interleukin-18 stimulates the production or activity of immune cells, for example T lymphocytes or natural killer cells and CM-CSF promotes the migration and maturation of immune cells including dendritic and other antigen presenting cells
- Still further, another embodiment is a method of treating a hyperproliferative disease comprising the step of administering topically to a subject a lactoferrin composition in an amount sufficient to provide an improvement in the hyperproliferative disease. The amount of the composition that is administered is about 0.1 μg to about 10 g per day. The composition may be a topical gel, a solution, capsule or a tablet having a lactoferrin concentration of about 0.01% to about 20%. More particularly, the lactoferrin is mammalian lactoferrin, for example, human or bovine, and the lactoferrin can be recombinant lactoferrin.
- Another embodiment is a method of treating a hyperproliferative disease by topically administering a lactoferrin composition in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy.
- Still further, another embodiment is a method of enhancing a local or systemic immune response following the step of administering topically to the subject a lactoferrin composition. The lactoferrin stimulates production of interleukin-18 and/or GM-CSF by the keratinocytes. It is envisioned that interleukin-18 stimulates the production or activity of immune cells, for example T lymphocytes or natural killer cells and GM-CSF promotes the migration and maturation of immune cells including dendritic and other antigen presenting cells.
- Yet further, another embodiment of the present invention is a method of stimulating, enhancing or up-regulating interleukin-18 and/or GM-CSF by administering a lactoferrin composition to a subject.
- 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. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims. The novel features which are believed to be characteristic of the invention, both as to its organization and method of operation, together with further objects and advantages will be better understood from the following description when considered in connection with the accompanying figures. It is to be expressly understood, however, that each of the figures is provided for the purpose of illustration and description only and is not intended as a definition of the limits of the present invention.
- For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawings.
-
FIG. 1 shows squamous cell tumor growth with and without oral, intravenous and intratumoral administration of recombinant human lactoferrin. -
FIG. 2 shows percent tumor growth inhibition in animals receiving lactoferrin, cisplatin and lactoferrin in combination with cisplatin. -
FIG. 3 shows the percent tumor growth inhibition with lactoferrin in combination with various doses of cisplatin. -
FIG. 4 shows the NK activity after treatment with lactoferrin. -
FIG. 5 shows squamous cell tumor growth with and without intratumoral administration of recombinant lactoferrin once or twice a day. - It is readily apparent to one skilled in the art that various embodiments and modifications can be made to the invention disclosed in this Application without departing from the scope and spirit of the invention.
- As used herein, the use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”
- The term “hyperproliferative disease” as used herein refers to any disease or disorder in which the cells proliferate more rapidly than normal tissue growth. Thus, a hyperproliferating cell is a cell that is proliferating more rapidly than normal cells.
- The term “parenteral administration” as used herein includes any form of administration in which the compound is absorbed into the subject without involving absorption via the intestines. Exemplary parenteral administrations that are used in the present invention include, but are not limited to intramuscular, intravenous, intraperitoneal, intratumoral, intraocular, or intraarticular administration.
- The term “intravenous administration” as used herein includes all techniques to deliver a lactoferrin composition to the systemic circulation via an intravenous injection or infusion.
- The term “intratumoral administration” as used herein includes all techniques to deliver a lactoferrin composition to the site of a tumor including injection, electroporation, creams, lotions or other forms of administration.
- The term “oral administration” as used herein includes oral, buccal, enteral or intragastric administration.
- The term “topical administration” as used herein includes application to a dermal, epidermal, subcutaneous or mucosal surface.
- The term “pharmaceutically acceptable carrier” as used herein includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well know in the art. Except insofar as any conventional media or agent is incompatible with the vectors or cells of the present invention, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.
- The term “lactoferrin” or “LF” as used herein refers to native or recombinant lactoferrin. Native lactoferrin can be obtained by purification from mammalian milk or colostrum or from other natural sources. Recombinant lactoferrin (rLF) can be made by recombinant expression or direct production in genetically altered animals, plants, fungi, bacteria, or other prokaryotic or eukaryotic species, or through chemical synthesis.
- The term “subject” as used herein, is taken to mean any mammalian subject to which the lactoferrin composition is administered according to the methods described herein. In a specific embodiment, the methods of the present invention are employed to treat a human subject. Another embodiment includes treating a human subject suffering from a hyperproliferative disease.
- The term “therapeutically effective amount” as used herein refers to an amount that results in an improvement or remediation of the symptoms of the disease or condition.
- The term “treating” and “treatment” as used herein refers to administering to a subject a therapeutically effective amount of a lactoferrin composition so that the subject has an improvement in the disease. The improvement is any improvement or remediation of the symptoms. The improvement is an observable or measurable improvement. Thus, one of skill in the art realizes that a treatment may improve the disease condition, but may not be a complete cure for the disease. Specifically, improvements in patients with cancer may include tumor stabilization, tumor shrinkage, increased time to progression, increased survival or improvements in the quality of life. Beneficial effect may also be reflected in an improvement of the patient's immune system as measured by the number and activity of circulating immune cells such as CD4+ cells, CD8+ cells, NK cells and CD40+ cells.
- The term “vicinity” as used herein refers to in or around the area or site of the tumor and/or hyperproliferative disease. For example, “vicinity of a tumor” may refer to the area in or around the tumor or margins of the tumor. Vicinity includes the area adjacent to the tumor, the area over the tumor, the area under the tumor, the margin area around the tumor, or the area adjacent the tumor margin area.
- The lactoferrin used according to the present invention can be obtained through isolation and purification from natural sources, for example, but not limited to mammalian milk. The lactoferrin is preferably mammalian lactoferrin, such as bovine or human lactoferrin. In preferred embodiments, the lactoferrin is human lactoferrin produced recombinantly using genetic engineering techniques well known and used in the art, such as recombinant expression or direct production in genetically altered animals, plants or eukaryotes, or chemical synthesis. See, i.e., U.S. Pat. Nos. 5,571,896; 5,571,697 and 5,571,691, which are herein incorporated by reference.
- Administration of the lactoferrin compositions according to the present invention will be via any common route, orally, parenterally, or topically. Exemplary routes include, but are not limited to oral, nasal, buccal, rectal, vaginal, intramuscular, intraperitoneal, intravenous, intraarterial, intratumoral or dermal. Such compositions would normally be administered as pharmaceutically acceptable compositions as described herein.
- The compositions of the present invention may be formulated in a neutral or salt form. Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. 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, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
- Sterile injectable solutions are prepared by incorporating the lactoferrin in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, 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. In the case of sterile powders for the preparation of sterile injectable solutions, 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.
- Further in accordance with the present invention, the inventive composition suitable for oral administration is provided in a pharmaceutically acceptable carrier with or without an inert diluent. The carrier should be assimilable or edible 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 lactoferrin preparation contained therein, its use in an orally administrable lactoferrin for use in practicing the methods of the present invention is appropriate. Examples of carriers or diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, binders, fillers and the like, or combinations thereof.
- In accordance with the present invention, the composition is combined with the carrier in any convenient and practical manner, i.e., by solution, suspension, emulsification, admixture, encapsulation, microencapsulation, absorption and the like. Such procedures are routine for those skilled in the art.
- In a specific embodiment of the present invention, the composition in powder form 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 through, i.e., denaturation in the stomach. Examples of stabilizers for use in an orally administrable composition include buffers, antagonists to the secretion of stomach acids, amino acids such as glycine and lysine, carbohydrates such as dextrose, mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc., proteolytic enzyme inhibitors, and the like. More preferably, for an orally administered composition, the stabilizer can also include antagonists to the secretion of stomach acids.
- Further, the composition for oral administration which is combined with a semi-solid or solid carrier can be further formulated into hard or soft shell gelatin capsules, tablets, or pills. More preferably, gelatin capsules, tablets, or pills are enterically coated. Enteric coatings prevent denaturation of the composition in the stomach or upper bowel where the pH is acidic. See, i.e., U.S. Pat. No. 5,629,001. Upon reaching the small intestines, the basic pH therein dissolves the coating and permits the composition to be released and absorbed by specialized cells, i.e., epithelial enterocytes and Peyer's patch M cells.
- In another embodiment, a powdered composition is combined with a liquid carrier such as, i.e., water or a saline solution, with or without a stabilizing agent.
- A specific formulation that may be used in the present invention is a solution of lactoferrin in a hypotonic phosphate based buffer that is free of potassium where the composition of the buffer is as follows: 6 mM sodium phosphate monobasic monohydrate, 9 mM sodium phosphate dibasic heptahydrate, 50 mM sodium chloride, pH 7.0±0.1. The concentration of lactoferrin in a hypotonic buffer may range from 10 microgram/ml to 100 milligram/ml. This formulation may be administered via any route of administration, for example, but not limited to intratumoral administration.
- Further, a composition for topical administration which is combined with a semi-solid carrier can be further formulated into a gel ointment. A preferred carrier for the formation of a gel ointment is a gel polymer. Preferred polymers that are used to manufacture a gel composition of the present invention include, but are not limited to carbopol, carboxymethyl-cellulose, and pluronic polymers. Specifically, a powdered lactoferrin composition is combined with an aqueous gel containing an polymerization agent such as Carbopol 980 at strengths between 0.5% and 5% wt/volume for application to the skin for treatment of hyperproliferative disease on or beneath the skin.
- Upon formulation, solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective to result in an improvement or remediation of the symptoms. The formulations are easily administered in a variety of dosage forms such as ingestible solutions, drug release capsules and the like. Some variation in dosage can occur depending on the condition of the subject being treated. The person responsible for administration can, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations meet sterility, general safety and purity standards as required by FDA Office of Biologics standards.
- In accordance with the present invention, a lactoferrin composition provided in any of the above-described pharmaceutical carriers is administered to a subject suspected of or having a hyperproliferative disease. One of skill in the art can determine the therapeutically effective amount of human lactoferrin to be administered to a subject based upon several considerations, such absorption, metabolism, method of delivery, age, weight, disease severity and response to the therapy.
- The route of administration will vary, naturally, with the location and nature of the lesion, and include, for example intradermal, transdermal, parenteral, intravenous, intramuscular, intranasal, subcutaneous, percutaneous, intratracheal, intraperitoneal, intratumoral, perfusion, lavage, direct injection, and oral administration.
- Oral administration of the lactoferrin composition includes oral, buccal, enteral or intragastric administration. It is also envisioned that the composition may be used as a food additive. For example, the composition is sprinkled on food or added to a liquid prior to ingestion.
- Intratumoral administration of the lactoferrin composition includes intratumoral injection, electroporation, or surgical or endoscopic implantation. Intratumoral injection, or injection into the tumor vasculature is specifically contemplated for discrete, solid, accessible tumors. Local, regional or systemic administration also may be appropriate.
- The hyperproliferative disease, includes but is not limited to neoplasms. A neoplasm is an abnormal tissue growth, generally forming a distinct mass that grows by cellular proliferation more rapidly than normal tissue growth. Neoplasms show partial or total lack of structural organization and functional coordination with normal tissue. These can be broadly classified into three major types. Malignant neoplasms arising from epithelial structures are called carcinomas, malignant neoplasms that originate from connective tissues such as muscle, cartilage, fat or bone are called sarcomas and malignant tumors affecting hematopoietic structures (structures pertaining to the formation of blood cells) including components of the immune system, are called leukemias, lymphomas and myelomas. A tumor is the neoplastic growth of the disease cancer. As used herein, a “neoplasm”, also referred to as a “tumor”, is intended to encompass hematopoietic neoplasms as well as solid neoplasms. Examples of neoplasms include, but are not limited to melanoma, non-small cell lung, small-cell lung, lung, hepatocarcinoma, retinoblastoma, astrocytoma, gliobastoma, gum, tongue, leukemia, neuroblastoma, head, neck, breast, pancreatic, prostate, renal, bone, testicular, ovarian, mesothelioma, sarcoma, cervical, gastrointestinal, lymphoma, brain, colon, bladder, myeloma, or other malignant or benign neoplasms.
- Other hyperproliferative diseases include, but are not limited to neurofibromatosis, rheumatoid arthritis, Waginer's granulomatosis, Kawasaki's disease, lupus erathematosis, midline granuloma, inflammatory bowel disease, osteoarthritis, leiomyomas, adenomas, lipomas, hemangiomas, fibromas, vascular occlusion, restenosis, atherosclerosis, pre-neoplastic lesions, carcinoma in situ, oral hairy leukoplakia, or psoriasis, and pre-leukemias, anemia with excess blasts, and myelodysplastic syndrome.
- Particular neoplasms of interest in the present invention include, but are not limited to hematopoietic neoplasms. For example, a hematopoietic neoplasm may include acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, juvenile myelomonocyte leukemia, multiple myeloma, chronic lymphocytic leukemia or other malignancy of hematologic origin.
- In a preferred embodiment of the present invention, the lactoferrin compositions are administered in an effective amount to decrease, reduce, inhibit or abrogate the growth of a tumor. The amount may vary from about 0.1 μg to about 100 g of the lactoferrin composition. Preferably, the lactoferrin composition is orally administered in the range of 1mg to 100 g per day, more preferably about 20 mg to about 10 g per day with the most preferred dose being 4.5 g per day. Intravenously administered lactoferrin can be in the range of 0.1 μg to about to 10 g per day, more preferably about 0.1 μg to about 1 mg with the most preferred dose being 250 mg per day. Preferably, a lactoferrin composition is intratumorally administered in the range of 0.1 μg to 10 g per day with the most preferred dose being 100 μg per day. Topically, the amount of lactoferrin may vary from about 1 μg to about 100 g of lactoferrin. Preferably, the topical gel, solution, capsule or tablet comprises a lactoferrin concentration of about 0.01% to about 20%. More preferably, the topical gel, solution, capsule or tablet may comprise a lactoferrin concentration of about 1% to about 8.5%.
- Treatment regimens may vary as well, and often depend on tumor type, tumor location, disease progression, and health and age of the patient. Obviously, certain types of tumor will require more aggressive treatment, while at the same time, certain patients cannot tolerate more taxing protocols. The clinician will be best suited to make such decisions based on the known efficacy and toxicity (if any) of the therapeutic formulations.
- In certain embodiments, the tumor being treated may not, at least initially, be resectable. Treatments with the lactoferrin composition may increase the resectability of the tumor due to shrinkage at the margins or by elimination of certain particularly invasive portions. Following treatments, resection may be possible. Additional treatments subsequent to resection will serve to eliminate microscopic residual disease at the tumor site.
- Alternatively, the present invention may be used at the time of surgery, and/or thereafter, to treat residual or metastatic disease. For example, a resected tumor bed may be injected or perfused with a formulation comprising the lactoferrin composition. The perfusion may be continued post-resection, for example, by leaving a catheter implanted at the site of the surgery. Periodic post-surgical treatment is also envisioned.
- Continuous administration also may be applied where appropriate, for example, where a tumor is excised and the tumor bed is treated to eliminate residual, microscopic disease. Delivery via syringe or catherization is preferred. Such continuous perfusion may take place for a period from about 1-2 hours, to about 6-12 hours, to about 12-24 hours, to about 1-2 days, to about 1-2 weeks or longer following the initiation of treatment. Generally, the dose of the therapeutic composition via continuous perfusion will be equivalent to that given by a single or multiple injections, adjusted over a period of time during which the perfusion occurs. It was further contemplated that limb perfusion may be used to administer therapeutic compositions of the present invention, particularly in the treatment of melanomas and sarcomas.
- In specific embodiments, the lactoferrin composition is given in a single dose or multiple doses. The single dose may be administered daily, or multiple times a day, or multiple times a week, or monthly or multiple times a month. In a further embodiment, the lactoferrin composition is given in a series of doses. The series of doses may be administered daily, or multiple times a day, weekly, or multiple times a week, or monthly, or multiple times a month.
- A further embodiment of the present invention is a method of treating a hyperproliferative disease comprising the step of supplementing a mucosal immune system by increasing the amount of lactoferrin in the gastrointestinal tract. Preferably, the lactoferrin is administered orally.
- Still yet, a further embodiment is a method of enhancing a mucosal immune response in the gastrointestinal tract in a subject comprising the step of administering orally to said subject a lactoferrin composition, preferably human lactoferrin. It is envisioned that lactoferrin stimulates interleukin-18 and GM-CSF in the gastrointestinal tract, which enhance immune cells. For example, interleukin-18 enhances T lymphocytes or natural killer cells and GM-CSF promotes maturation and migration of immune cells including dendritic and other antigen presenting cells. In specific embodiments, interleukin-18 (IL-18) enhances CD4+, CD8+ and CD3+ cells. It is known by those of skill in the art that IL-18 is a Thi cytokine that acts in synergy with interleukin-12 and interleukin-2 in the stimulation of lymphocyte IFN-gamma production. Other cytokines may also be enhanced for example, but not limited to IL-1b or, IL-12 or IFN-gamma. It is also envisioned that lactoferrin stimulates interleukin-18 following oral administration, which inhibits angiogenesis and thereby has activity against tumor cells which are dependent on neovascularization.
- A further embodiment of the present invention is a method of treating a hyperproliferative disease comprising the step of supplementing the systemic immune system by increasing the amount of lactoferrin in the systemic circulation. Preferably, the lactoferrin composition is administered intravenously. It is envisioned that lactoferrin stimulates interleukin-18 and GM-CSF in the tissue, which enhance immune cells. For example, interleukin-18 enhances T lymphocytes or natural killer cells and GM-CSF promotes maturation and migration of immune cells including dendritic and other antigen presenting cells. In specific embodiments, interleukin-18 (IL-18) enhances CD4+, CD8+ and CD3+ cells. It is known by those of skill in the art that IL-18 is a Th1 cytokine that acts in synergy with interleukin-12 and interleukin-2 in the stimulation of lymphocyte IFN-gamma production. Other cytokines may also be enhanced for example, but not limited to IL-1b or, IL-12 or IFN-gamma. It is also envisioned that lactoferrin stimulates interleukin-18 following intravenous administration, which inhibits angiogenesis and thereby has activity against tumor cells which are dependent on neovascularization.
- A further embodiment of the present invention is a method of treating a hyperproliferative disease comprising the step of supplementing a local or systemic immune system by increasing the amount of lactoferrin in the vicinity of the tumor. Vicinity of the tumor refers to the general area of the tumor, for example the lactoferrin can be administered directly into or on the tumor, or in the general area of the tumor, but not directly into the tumor. The general area may include the margin area or near or adjacent the margin area of the tumor. Preferably, the lactoferrin composition is administered intratumorally. It is envisioned that lactoferrin stimulates interleukin-18 and GM-CSF in the local tissue, which enhances immune cells. For example, interleukin-18 enhances T lymphocytes or natural killer cells and GM-CSF promotes maturation and migration of immune cells including dendritic and other antigen presenting cells. In specific embodiments, interleukin-18 (IL-18) enhances CD4+, CD8+ and CD3+ cells. It is known by those of skill in the art that IL-18 is a Th1 cytokine that acts in synergy with interleukin-12 and interleukin-2 in the stimulation of lymphocyte IFN-gamma production. Other cytokines may also be enhanced for example, but not limited to IL-1b or, IL-12 or IFN-gamma. It is also envisioned that lactoferrin stimulates interleukin-18 following intratumoral administration, which inhibits angiogenesis and thereby has activity against tumor cells which are dependent on neovascularization.
- A further embodiment of the present invention is a method of treating a hyperproliferative disease comprising the step of supplementing a local or systemic immune system by increasing the amount of lactoferrin in the skin in the vicinity of the tumor. Preferably, the lactoferrin composition is administered topically. As above, administration in the vicinity of the tumor includes administration near or adjacent to the margins of the tumor or directly in the margin area of the tumor. It is envisioned that lactoferrin stimulates interleukin-18 and GM-CSF in the local tissue (e.g., keratinocytes), which enhances immune cells. For example, interleukin-18 enhances T lymphocytes or natural killer cells and GM-CSF promotes maturation and migration of immune cells including dendritic and other antigen presenting cells. In specific embodiments, interleukin-18 (IL-18) enhances CD4+, CD8+ and CD3+ cells. It is known by those of skill in the art that IL-18 is a Th1 cytokine that acts in synergy with interleukin-12 and interleukin-2 in the stimulation of lymphocyte IFN-gamma production. Other cytokines may also be enhanced for example, but not limited to IL-1b or, IL-12 or IFN-gamma. It is also envisioned that lactoferrin stimulates interleukin-18 following intratumoral administration, which inhibits angiogenesis and thereby has activity against tumor cells which are dependent on neovascularization.
- In order to increase the effectiveness of the human lactoferrin composition of the present invention, it may be desirable to combine the composition of the present invention with other agents effective in the treatment of hyperproliferative disease, such as anti-cancer agents, or with surgery. 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 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. Anti-cancer agents include biological agents (biotherapy), chemotherapy agents, and radiotherapy agents. More generally, these other compositions would be provided in a combined amount effective to kill or inhibit proliferation of the cell. This process may involve administering the human lactoferrin composition of the present invention and the agent(s) or multiple factor(s) at the same time. This may be achieved by administering a single composition or pharmacological formulation that includes both agents, or by administering two distinct compositions or formulations, at the same time, or at times close enough so as to result in an overlap of this effect, wherein one composition includes the human lactoferrin composition and the other includes the second agent(s).
- Alternatively, the lactoferrin composition of the present invention may precede or follow the other anti-cancer agent treatment by intervals ranging from minutes to weeks. In embodiments where the other anti-cancer agent and lactoferrin composition are administered or 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 lactoferrin composition would still be able to exert an advantageously combined effect on the cell. In such instances, it is contemplated that one may contact the cell with/administer both modalities within about 1-14 days of each other and, more preferably, within about 12-24 hours of each other. In some situations, it may be desirable to extend the time period for treatment significantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations.
- 1. Chemotherapy
- Cancer therapies also include a variety of chemical based treatments. Some examples of chemotherapeutic agents include without limitation antibiotic chemotherapeutics such as Doxorubicin, Daunorubicin, Adriamycin, Mitomycin (also known as mutamycin and/or mitomycin-C), Actinomycin D (Dactinomycin), Bleomycin, Plicomycin, plant alkaloids such as Taxol, Vincristine, Vinblastine, miscellaneous agents such as platinum based agents (e.g., Cisplatin (CDDP)), etoposide (VP16), Tumor Necrosis Factor, and alkylating agents such as, Carmustine, Melphalan (also known as alkeran, L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, (a phenylalanine derivative of nitrogen mustard), Cyclophosphamide, Chlorambucil, Busulfan (also known as myleran), taxane based agents (e.g., docetaxel) and Lomustine.
- Some examples of other agents include, but are not limited to, Carboplatin, Procarbazine, Mechlorethamine, Irinotecan, Topotecan, Ifosfamide, Nitrosurea, Etoposide (VP16), Tamoxifen, Raloxifene, Toremifene, Idoxifene, Droloxifene, TAT-59, Zindoxifene, Trioxifene, ICI 182,780, EM-800, Estrogen Receptor Binding Agents, Gemcitabinen, Navelbine, Farnesyl-protein transferase inhibitors, Transplatinum, 5-Fluorouracil, hydrogen peroxide, and Methotrexate, Temazolomide (an aqueous form of DTIC), Mylotarg, Dolastatin-10, Bryostatin, or any analog or derivative variant of the foregoing.
- 2. Radiotherapeutic Agents
- Radiotherapeutic agents and factors include radiation and waves that induce DNA damage for example, 7-irradiation, X-rays, UV-irradiation, microwaves, electronic emissions, radioisotopes, and the like. Therapy may be achieved by irradiating the localized tumor site with the above described forms of radiations. It is most likely that all of these factors effect a broad range of damage to DNA, the precursors of DNA, the replication and repair of DNA, and the assembly and maintenance of chromosomes.
- Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 weeks), 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.
- 3. Surgery
- Approximately 60% of persons with cancer will undergo surgery of some type, which includes preventative, diagnostic or staging, curative and palliative 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. In addition to tumor resection, treatment by surgery includes laser surgery, cryosurgery, electrosurgery, 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.
- Upon excision of part of all of cancerous cells, tissue, or tumor, 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.
- 4. Other Biotherapy Agents
- It is contemplated that other biological agents may be used in combination with the present invention to improve the therapeutic efficacy of treatment. These additional agents include, without limitation, agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers, or other biological agents, as well as biotherapy such as for example, hyperthermia.
- Hyperthermia is a procedure in which a patient's tissue is exposed to high temperatures (up to 106° F.). External or internal heating devices may be involved in the application of local, regional, or whole-body hyperthermia. Local hyperthermia involves the application of heat to a small area, such as a tumor. Heat may be generated externally with high-frequency waves targeting a tumor from a device outside the body. Internal heat may involve a sterile probe, including thin, heated wires or hollow tubes filled with warm water, implanted microwave antennae, or radiofrequency electrodes.
- A patient's organ or a limb is heated for regional therapy, which is accomplished using devices that produce high energy, such as magnets. Alternatively, some of the patient's blood may be removed and heated before being perfused into an area that will be internally heated. Whole-body heating may also be implemented in cases where cancer has spread throughout the body. Warm-water blankets, hot wax, inductive coils, and thermal chambers may be used for this purpose.
- Hormonal therapy may also be used in conjunction with the present invention. 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 and this often reduces the risk of metastases.
- Adjuvant therapy may also be used in conjunction with the present invention. The use of adjuvants or immunomodulatory agents include, but are not limited to tumor necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; F42K and other cytokine analogs; or MIP-1, MIP-1beta, MCP-1, RANTES, and other chemokines.
- 5. Immunotherapy
- 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. Alternatively, 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.
- It is contemplated that vaccines that are used to treat cancer may be used in combination with the present invention to improve the therapeutic efficacy of the treatment. Such vaccines include peptide vaccines or dendritic cell vaccines. Peptide vaccines may include any tumor-specific antigen that is recognized by cytolytic T lymphocytes. Yet further, one skilled in the art realizes that dendritic cell vaccination comprises dendritic cells that are pulsed with a peptide or antigen and the pulsed dendritic cells are administered to the patient.
- Examples of tumor-specific antigens that are being used as vaccines in melanoma include, but are not limited to gp100 or MAGE-3. These antigens are being administered as peptide vaccines and/or as dendritic cell vaccines.
- The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
- Human squamous cell carcinoma (O12) was used. The cells were injected into the right flank of athymic nude mice. rhLF was administered either intratumorally (49 animals, 7 doses ranging from 0.05 μg to 125 μg per dose), intravenously (7 animals, 125 ug/dose) or orally (7
animals 20 mg/dose). Control animals were treated with only the vehicle; no rhLF was administered to the control animals. rhLF was administered twice a day for either five days (intravenous group) or eight days (all other groups) starting 11 days after inoculation with tumor cells to allow formation of established tumors. - The efficacy of treatment was evaluated by measuring the solid tumor size during and at the end of the experiment; the body weights were also determined at the time of tumor measurements. As seen in
FIG. 1 and Table 1, treatment with rhLF reduced rates of tumor growth relative to the control by 46% to 80%. In fact, oral treatment with 20 mg rhLF most significantly reduced the tumor growth, by 80% compared to the control (p=0.0073). -
TABLE 1 Summary of tumor growth inhibition by rhLF in O12 tumor model in mice Inhibition Relative to Placebo P value Day 19* Day 28*Day 19* Day 28*Intratumoral 28% 46% 0.139 0.0263** N = 49 Intravenous 55% 65% 0.0666 0.0233** N = 7 Oral 76% 80% 0.0175** 0.0073*** N = 7 *following start of treatment **statistically significant (p < 0.05) ***highly statistically significant (p < 0.01) - Results from this study showed that rhLF administered by multiple routes significantly inhibited tumor growth in a squamous cell tumor model in mice, with oral administration being the most effective. Based upon these results, it was further contemplated that oral lactoferrin affects the tumor by enhancing immune cell activity.
- Tumor cells from a broad range of tumor types are injected into the right flank of athymic nude mice. Animals are administered either rhLF, native hLF or bovine LF orally. Control animals are treated with only the vehicle, no rhLF is administered to the control animals. rhLF is administered either once or twice a day for either one, five, seven or fourteen days or eight days starting approximately eleven days after inoculation with tumor cells to allow formation of established tumors or at such other time as is generally done with standard or published regimens.
- The efficacy of treatment is evaluated by measuring the solid tumor size during and at the end of the experiment; the body weights are also determined at the time of tumor measurements. The immune response is measured by measuring the amount of cytokines, T-cells and NK cells in circulation and in the intestine.
- Recombinant human lactoferrin and bovine lactoferrin were orally administered to mice, and the production of IL-18 in the small intestine was measured.
- Mice were treated for three days daily with 65 mg/kg/day of rhLF, 300 mg/kg/day of rhLF or 300 mg/kg/day of bLF. For a control, mice were only administered the pharmaceutical carrier. Twenty-four hours following administration of the LF or control for 3 days, animals were weighed and blood and serum were collected. Serum was used for cytokine ELISA assays.
- Also, at these time points, animals were sacrificed and the small intestinal tissue was removed for further analysis. Small intestinal epithelium was homogenized using a lysis buffer consisting of PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulphate containing 10 μg/ml PhenylMetheylsulfonyl fluoride. Homogenate was centrifuged at 15,000 rpm for 10 minutes and the supernatant stored at −80 C till it was tested for IL-18 levels.
- As seen in Table 2 and Table 3, administration of rhLF at both doses significantly enhanced the amounts of IL-18 in both the serum and in the intestinal extract. Bovine LF caused a lesser increase in the intestinal IL-18 levels and did not increase the serum levels of IL-18.
-
TABLE 2 Effect of rhLF and bLF on IL-18 levels in the gut and serum Intestinal Extract (pg) Serum (pg) Control 955 141 300 mg/kg bLF 4,515 134 65 mg/kg rhLF 7,879 259 300 mg/kg rhLF 8,350 328 -
TABLE 3 Stimulation by rhLF and bLF of IL-18 levels in the gut and serum Intestinal Extract Serum % Increase P-value % Increase P-value Increase Over Control 300 mg/kg bLF 373% 0.0086 −5% 0.5411 65 mg/kg rhLF 725% 0.0034 84% 0.0132 300 mg/kg rhLF 775% 0.0001 132% 0.0007 Increase Over Blf 65 mg/kg rhLF 75% 0.1490 94% 0.0366 300 mg/kg rhLF 85% 0.0617 145% 0.0084 - Balb/c naïve mice were treated orally with rhLF or placebo once a day for 3 days (see Table 4).
-
TABLE 4 Treatment Regimen Treatment* N Dose (mg/kg) Route Schedule Group 1 Placebo 6 0 — — Group 2RhLF 7 300 mg/kg/day Oral 3 days - On
day 4, mice were sacrificed and spleens were collected. NK cells were separated using a magnetic bead cell sorting assay (MACS anti-NK—DX5) and counted. Cells were then tested in vitro for NK-activity against YAC targets using a lactate dehydrogenase (LDH) release test. - Table 5 shows that oral rhLF treatment resulted in a significant increase of NK activity ex-vivo against YAC-target cells (10% @ 30:1 versus 2.8% of ctrl group). No significant change in NK activity was observed in placebo treated mice.
-
TABLE 5 NK activity in mice treated with oral rhLF Control Low Medium High 0.056 0.09 0.407 Placebo RhLF-treated Raw data Raw data E:T E E:T E % Cytotoxicity* E:T cell cell % Cytotoxicity* cell cell Increased ratio mix ctrl Final mix ctrl Final over ctrl 30:1 0.281 0.215 2.86 0.358 0.267 9.81 7** 15:1 0.176 0.110 2.85 0.214 0.143 4.12 1.3 7.5:1 0.117 0.054 2.21 0.131 0.074 0.44 0 3.7:1 0.086 0.030 0.19 0.096 0.042 0 0 *% Cytotoxicity = [(Effector:target cell mix − effectors cell ctrl)] − low ctrl/[(high ctrl − low ctrl)] × 100 **p < 0.05 ((2-tailed p value) - Recombinant human lactoferrin or placebo were orally administered to mice, and the production of GM-CSF in the small intestine was measured.
- Mice (5 animals per group) were treated for three days daily with 300 mg/kg/day of rhLF. For a control, mice were only administered the pharmaceutical carrier. Twenty-four hours following administration of the LF or placebo for 3 days, animals were and the small intestinal tissue was removed for further analysis. Small intestinal epithelium was homogenized using a lysis buffer consisting of PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulphate containing 10 μg/ml PhenylMetheylsulfonyl fluoride. Homogenate was centrifuged at 15,000 rpm for 10 minutes and the supernatant stored at −80 C till it was tested for GM-CSF levels using an ELISA kit.
- As shown in Table 6, treatment with rhLF increased the production of a key immunostimulatory cytokine, GM-CSF, in the small intestine relative to the placebo treated animals.
-
TABLE 6 Effect of rhLF on GM-CSF levels in the gut and serum Mean (SEM) in pg Increase over Placebo Placebo 6.48 (0.32) — 300 mg/kg rhLF 7.74 (0.19) 19.4% (p < 0.01) - A murine squamous carcinoma cell line (SCCVII) was injected into the floor of the mouth through the neck skin of immunocompetent C3H mice (Day 0). Five days after tumor cell implantation (Day 5), a skin incision was made in the lower neck and surgical dissection revealed the established tumors. Tumors were measured in three dimensions with calipers.
- Tumor-bearing mice were randomized into a control group and seven groups receiving rhLF and/or cisplatin. RhLF (4 mg; 200 mg/Kg) was administered once daily by oral gavage for 8 days on
days 5 through 12. Cisplatin was administered as a single dose of 5 mg/Kg given intraperitoneally either at the start of rhLF (day 5), in the middle (day 8) or at the end (day 12) of rhLF therapy. Animals were sacrificed onday 12 post-implantation and the residual tumor masses were measured and processed for later additional analyses. -
TABLE 7 Experimental Groups Description N RhLF mg/kg Cisplatin Group A Placebo 5 0 (Placebo) 0 Group B RhLF Alone 5 200 mg/ kg 0 Group C CP Day 5 5 0 5 mg/kg on day 5*Group D CP Day 8 5 0 5 mg/kg on day 8*Group E CP Day 12 4 0 5 mg/kg on day 12Group F RhLF/CP-5 5 200 mg/ kg 5 mg/kg on day 5*Group G RhLF/CP-8 5 200 mg/ kg 5 mg/kg on day 8*Group H RhLF/CP-12 5 200 mg/ kg 5 mg/kg on day 12* - Mice treated either with rhLF alone, cisplatin alone or both agents, showed a tumor growth inhibition (TGI) relative to the placebo animals. The maximum inhibition was observed in the group receiving both therapies (Table 7 and
FIG. 2 ). - In all cases, the animals receiving rhLF+cisplatin showed a TGI relative to the relevant group receiving cisplatin alone. When pooled for analysis, animals receiving rhLF+cisplatin showed a 77% TGI relative to the placebo animals (P<0.0001), a 66% TGI relative to rhLF alone (P<0.01) and a 63% TGI relative to cisplatin alone (P<0.01).
- Cisplatin dosing immediately prior to the start of rhLF (RhLF+CP-5) or during the period of rhLF administration (RhLF+CP-8) provided greater incremental benefit than when cisplatin was administered following completion of rhLF therapy (RhLF+CP-12). However, only the straddling regimen (RhLF+CP-8) provided a statistically significant improvement (P<0.01) TGI of 77% over cisplatin alone (CP Day 8).
-
TABLE 8 Tumor Growth Inhibition (TGI) by Treatment Group Growth Relative to Placebo* Group (SEM) TGI (%) P-value A (Placebo) 741 (79) — — B (RhLF alone) 496 (155) 33% 0.0989 C (CP Day 5) 240 (137) 68% 0.0066 D (CP Day 8) 693 (146) 6% 0.3898 E (CP Day 12) 433 (175) 42% 0.0634 F (RhLF + CP-5) 14 (5) 98% <0.0001 G (RhLF + CP-8) 159 (48) 79% 0.0001 H (RhLF + CP-12) 331 (47) 55% 0.0011 C to E (All CP) 457 (96) 38% 0.0564 F to H (All 168 (40) 77% <0.0001 rhLF/CP) *Inhibition and 1-tailed P-value relative to the placebo group **Inhibition and 1-tailed P-value compared to the respective Cisplatin groups - A murine squamous carcinoma cell line (SCCVII) was injected into the floor of the mouth through the neck skin of immunocompetent C3H mice (Day 0) as described in Example 6. On
Day 5 days after initial implantation, tumors were measured for the baseline, then treated with either cisplatin (Day 8, i.p., 5 mg/kg) alone or cisplatin plus three doses of oral rhLF (daily by gavage for 7-8 days ondays 5 through 11/12). Animals were sacrificed onDay 11/12 and tumors measured. There was a dose dependent inhibition of tumor growth in the animals receiving both rhLF and cisplatin as compared to the animals receiving cisplatin alone as shown inFIG. 3 . - A murine squamous carcinoma cell line (SCCVII) was injected into the floor of the mouth through the neck skin of immunocompetent C3H mice (Day 0) as described in Example 7. On
Day 5 after initial implantation, tumors were measured for the baseline, then treated with either oral placebo alone (once daily fromdays 5 to 12; 6 animals), placebo and docetaxel (i.v. bolus of 31.3 mg/kg docetaxel onDay 8; 9 animals), or docetaxel plus oral rhLF (200 mg/kg, administered once daily by gavage fromdays 5 to 12; 9 animals). Animals were sacrificed onDay 14 and tumors measured. Docetaxel alone caused an inhibition of tumor growth relative to placebo and the combination of rhLF and docetaxel induced a further growth inhibition. Inhibition and p-values (1-tailed) are shown in Table 9. -
TABLE 9 Tumor Growth Inhibition (TGI) by Treatment Group Relative Growth to Placebo* Relative to Docetaxel Group (SEM) TGI (%) P-value TGI (%) P-value Placebo 5,157 — — — — (497) Docetaxel 2,103 59% <0.0001 — — (209) Docetaxel + rhLF 1,288 75% <0.0001 39% 0.0175 (286) - A murine squamous carcinoma cell line (SCCVII) was injected into the floor of mouth through the neck skin of immunocompetent C3H mice (Day 0). Five days after tumor cell implantation (Day 5), a skin incision was made in the lower neck and surgical dissection revealed the established tumors. Tumors were measured in three dimensions with calipers.
- Tumor-bearing mice were randomized into six groups receiving rhLF (200 mg/Kg) and/or radiotherapy as described below. RhLF (4 mg; 200 mg/kg) was administered by oral gavage once daily for 8 days on
days 5 through 12. Radiotherapy was administered as single dose of 2 Gray given at the beginning (day 5) or at during (day 8) rhLF-therapy. Animals were sacrificed onday 14 post-treatment and the residual tumor masses were measured and processed for later additional analyses. -
TABLE 10 Experimental Groups Description N RhLF mg/kg* Radiation Group A Placebo 10 0 (Placebo) None Group B RhLF Alone 10 200 mg/kg None Group C Radiation Day 5 8 0 2 Gray on day 5Group D RhLF/ Rad 510 200 mg/ Kg 2 Gray on day 5Group E Radiation Day 8 10 0 2 Gray on day 8Group F RhLF/ Rad 810 200 mg/ kg 2 Gray on day 8*RhLF/placebo was administered once daily by oral gave from Days 5 to 12. - Mice receiving rhLF alone, radiotherapy alone, or combination therapy showed a significant tumor growth inhibition (TGI) relative to placebo treated mice. The mice receiving both rhLF and radiation showed a modest increase in TGI over monotherapy with rhLF (28%, P<0.05) and radiation (15%, P=0.1207).
-
TABLE 11 Tumor Growth Inhibition (TGI) by Treatment Group: Growth Relative to Placebo Group (SEM) Inhibition* P-value* A (Placebo) 2348 (395) — B (rhLF alone) 1074 (163) 54% 0.0040 C (Radiation Day 5) 827 (105) 65% 0.0021 D (rhLF/Rad 5) 750 (125) 68% 0.0006 E (Radiation Day 8) 977 (112) 58% 0.0018 F (rhLF/Rad 8) 797 (119) 66% 0.0007 C/E (Both Radiation) 911 (78) 61% <0.0001 D/F (Both rhLF/Rad) 774 (84) 67% <0.0001 *Inhibition and 1-tailed P-value compared to the placebo group - Thus, lactoferrin stimulated the immune system. Still further, lactoferrin in combination with cisplatin, docetaxel and/or radiation resulted in inhibition of tumor growth.
- Recombinant human lactoferrin was orally administered to human patients with a range of metastatic cancer types that had failed standard chemotherapy in two different studies conducted in multiple centers in four countries (Argentina, Brazil, Chile, U.S.) RhLF was administered at doses of 1.5 to 9 grams daily in two divided doses in cycles of 14 each with a 14 day gap.
- Tumor size progression was monitored through CT scans and tumor markers where available. CT scans were performed at baseline and after each 8-week period once treatment was initiated, and also compared with a pre-baseline scan conducted prior to enrollment in the study. Tumor markers are measured every 4 weeks. Blood samples were collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples were collected to measure circulating IL-18, IL-1, IL-2, and IL-4, IL-5, IL-10, IL-12 and IFN-γ.
- Out of nineteen evaluable patients (those with a baseline CT scan and at least one post-treatment scan), nine patients (47%) exhibited stable disease by the RECIST criteria at the time of the first post-treatment scan. Patients with a broad range of tumor types showed a benefit from lactoferrin administration.
- Table 12 shows the tumor response of five individual patients with different tumor types. In all cases, the percent growth of the tumor size prior to treatment of rhLF (the relevant duration of time is shown in parentheses) and the growth of the tumor in the ensuing two time periods, as measured by CT, showed a diminution in their rate of tumor growth or an actual shrinkage.
-
TABLE 12 Tumor Response of Patients Receiving Oral rhLF for treatment of Metastatic Cancer Pretreatment Post Treatment 1 Post Treatment 2 % Growth % Growth % Growth Patient# Cancer (Weeks) (Weeks) (Weeks) # 204 Breast 40% (8) 0% (10) 0% (6.5) # 106 Melanoma 24% (19) −18% (11) Not yet done # 104 Gastric 25% (5.5) 10% (10) −5% (7) # 102 Ovarian 30% (21) −5% (10.5) −7% (8.5) # 007 Lung 160% (5.5) 13% (7.5) 12% (8.5) - Recombinant human lactoferrin is orally administered to human patients to inhibit tumor growth either alone or in combination with standard anti-cancer regimens.
- Briefly, rhLF is administered using the optimum regimen and doses identified in Example 10 and the standard anti-cancer regimen(s) for the selected tumor type is used as part of the combination therapy. The route of administration and regimen of the additional anti-cancer therapy is as approved by the FDA for that indication or as described in a peer reviewed publication.
- Tumor size progression is monitored through CT scans and tumor markers where available. CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks once treatment is initiated. Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, and IL-12 and IFN-γ.
- Balb/c naïve mice were treated orally with rhLF or placebo once a day for 3 days. One day later (day 4), mice were sacrificed and spleens collected. NK cells were separated using a magnetic bead cell sorting assay (MACS anti-NK—DX5) and counted. Cells were then tested in vitro for NK-activity against YAC targets using a lactate dehydrogenase (LDH) release test.
- As shown in
FIG. 4 , oral rhLF treatment resulted in a significant increase of NK activity ex-vivo against YAC-target cells. At a 30:1 E:T ratio rhLF administration resulted in a 243% relative increase over placebo-treated animals (from 2.86% to 9.81%; p<0.05). - Recombinant lactoferrin, bovine lactoferrin and native lactoferrin are intravenously administered to animals, preferably rats, and the production of IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-gamma in the plasma, serum and blood packed cells are measured.
- Briefly, rats are treated for fourteen consecutive days with 0.05 μg to 1000 μg per dose. For a control, rats are only administered the pharmaceutical carrier. At specific time points following administration of the LF or control for 0 days, 2 days, 3 days, 5 days, 9 days and 14 days, animals are weighed and blood and serum are collected. The levels of CD4+, CD8+ and NK cells are counted from the blood that was collected. Plasma, serum and an extract of the blood cells are used for cytokine ELISA assays.
- Also, at 24 day time point, animals are sacrificed and tissues are removed for further analysis. Tissues are homogenized using a lysis buffer consisting of PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulphate containing 10 μg/ml PhenylMetheylsulfonyl fluoride. Homogenate is centrifuged at 15,000 rpm for 10 minutes and the supernatant stored at −80 C till it is tested for the cytokines IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-gamma.
- Tumor cells to be tested are injected into the right flank of athymic nude mice. Animals are administered rhLF intravenously alone and in combination with other anti-cancer regimens as described in Example 13. Control animals are treated with only the vehicle; no rhLF is administered to the control animals. rhLF is administered using regimens identified as being optimal in the trials described in Example 13. Anti-cancer therapy is administered using standard or published regimens. Therapy starts approximately 11 days after inoculation with tumor cells to allow formation of established tumors or at such other time as is generally done with standard or published regimens.
- The efficacy of individual and combination treatments are evaluated by measuring the solid tumor size during and at the end of the experiment; the body weights are also determined at the time of tumor measurements.
- Recombinant lactoferrin is intravenously administered to patients to inhibit tumor growth.
- Briefly, rhLF at a dose of 500 mg per day for eight days to patients suffering from unresectable or metastatic cancer. Alternatively, rhLF is administered for one to eight days to patients suffering from metastatic cancer in daily doses of 0.1, 1, 10, 100, and 1000 mg. The dose is administered intravenously.
- Tumor size progression is monitored through CT scans and tumor markers where available. CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks. Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ.
- Recombinant lactoferrin is intravenously administered to patients to inhibit tumor growth either alone or in combination with standard anti-cancer regimens.
- Briefly, rhLF is administered using the optimum regimen and doses identified in Example 15 and the standard anti-cancer regimen(s) for the selected tumor type is used as part of the combination therapy. The route of administration and regimen of the additional anti-cancer therapy is as approved by the FDA for that indication or as described in a peer reviewed publication.
- Tumor size progression is monitored through CT scans and tumor markers where available. CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks once treatment is initiated. Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ.
- O12 human oropharyngeal squamous cell carcinoma tumor cells were injected to the right flank of athymic nude mice. Recombinant human lactoferrin and vehicle controls were dosed via intratumoral injection. Each animal was administered different concentrations of rhLF in 50 μL doses consisting of four separate injections of approximately 12.5 μL of the dose, at different directions and angles (approximately S/N/E/W) to ensure that the dose was distributed evenly throughout the tumor (fanning).
-
TABLE 13 Treatment schedule of intratumor injections of recombinant human lactoferrin in O12 human squamous carcinoma cell tumors in nude mice Dose of rhLF per animal in group Group Regimen 0 1 2 3 4 5 E. A Once on day 1, kill 80 100 μg 250 μg 500 μg 250 μg* na days later (nude mice) C Twice/day for 8 days 0 25 μg 50 μg 125 μg 250 μg 500 μg starting on Day 11after inoculation, kill on Day 20 (nude mice) - Table 13 shows the regimen followed for each experimental group and the dose of rhLF per injection for each animal per group. In this study, rhLF was administered directly into the tumor. Each animal was tracked daily for tumor growth by external caliper measurements of the protruding tumor.
- Using this model, significant reduction of tumor growth was evident in both rhLF treated groups relative to the control animals. Compared to the median tumor size for the pooled placebo samples from groups A and C, the rates of tumor growth in animals receiving a single dose of rhLF (Group A) were reduced by 50% on
day 11 after the administration of rhLF (p<0.05). The rates of tumor growth in animals dosed twice daily (Group C) were reduced by 56% when compared to the pooled control group (p<0.01) (SeeFIG. 5 ). - Normal C3H/HeJ mice were implanted with one of two mouse tumors following the methodology described in Example 17. Tumors used were SCCVII and RIF mouse tumor cell lines. Following establishment of the tumors in the mice, tumors were injected intratumorally daily for 4 days with 250 or 500 μg rhLF per dose or with vehicle control. Twenty four hours following the last intratumoral injection, animals were sacrificed and the blood examined for lymphocyte populations. The number of circulating lymphocytes were increased by 34% to 56% relative to the placebo treated control animals (Table 14).
-
TABLE 14 Increase in circulating lymphocytes following intratumoral administration of rhLF CD3+ CD4+ CD8+ Number of Cells Placebo 2104 1800 785 rhLF treated 3291 2621 1054 Increase with rhLF 56% 46% 34% - Tumor cells to be tested are injected into the right flank of athymic nude mice. Animals are administered rhLF intratumorally alone and in combination with other anti-cancer regimens as described in Example 1 or Example 17. Control animals are treated with only the vehicle; no rhLF is administered to the control animals. Anti-cancer therapy is administered using standard or published regimens. Therapy starts approximately 11 days after inoculation with tumor cells to allow formation of established tumors or at such other time as is generally done with standard or published regimens.
- The efficacy of individual and combination treatments are evaluated by measuring the solid tumor size during and at the end of the experiment; the body weights are also determined at the time of tumor measurements.
- Recombinant lactoferrin is intratumorally administered to patients to inhibit tumor growth.
- Briefly, rhLF at a dose of 1000 μg per day for eight days to patients suffering from unresectable or metastatic cancer. Alternatively, rhLF is administered for one to eight days to patients suffering from metastatic cancer in daily doses of 10, 50, 100, 500 and 1000 μg. The dose is administered intratumorally.
- Tumor size progression is monitored through CT scans and tumor markers where available. CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks. Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ.
- Recombinant lactoferrin is intratumorally administered to patients to inhibit tumor growth either alone or in combination with standard anti-cancer regimens.
- Briefly, rhLF is administered using the optimum regimen and doses identified in Example 20 and the standard anti-cancer regimen(s) for the selected tumor type is used as part of the combination therapy. The route of administration and regimen of the additional anti-cancer therapy is as approved by the FDA for that indication or as described in a peer reviewed publication.
- Tumor size progression is monitored through CT scans and tumor markers where available. CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks once treatment is initiated. Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ.
- Recombinant lactoferrin in a gel formulation is administered to patients to inhibit tumor growth.
- Briefly, rhLF gel at strengths of 1%, 2.5% or 8.5% is applied twice a day to a skin or subcutaneous cancerous lesion in a patient with metastatic disease. Application of rhLF gel continues till tumor progression.
- Size progression of the metastatic disease is monitored through CT scans and tumor markers where available. CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks. Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ.
- Recombinant lactoferrin in a gel formulation is administered to patients to inhibit tumor growth either alone or in combination with standard anti-cancer regimens.
- Briefly, rhLF is administered using the optimum regimen and doses identified in Examples 22 and the standard anti-cancer regimen(s) for the selected tumor type is used as part of the combination therapy. The route of administration and regimen of the additional anti-cancer therapy is as approved by the FDA for that indication or as described in a peer reviewed publication.
- Size progression of the metastatic disease is monitored through CT scans and tumor markers where available. CT scans are performed at baseline and after each 8-week period once treatment is initiated. Tumor markers are measured every 4 weeks once treatment is initiated. Blood samples are collected to measure subclasses of circulating lymphocytes and NK cell activity. Plasma, serum and blood cell extract samples are collected to measure circulating IL-18, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ.
- All patents and publications mentioned in the specifications are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
- U.S. Pat. No. 5,629,001
- Bezault J et. al., Cancer Res. 1994, 54(9):2310-2.
- Broxmeyer H E. Blood. 1983; 61:982-993.
- Damiens E, et al., Biochim Biophys Acta. 1998, 1402(3):277-87.
- Dhennin-Duthille I, et al., J Cell Biochem. 2000, 79(4):583-93.
- Erlandsson, Cancer Genet. Cytogenet, 104:1-18, 1998.
- Gahr M, et al., J Leukocyte Biol. 1991; 49: 427-33.
- Gertig and Hunter, Semin. Cancer Biol., 8(4):285-298, 1997.
- Horowitz D A, et al., J Immunol. 1984; 132: 2370-4.
- Iigo M, et al., Clin Exp Metastasis. 1999, 17(1):35-40.\
- Kolmel, J. Neurooncol., 38:121-125, 1998.
- Kuhara T, et al., Nutr Cancer. 2000, 38(2):192-9.
- Magi-Galluzzi et al., Anal. Quant. Cytol. Histol., 20:343-350, 1998.
- Mangray and King, Front Biosci., 3:D1148-1160, 1998.
- Masuda C, et al. Jpn J Cancer Res. 2000, 91(6):582-8.
- Mayer, Radiat Oncol Investig. 6:281-8, 1998.
- Mumby and Walter, Cell Regul., 2:589-598, 1991.
- Natoli et al., Biochem. Pharmacol., 56(8):915-920, 1998.
- Ohara, Acta Oncol. 37:471-4, 1998.
- Shau H, et al., J Leukocyte Biol. 1992; 51:343-9.
- Solyanik et al., Cell Prolif, 28:263-278, 1995.
- Spik G, et al., Adv Exp Med Biol. 1994; 357:13-9.
- Stokke et al., Cell Prolif, 30(5):197-218, 1997.
- Tanaka T, et al. Jpn J Cancer Res. 2000, 91(1):25-33.
- Tsuda H, et al., Biofactors. 2000; 12(1-4):83-8.
- Ushida Y, et al. Jpn J Cancer Res. 1999, 90(3):262-7.
- Wang W P, et al., Jpn J Cancer Res. 2000, 91(10):1022-7.
- Yoo Y C, et al., Adv Exp Med Biol. 1998, 443:285-91.
- Yoo Y C, et al., Jpn J Cancer Res. 1997, 88(2):184-90.
- Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended description. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure of the present invention, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention. Accordingly, the appended descriptions are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.
Claims (99)
1. A method of treating a hyperproliferative disease comprising the step of administering orally to a subject a human lactoferrin composition in an amount sufficient to provide an improvement in the hyperproliferative disease in said subject.
2. The method of claim 1 , wherein said human lactoferrin composition is dispersed in a pharmaceutically acceptable carrier.
3. The method of claim 1 , wherein said human lactoferrin is recombinant human lactoferrin.
4. The method of claim 1 further comprising administering an antacid in conjunction with said human lactoferrin composition.
5. The method of claim 1 , wherein the amount of the composition that is administered is about 1 mg to about 100 g per day.
6. The method of claim 1 , wherein the amount of the composition that is administered is about 20 mg to about 10 g per day.
7. The method of claim 1 , wherein the hyperproliferative disease is further defined as cancer.
8. The method of claim 7 , wherein the cancer comprises a neoplasm.
9. The method of claim 8 , wherein the neoplasm is selected from the group consisting of melanoma, non-small cell lung, small-cell lung, lung hepatocarcinoma, retinoblastoma, astrocytoma, gliobastoma, leukemia, neuroblastoma, squamous cell, head, neck, gum, tongue, breast, pancreatic, prostate, renal, bone, testicular, ovarian, mesothelioma, sarcoma, cervical, gastrointestinal, lymphoma, brain, colon, and bladder.
10. The method of claim 7 , wherein the neoplasm is a hematopoietic neoplasm.
11. The method of claim 10 , wherein the hematopoietic neoplasm is selected from the group consisting of acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, juvenile myelomonocyte leukemia, multiple myeloma, and chronic lymphocytic leukemia.
12. The method of claim 1 , wherein the hyperproliferative disease is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, leiomyomas, adenomas, lipomas, hemangiomas, fibromas, vascular occlusion, restenosis, atherosclerosis, pre-neoplastic lesions, carcinoma in situ, oral hairy leukoplakia, and psoriasis.
13. A method of treating a hyperproliferative disease comprising the step of supplementing the mucosal immune system in a subject by increasing the amount of human lactoferrin in the gastrointestinal tract.
14. The method of claim 13 , wherein said human lactoferrin is recombinant human lactoferrin.
15. The method of claim 13 , wherein human lactoferrin is administered orally.
16. The method of claim 13 , wherein human lactoferrin stimulates the production of interleukin-18.
17. The method of claim 13 , wherein human lactoferrin stimulates the production of GM-CSF.
18. A method of enhancing a mucosal immune response in the gastrointestinal tract in a subject comprising the step of administering orally to said subject a human lactoferrin.
19. The method of claim 18 , wherein said human lactoferrin is recombinant human lactoferrin.
20. The method of claim 18 , wherein the human lactoferrin stimulates interleukin-18 in the gastrointestinal tract.
21. The method of claim 20 , wherein interleukin-18 stimulates the production, maturation or activity of immune cells.
22. The method of claim 21 , wherein the immune cells are T lymphocytes or natural killer cells.
23. The method of claim 22 , wherein the T lymphocytes are selected from the group consisting of CD4+, CD8+ and CD3+ cells.
24. The method of claim 17 , wherein the human lactoferrin stimulates GM-CSF in the gastrointestinal tract.
25. The method of claim 20 , wherein GM-CSF stimulates the production, maturation or activity of immune cells.
26. The method of claim 25 , wherein the immune cells are dendritic or other antigen presenting cells.
27. The method of claim 18 , wherein said subject suffers from a hyperproliferative disease.
28. The method of claim 1 further comprising additionally administering chemotherapy, immunotherapy, surgery, biotherapy, radiotherapy or a combination thereof.
29. The method of claim 28 , wherein the chemotherapy is a platinum based agent.
30. The method of claim 29 where the platinum based agent in cisplatin.
31. The method of claim 28 , wherein the chemotherapy is a taxane based agent.
32. The method of claim 31 , wherein the chemotherapy is docetaxel.
33. The method of claim 1 further comprising additionally administering radiotherapy.
34. A method of reducing growth of a neoplasm in a subject comprising the step of administering orally to the subject a human lactoferrin composition in an amount sufficient to reduce the growth of the neoplasm in said subject.
35. The method of claim 34 further comprising additionally administering chemotherapy, immunotherapy, surgery, biotherapy, radiotherapy or a combination thereof.
36. The method of claim 35 , wherein the chemotherapy is a platinum based chemotherapy.
37. The method of claim 36 , wherein the platinum based chemotherapy is cisplatin.
38. The method of claim 35 , wherein the chemotherapy is a taxane based chemotherapy.
39. The method of claim 37 wherein the chemotherapy is a docetaxel.
40. The method of claim 34 further comprising additionally administering radiotherapy.
41. A method of treating a hyperproliferative disease comprising administering orally to a subject a human lactoferrin composition in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy.
42. A method of treating a hyperproliferative disease comprising the step of administering intravenously to a subject a lactoferrin composition in an amount sufficient to provide an improvement in the hyperproliferative disease in said subject.
43. The method of claim 42 , wherein said lactoferrin composition is dispersed in a pharmaceutically acceptable carrier.
44. The method of claim 42 , wherein said lactoferrin is mammalian lactoferrin.
45. The method of claim 44 , wherein said lactoferrin is human.
46. The method of claim 44 , wherein said lactoferrin is bovine.
47. The method of claim 44 , wherein said lactoferrin is recombinant lactoferrin.
48. The method of claim 42 , wherein the amount of the composition that is administered is about 0.1 μg to about 10 g per day.
49. The method of claim 42 , wherein the amount of the composition that is administered is about 1 μg to about 1 g per day.
50. The method of claim 42 , wherein the hyperproliferative disease is further defined as cancer.
51. The method of claim 50 , wherein the cancer comprises a neoplasm.
52. The method of claim 51 , wherein the neoplasm is selected from the group consisting of melanoma, non-small cell lung, small-cell lung, lung hepatocarcinoma, retinoblastoma, astrocytoma, gliobastoma, leukemia, neuroblastoma, squamous cell, head, neck, gum, tongue, breast, pancreatic, prostate, renal, bone, testicular, ovarian, mesothelioma, sarcoma, cervical, gastrointestinal, lymphoma, brain, colon, and bladder.
53. The method of claim 52 , wherein the neoplasm is a hematopoietic neoplasm.
54. The method of claim 53 , wherein the hematopoietic neoplasm is selected from the group consisting of acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, juvenile myelomonocyte leukemia, multiple myeloma, and chronic lymphocytic leukemia.
55. The method of claim 42 , wherein the hyperproliferative disease is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, leiomyomas, adenomas, lipomas, hemangiomas, fibromas, vascular occlusion, restenosis, atherosclerosis, pre-neoplastic lesions, carcinoma in situ, oral hairy leukoplakia, and psoriasis.
56. A method of treating a hyperproliferative disease comprising the step of supplementing a systemic immune system in a subject by increasing the amount of lactoferrin in the systemic circulation.
57. The method of claim 56 , wherein said lactoferrin is recombinant lactoferrin.
58. The method of claim 56 , wherein said lactoferrin is administered intravenously.
59. The method of claim 56 , wherein said lactoferrin stimulates the production of interleukin-18.
60. The method of claim 56 , wherein said lactoferrin stimulates the production of GM-CSF.
61. A method of enhancing a systemic immune response following the step of administering intravenously to said subject a lactoferrin composition.
62. The method of claim 61 , wherein said lactoferrin is recombinant lactoferrin.
63. The method of claim 61 , wherein said lactoferrin stimulates interleukin-18.
64. The method of claim 61 , wherein said lactoferrin stimulates GM-CSF.
65. The method of claim 63 , wherein interleukin-18 stimulates the production, maturation or activity of immune cells.
66. The method of claim 65 , wherein the immune cells are T lymphocytes or natural killer cells.
67. The method of claim 66 , wherein the T lymphocytes are selected from the group consisting of CD4+, CD8+ and CD3+ cells.
68. The method of claim 63 , wherein GM-CSF stimulates the production, maturation or activity of immune cells.
69. The method of claim 65 , wherein the immune cells are dendritic or other antigen presenting cells.
70. The method of claim 61 , wherein said subject suffers from a hyperproliferative disease.
71. The method of claim 42 further comprising additionally administering chemotherapy, immunotherapy, surgery, biotherapy, radiotherapy or a combination thereof.
72. A method of treating a hyperproliferative disease comprising administering intravenously to a subject a lactoferrin composition in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy.
73. A method of treating a hyperproliferative disease comprising the step of administering topically to a subject a lactoferrin composition in an amount sufficient to provide an improvement in the hyperproliferative disease in said subject.
74. The method of claim 73 , wherein said lactoferrin composition is dispersed in a pharmaceutically acceptable carrier.
75. The method of claim 73 , wherein the amount of the composition that is administered is about 0.1 μg to about 10 g per day.
76. The method of claim 73 , wherein the composition is a topical gel, a solution, capsule or a tablet having a lactoferrin concentration of about 0.01% to about 20%.
77. The method of claim 76 , wherein the lactoferrin concentration of about 1.0% to about 8.5%.
78. The method of claim 73 , wherein the hyperproliferative disease is further defined as cancer.
79. The method of claim 78 , wherein the cancer comprises a neoplasm.
80. The method of claim 79 , wherein the neoplasm is selected from the group consisting of melanoma, non-small cell lung, small-cell lung, lung hepatocarcinoma, retinoblastoma, astrocytoma, gliobastoma, leukemia, neuroblastoma, squamous cell, head, neck, gum, tongue, breast, pancreatic, prostate, renal, bone, testicular, ovarian, mesothelioma, sarcoma, cervical, gastrointestinal, lymphoma, brain, colon, and bladder.
81. A method of enhancing a local or systemic immune response following the step of administering topically to said subject a lactoferrin composition.
82. The method of claim 81 , wherein said lactoferrin is recombinant lactoferrin.
83. The method of claim 81 , wherein said lactoferrin stimulates interleukin-18.
84. The method of claim 81 , wherein said lactoferrin stimulates GM-CSF.
85. The method of claim 83 , wherein interleukin-18 stimulates the production, maturation or activity of immune cells.
86. The method of claim 85 , wherein the immune cells are T lymphocytes or natural killer cells.
87. The method of claim 86 , wherein the T lymphocytes are selected from the group consisting of CD4+, CD8+ and CD3+ cells.
88. The method of claim 84 , wherein GM-CSF stimulates the production, maturation or activity of immune cells.
89. The method of claim 88 , wherein the immune cells are dendritic or other antigen presenting cells.
90. The method of claim 81 , wherein said subject suffers from a hyperproliferative disease.
91. The method of claim 81 further comprising additionally administering chemotherapy, immunotherapy, surgery, biotherapy, radiotherapy or a combination thereof.
92. A method of treating a hyperproliferative disease comprising administering topically to a subject a lactoferrin composition in combination with chemotherapy, biotherapy, immunotherapy, surgery or radiotherapy.
93. A method of treating a hyperproliferative disease comprising the step of supplementing a local or systemic immune system in a subject by increasing the amount of lactoferrin in the vicinity of a tumor.
94. The method of claim 93 , wherein said lactoferrin is recombinant lactoferrin.
95. The method of claim 93 , wherein said lactoferrin is administered topically.
96. The method of claim 95 , wherein said lactoferrin stimulates the production of interleukin-18.
97. The method of claim 95 , wherein said lactoferrin stimulates the production of GM-CSF.
98. A method of stimulating interleukin-18 in a subject comprising the step of administering to said subject a lactoferrin composition.
99. A method of stimulating GM-CSF in a subject comprising the step of administering to said subject a lactoferrin composition.
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US10159571B2 (en) | 2012-11-21 | 2018-12-25 | Corquest Medical, Inc. | Device and method of treating heart valve malfunction |
US10307167B2 (en) | 2012-12-14 | 2019-06-04 | Corquest Medical, Inc. | Assembly and method for left atrial appendage occlusion |
US10314594B2 (en) | 2012-12-14 | 2019-06-11 | Corquest Medical, Inc. | Assembly and method for left atrial appendage occlusion |
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Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6399570B1 (en) | 1999-02-05 | 2002-06-04 | Agennix, Inc. | Antimicrobial/endotoxin neutralizing polypeptide |
PT1507554E (en) * | 2002-05-10 | 2011-11-21 | Agennix Inc | Lactoferrin in the treatment of malignant neoplasms and other hyperproliferative diseases |
US7238661B2 (en) * | 2002-05-24 | 2007-07-03 | Agennix, Inc. | Oral lactoferrin in the treatment of respiratory disorders |
CA2499014A1 (en) * | 2002-09-16 | 2004-03-25 | Agennix Incorporated | Lactoferrin compositions and methods of wound treatment |
WO2004052281A2 (en) * | 2002-12-06 | 2004-06-24 | Agennix Incorporated | Oral lactoferrin in the treatment of sepsis |
WO2004052305A2 (en) | 2002-12-10 | 2004-06-24 | Agennix Incorporated | Lactoferrin as an agent in the prevention of organ transplant rejection and graft-versus-host-disease |
AU2003293500A1 (en) * | 2002-12-12 | 2004-07-09 | Agennix Incorporated | Lactoferrin in the reduction of pain |
EP1635766A4 (en) * | 2003-06-06 | 2009-09-30 | Agennix Inc | Lactoferrin as an adjuvant in cancer vaccines |
WO2005018542A2 (en) * | 2003-07-10 | 2005-03-03 | Agennix Incorporated | Use of lactoferrin in prophylaxis against infection and/or inflammation in immunosuppressed subjects |
GB0413954D0 (en) * | 2004-06-22 | 2004-07-28 | Altunkaya Ali | Compositions for topical treatment |
WO2006047744A2 (en) * | 2004-10-26 | 2006-05-04 | Agennix Incorporated | Compositions of lactoferrin related peptides and uses thereof |
CA2587727A1 (en) * | 2004-11-19 | 2006-05-26 | Jagat Rakesh Kanwar | Methods of immune or haematological enhancement, inhibiting tumour formation or growth, and treating or preventing cancer |
WO2007022537A2 (en) * | 2005-08-19 | 2007-02-22 | Agennix Incorporated | Use of lactoferrin as a chemokine and a chemotactic modulator |
JP2009528131A (en) * | 2006-03-03 | 2009-08-06 | ジェネトロニクス,インコーポレイティド | Method and apparatus for treating microscopic residual tumor remaining in tissue after surgical resection |
WO2007145520A1 (en) * | 2006-06-14 | 2007-12-21 | N.V. Nutricia | Anti-inflammatory composition comprising glycine and lactoferrin and the use thereof |
JP5882735B2 (en) * | 2008-09-19 | 2016-03-09 | ネステク ソシエテ アノニム | Nutritional support to prevent or alleviate bone marrow paralysis or neutropenia during anticancer treatment |
DK2391225T3 (en) * | 2009-01-28 | 2020-07-20 | Perraudin Jean Paul | PROCEDURE FOR PREPARING LACTOFERRIN |
JP2015067560A (en) * | 2013-09-27 | 2015-04-13 | 国立大学法人広島大学 | Cancer metastasis inhibitor comprising lactoferrin |
WO2015089316A1 (en) * | 2013-12-12 | 2015-06-18 | Cornell University | Methods for preventing and treating oral cancers |
CN106174462A (en) * | 2016-04-17 | 2016-12-07 | 马鞍山市志诚科技有限公司 | The nutrient formulation nano-particle of a kind for the treatment of of vascular tumor and preparation processing method |
WO2018079701A1 (en) * | 2016-10-28 | 2018-05-03 | 株式会社Nrlファーマ | Anticancer therapeutic adjuvant containing protein having lactoferrin activity |
CN111544579A (en) * | 2020-03-13 | 2020-08-18 | 中国农业科学院北京畜牧兽医研究所 | Anti-cancer pharmaceutical composition |
Family Cites Families (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6351337A (en) * | 1986-08-22 | 1988-03-04 | Snow Brand Milk Prod Co Ltd | Antitumor agent |
US4977137B1 (en) * | 1987-06-03 | 1994-06-28 | Baylor College Medicine | Lactoferrin as a dietary ingredient promoting the growth of the gastrointestinal tract |
US5571697A (en) * | 1989-05-05 | 1996-11-05 | Baylor College Of Medicine Texas Medical Center | Expression of processed recombinant lactoferrin and lactoferrin polypeptide fragments from a fusion product in Aspergillus |
US5849881A (en) * | 1989-05-05 | 1998-12-15 | Baylor College Medicine | Production of recombinant lactoferrin and lactoferrin polypeptides using cDNA sequences in various organisms |
US5766939A (en) * | 1989-05-05 | 1998-06-16 | Baylor College Of Medicine | Production of recombinant lactoferrin and lactoferrin polypeptides using CDNA sequences in various organisms |
IL94183A (en) * | 1989-05-05 | 2003-09-17 | Baylor College Medicine | cDNA SEQUENCE CODING FOR HUMAN LACTOFERRIN PROTEIN OR PORTION THEREOF AND LACTOFERRIN PROTEIN PRODUCED FROM SAID SEQUENCE |
US5571691A (en) * | 1989-05-05 | 1996-11-05 | Baylor College Of Medicine | Production of recombinant lactoferrin and lactoferrin polypeptides using CDNA sequences in various organisms |
US6100054A (en) * | 1989-05-05 | 2000-08-08 | Baylor College Of Medicine | Production for recombinant lactoferrin and lactoferrin polypeptides using DNA sequences in various organisms |
US5198419A (en) * | 1989-12-08 | 1993-03-30 | Immuno Japan Inc. | Formulated medicines for enhancing the efficacy of beta-lactam antibiotics in prophylaxis and treatment against infectious disease due to pathogenic bacteria |
EP0590060B1 (en) | 1991-06-21 | 1997-09-17 | University Of Cincinnati | Orally administrable therapeutic proteins and method of making |
JP3184923B2 (en) * | 1992-01-08 | 2001-07-09 | ビオ セレ ラボラトワール エス ア | Anti-rheumatic drug |
ZA932568B (en) * | 1992-04-24 | 1993-11-12 | Baylor College Midecine A Non | Production of recombinant human lactoferrin |
CA2086874E (en) * | 1992-08-03 | 2000-01-04 | Renzo Mauro Canetta | Methods for administration of taxol |
US5679807A (en) * | 1995-01-30 | 1997-10-21 | Hauser, Inc. | Preparation of taxol and docetaxel through primary amines |
JPH08217693A (en) * | 1995-02-17 | 1996-08-27 | Yoshihisa Naito | New medicine composition |
JP3888707B2 (en) * | 1996-01-22 | 2007-03-07 | 森永乳業株式会社 | Antiangiogenic agent |
JP3496387B2 (en) | 1996-01-23 | 2004-02-09 | 花王株式会社 | Hair cosmetics |
US6111081A (en) * | 1996-05-31 | 2000-08-29 | Baylor College Of Medicine | Lactoferrin variants and uses thereof |
WO1998006425A1 (en) | 1996-08-12 | 1998-02-19 | A+ Science Invest Ab | Treatment and prevention of infections, inflammations and/or tumours with lactoferrin and/or lactoferricin |
US6333311B1 (en) * | 1997-02-03 | 2001-12-25 | Pharming | Useful properties of human lactoferrin and variants thereof |
WO1998044940A1 (en) | 1997-04-10 | 1998-10-15 | Agennix, Inc. | Use of lactoferin in the treatment of allergen induced disorders |
JP2002519332A (en) * | 1998-06-26 | 2002-07-02 | エヌ・ヴェー・ニュートリシア | Pharmaceutical preparation for use in treating or preventing surface infections caused by microorganisms |
GB9818938D0 (en) * | 1998-08-28 | 1998-10-21 | Alpharma As | Bioactive peptides |
US6399570B1 (en) * | 1999-02-05 | 2002-06-04 | Agennix, Inc. | Antimicrobial/endotoxin neutralizing polypeptide |
JP2000229881A (en) * | 1999-02-10 | 2000-08-22 | Morinaga Milk Ind Co Ltd | Prognosis-improving agent for cancerous disease |
RU2165769C1 (en) | 2000-07-13 | 2001-04-27 | Якубовская Раиса Ивановна | Antibacterial, antioxidant, immunomodulating and anticancer preparation and method of its embodiment |
US20030096736A1 (en) * | 2001-05-09 | 2003-05-22 | Kruzel Marian L. | Lactoferrin for age related disorders in humans |
PT1507554E (en) * | 2002-05-10 | 2011-11-21 | Agennix Inc | Lactoferrin in the treatment of malignant neoplasms and other hyperproliferative diseases |
US7238661B2 (en) * | 2002-05-24 | 2007-07-03 | Agennix, Inc. | Oral lactoferrin in the treatment of respiratory disorders |
CA2499014A1 (en) * | 2002-09-16 | 2004-03-25 | Agennix Incorporated | Lactoferrin compositions and methods of wound treatment |
EP1635766A4 (en) * | 2003-06-06 | 2009-09-30 | Agennix Inc | Lactoferrin as an adjuvant in cancer vaccines |
WO2005018542A2 (en) * | 2003-07-10 | 2005-03-03 | Agennix Incorporated | Use of lactoferrin in prophylaxis against infection and/or inflammation in immunosuppressed subjects |
CA2587727A1 (en) | 2004-11-19 | 2006-05-26 | Jagat Rakesh Kanwar | Methods of immune or haematological enhancement, inhibiting tumour formation or growth, and treating or preventing cancer |
JP2007233064A (en) | 2006-03-01 | 2007-09-13 | Bitsign:Kk | Display system and display device |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US10159571B2 (en) | 2012-11-21 | 2018-12-25 | Corquest Medical, Inc. | Device and method of treating heart valve malfunction |
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US10314594B2 (en) | 2012-12-14 | 2019-06-11 | Corquest Medical, Inc. | Assembly and method for left atrial appendage occlusion |
US9566443B2 (en) | 2013-11-26 | 2017-02-14 | Corquest Medical, Inc. | System for treating heart valve malfunction including mitral regurgitation |
US10842626B2 (en) | 2014-12-09 | 2020-11-24 | Didier De Canniere | Intracardiac device to correct mitral regurgitation |
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EP2286827A1 (en) | 2011-02-23 |
US20110076295A1 (en) | 2011-03-31 |
US7901879B2 (en) | 2011-03-08 |
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WO2003094952A1 (en) | 2003-11-20 |
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CN100467059C (en) | 2009-03-11 |
JP2005533029A (en) | 2005-11-04 |
EP1507554B1 (en) | 2011-08-10 |
DK1507554T3 (en) | 2011-11-21 |
WO2003099323A1 (en) | 2003-12-04 |
HK1083203A1 (en) | 2006-06-30 |
JP4685443B2 (en) | 2011-05-18 |
US20100137208A1 (en) | 2010-06-03 |
CN1668326A (en) | 2005-09-14 |
JP2011079858A (en) | 2011-04-21 |
CN1668325A (en) | 2005-09-14 |
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US8242079B2 (en) | 2012-08-14 |
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HK1080722A1 (en) | 2006-05-04 |
US20040009895A1 (en) | 2004-01-15 |
EP1507554A4 (en) | 2007-05-09 |
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