WO2004073730A1 - Anticancer agent comprising lk8 protein as an active ingredient - Google Patents
Anticancer agent comprising lk8 protein as an active ingredient Download PDFInfo
- Publication number
- WO2004073730A1 WO2004073730A1 PCT/KR2004/000357 KR2004000357W WO2004073730A1 WO 2004073730 A1 WO2004073730 A1 WO 2004073730A1 KR 2004000357 W KR2004000357 W KR 2004000357W WO 2004073730 A1 WO2004073730 A1 WO 2004073730A1
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- WO
- WIPO (PCT)
- Prior art keywords
- protein
- anticancer agent
- cancer
- metastasis
- tumor
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- the present invention relates to an anticancer agent comprising a certain protein as an active ingredient, more precisely, to an anticancer agent comprising a protein corresponding to kringle KV38 of apolipoprotein (a) as an active ingredient.
- a tumor is developed by uncontrollable disordered abnormal cell proliferation. If this tumor shows a destructive growth, invasiveness and metastasis, it is regarded as a malignant tumor. Invasiveness is a character to infiltrate or destroy surrounding tissues, and in particular, a basal layer forming a boundary of tissues is destroyed by the character, resulting in the local spread and sometimes inflow of a tumor through circulatory system. Metastasis means the spread of tumor cells from the original birthplace to other areas through lymphatic or blood vessels. In a broad sense, metastasis also means the direct extension of tumor cells through peritoneal cavity or other space.
- the surgical operation is a way to remove diseased tissues.
- tumors in specific regions such as breast, colon and skin can be effectively removed by the surgical operation.
- a tumor in vertebra or dispersive tumor like leukemia cannot be properly treated by the surgical operation.
- Chemotherapy blocks cell replication or metabolism, and has been used for the treatment of breast cancer, lung cancer and testis cancer. Though, patients with cancers who have been treated by chemotherapy have seriously suffered from the side effects of systemic chemotherapy. Motion sickness and vomiting, are common but serious examples of all. The side effects of chemotherapy can even affect the life of a patient since they might drop the adaptability of a patient rapidly. Besides, Dose Limiting Toxicity (DLT) is also one of major side effects of chemotherapy, which draws a careful attention in the administration of a medicine. Mucositis is an example of DLT against anticancer agents such as 5-fluoruracil which is an anti etabolic cytotoxic agent, and methotrexate, and anticancer antibiotics like doxorubicin. If a patient suffers seriously from such side effects of chemotherapy, he or she should be hospitalized and given an anodyne for reducing pain. So, side effects of chemotherapy and radiotherapy are the biggest problem for the treatment of cancer patients .
- DLT Dose Limiting
- an anticancer agent originated from a living creature in order to reduce side effects of chemotherapy.
- a promising subject has been found which does not attack cancer cells directly but prevents cancer cells from growing by working toward various endothelial cells helping cancer cell growth. So, an anticancer agent containing the subject can not only treat cancers but also prevent metastasis.
- Kringle is a kind of a protein structure which is composed of 80 amino acids and three intramolecular disulfide bonds. Kringle structure is found in many proteins such as prothrombin
- Kringle is composed of an individual folding unit. The functions of kringle have not been clearly explained, yet.
- Apo(a) includes two types of kringle domains, KIV and KV, and an inactive protease-like region.
- the kringle domain KIV is divided into 10 subtypes
- Lp(a)' a lipoprotein
- LDL low- density lipoprotein
- the present inventors Based on the fact that artherosclerosis and cancer cell growth depend on angiogenesis, the present inventors have studied on an anticancer activity of KV38, one of human apo(a) kringles. As a result, the present inventors have completed this invention by confirming that the protein can be effectively used as an anticancer agent because it inhibits angiogenesis by an endogenous growth factor like bFGF which is necessary for cancer cell growth.
- LK8 protein' a human apo(a) kringle KV38
- the present invention provides an anticancer agent comprising a LK8 protein as an active ingredient.
- the anticancer agent of the present invention is characterized by including LK8 protein having an amino acid sequence represented by SEQ. ID. No 1 as an active ingredient. It is preferred to use the agent as a metastasis inhibitor, more preferably, it is used for the suppression of metastasis of colon carcinoma or rectal cancer to live .
- the anticancer agent is preferably used for the treatment of primary tumors. More preferably ⁇ the agent is used for the treatment of a cancer selected from a group consisting of prostate cancer, lung cancer, colon cancer and rectal cancer.
- the anticancer agent of the present invention it is preferred for the anticancer agent of the present invention to contain LK8 protein by 0.1 ⁇ 100 mg/kg, more preferred to contain LK8 protein by 1 ⁇ 50 mg/kg, and administration times are 1 ⁇ 4 per day.
- the composition is not limited thereto, and is possibly changed according to the conditions of a patient, and types and progressing speed of a disease.
- KV38 means an apo(a) kringle
- LK8 means a recombinant protein of KV38.
- both KV38 and LK8 protein are called as LK8 protein in general unless mentioned specifically.
- LK8 protein of the present invention is a domain corresponding to KV38 kringle of many apo(a) kringle domains and has an inhibiting effect on proliferation and differentiation of cancer cells and metastasis by suppressing the activity of endothelial cells in vi tro and in vivo as well.
- the systemic administration of LK8 protein results in the inhibition of a primary tumor and its metastasis (see FIG. 2 ⁇ FIG. 6) .
- LK8 protein of the present invention can be effectively used as an anticancer agent especially for primary tumors and as a metastasis inhibitor owing to its functions of suppressing tumor growth and metastasis.
- the treatment effect will be enhanced if LK8 protein of the present invention is used together with conventional chemotherapy or radiotherapy. Radiotherapy is performed to destroy a primary tumor, and if LK8 protein is administered during radiotherapy, metastasis can be prevented more effectively.
- chemotherapy cytotoxicity caused by huge dosage of chemical anticancer agents is the biggest problem. If LK8 protein of the invention is administered during chemotherapy, the decreased amount of chemical anticancer agents will bring equivalent or even improved anticancer effects as well as lessen the cytotoxicity.
- LK8 protein is administered together with surgical operation, radiotherapy, chemotherapy or immunotherapy, the treatment effect will be maximized.
- the continuous administration of LK8 protein extends dormancy of micrometastasis, suppresses the growth of a primary tumor and stabilizes conditions.
- Many conventional anticancer agents are designed for long term administration, causing troubles such as continuous production of a protein and high price of the product. The alternative to them is gene therapy.
- LK8 protein is also expected to maximize the effect of an anticancer agent or a metastasis 'inhibitor if it is used in gene therapy.
- the anticancer agent comprising LK8 protein of the present invention can be administered orally or parenterally and be used in general forms of pharmaceutical formulation.
- the anticancer agent can be prepared for oral or parenteral administration by mixing with generally used fillers, extenders, binders, wetting agents, disintegrating agents, diluents such as surfactants, or excipients.
- Solid formulations for oral administration are tablets, pills, dusting powders,, granules and capsules. These solid formulations are prepared by mixing one or more suitable excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. Except for the simple excipients, lubricants, for example magnesium stearate, talc, etc, can be used.
- Liquid formulations for oral administrations are suspensions, solutions, emulsions and syrups, and the above mentioned formulations can contain various excipients such as wetting agents, sweeteners, aromatics and preservatives in addition to generally used simple diluents such as water and liquid paraffin.
- Formulations for parenteral administration are sterilized aqueous solutions, water-insoluble excipients, suspensions, emulsions, and suppositories.
- Water insoluble excipients and suspensions can contain, in addition to the active compound or compounds, propylene glycol, polyethylene glycol, vegetable oil like olive oil, injectable ester like ethylolate, etc.
- Suppositories can contain, in addition to the active compound or compounds, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerinated gelatin, etc.
- LD 50 of the LK8 protein is about 1,000 mg/kg, suggesting that the anticancer agent of the present invention is very much safe (see Table 2) .
- FIG. 1 is a schematic representation of the expression vector ⁇ pMBRI-LK8 (8.25 kb) ' of LK8 gene, in which LK8 cDNA (261 bp) is inserted between AOX1 promoter and AOX1 terminator,
- FIG. 2 is a set of photographs and a graph showing that the pulmonary metastasis of a murine melanoma cell line, B16F10, which was injected into mouse (C57BL/6) tail vein, is inhibited by the treatment of LK8 protein,
- FIG. 3 is a set of photographs and a graph showing that the metastasis of liver by a mouse colorectal cancer cell line CT-26 transplanted into mouse spleen is inhibited by the treatment of
- FIG. 4 is a set of graphs showing the changes of the size of a tumor in a mouse transplanted with human prostate carcinoma PC-3 cells, according to the administration of LK8 protein,
- FIG. 5 is a graph showing the changes of the size of a tumor in a mouse transplanted with human lung carcinoma A549 cells, according to the administration of LK8 protein
- FIG. 6 is a set of graphs showing the changes of the size of a tumor (a) and the weight of a tumor (b) in mice transplanted with human rectal and colon carcinoma LS 174T cells, according to the administration of LK8 protein.
- LK8 expression vector In order to prepare LK8 protein effectively, the present inventors constructed LK8 expression vector first.
- pPIC9 vector (8.0 kb, Invitrogen, Netherland) was used as a basic vector.
- pPIC9 expression vector includes promoter AOXl which provides high expression by methanol, ⁇ - factor secretion signal which enables the secretion of an expressed protein, 3'AOXl (TT) , AOXl polyadenylation signal, which enables effective termination of transcription and polyadenylation, and a DNA fragment coding histidinol dehydrogenase of wild type Pichia pas tori s used as a selectable marker for a transformant of the above strain, in order.
- promoter AOXl which provides high expression by methanol
- ⁇ - factor secretion signal which enables the secretion of an expressed protein
- 3'AOXl (TT) 3'AOXl
- AOXl polyadenylation signal
- LK8 gene was amplified by PCR with primers LK8N-Xhol' represented by SEQ. ID. No 2 and LK8C-EcoRI'' represented by SEQ. ID. No 3, using pETl5b/LK8 (see PCT/KR99/00554 ) as a template.
- the PCR product was digested with restriction enzymes Xhol and EcoRI , followed by subcloning by inserting the product into pPIC9 vector which was digested with the same restriction enzymes.
- the LK8 gene expression vector x pMBRI-LK8 (8.25 kb) was constructed (FIG. 1).
- ⁇ l-2> Preparation of a transformant including
- Pichia pas toris a methylotrophic yeast, was used as a host for the preparation of a recombinant transformant.
- LK8 gene expression vector ⁇ pMBRI-LK8' was treated with a restriction enzyme Sa d , leading to linearization.
- the vector was inserted into AOXl gene of the above host strain chromosome by homologous recombination.
- electroporation was performed for transformation.
- a recombinant yeast transformant was selected from histidine-deficient medium by examining colony forming.
- PCR was performed to confirm if LK8 cDNA was inserted into AOXl region of chromosome of the selected recombinant transformant.
- the recombinant transformant was cultured and the expression of LK8 gene was induced by methanol .
- the expression of LK8 gene was confirmed, suggesting that the protein was mass-secreted in the culture medium.
- the secreted LK8 protein of the present invention was composed of amino acid sequence represented by SEQ. ID. No 1.
- a recombinant strain was obtained by inserting LK8 gene into Pi chia pas toris .
- the established strain was seed- cultured for 24 hours to obtain appropriate biomass and activity (when it was diluted by 20 times, OD 6 oo was 0.8 - 1.2) .
- Seed culture was performed in YDP medium (1% yeast extract, 2% peptone, 2% dextrose) for 24 hours by shaking culture. 75 L fermenter was used. The volume of a beginning medium was 20 L and the final volume of culture solution was adjusted to 40 L by fed-batch culture method.
- YDP medium 1% yeast extract, 2% peptone, 2% dextrose
- LK8 protein prepared in the above ⁇ Example 1>, was injected subcutaneously twice (1 mg/kg/day, 0.2 mg/kg/day) a day for 14 days.
- a control group was injected with PBS instead of LK8 protein.
- the mouse was dissected, and lung was taken to count the number of colony of the metastasized cancer cells (melanoma cells). As a result, huge colonies were formed in lungs of the control group mice injected with PBS, suggesting the transfer of melanoma cells (FIG. 2a) .
- CT-26 cells American Type Culture Collection
- mouse colorectal cancer cells were injected in spleen to induce metastasis into liver. Then, metastasis-inhibiting effect of LK8 protein was investigated. Particularly, CT-26 cells, which were 80% grown up on a plate, were washed with PBS, followed by singularizing with 0.02% EDTA. The single cells were washed with PBS again, then resuspended in PBS carefully. The suspension was stained with Trypan blue to count the number of cells. Cell density was adjusted to 5 X 10 5 /ml, which was injected into each mouse by 100 ⁇ Jl . 6 ⁇ 8 week old BALB/c mice (Charles River Japan, Inc.) were used.
- LK8 protein was subcutaneously injected to a experimental group twice a day by 10 mg/kg /day, and likewise, saline was injected as a control group. 14 days later, the mice were sacrificed to examine the liver (FIG. 3a) , and the number of colonies seen on surface of the liver was counted, which was fixed in 10% formalin solution. There was no big difference in weight among groups. However, the number of colonies which were transferred to liver was much less in an experimental group which was administered with LK8 protein by 10 mg/kg/day than in a control group. The decrease of the number of colonies in an experimental group injected with LK8 protein by
- Example 4 Growth inhibition of a primary tumor
- LK8 protein In order to investigate the effect of LK8 protein on the anti-angiogenesis in vivo, a xenografted tumor model was used. Every relevant experiment was performed with 4 week old randomly crossed female Balb/c nu/nu nude mice (Charles River Japan, Inc.), which were raised under sterilized condition.
- PC-3 cells 5 X 10 6 PC-3 cells were subcutaneously injected in central muscular region of the back of the nude mouse. Exactly 10 days after the transplantation,
- LK8 protein was injected by 100 mg/kg/day. Meanwhile, a control group was injected PBS only instead of LK8 protein. The treatment was continued for 30 days, then, the size of a tumor was measured every 3 or 4 days. As a result, tumor growth was inhibited by the treatment of LK8 protein, which was about 60% inhibition comparing to a control group (FIG. 4a) . When the LK8 protein was injected by 50 mg/kg/day, tumor growth was inhibited in similar fashion over 60% comparing to a control group (FIG. 4b) .
- Human lung carcinoma A549 cells (American Type Culture Collection) were cultured in DMEM medium (GIBCOTM, Invitrogen Corporation) supplemented with 10% FBS . Then, 1 X 10 7 tumor cells were subcutaneously injected in central muscular region of the back of the nude mouse. Exactly 5 days after the transplantation, LK8 protein was injected by 50 mg/kg/day. A control group was administered PBS only instead of LK8 protein. The treatment was continued for 46 days, then, the size of a tumor was measured every 3 or
- LS 174T cells Human colon and rectal carcinoma LS 174T cells (American Type Culture Collection) were cultured in RPMI medium (GIBCOTM, Invitrogen Corporation) supplemented with 10% FBS. Then, 5 X 10 6 tumor cells were subcutaneously injected in central muscular region of the back of the nude mouse. Exactly 5 days after the transplantation, LK8 protein was injected by 50 mg/kg/day. A control group was administered PBS only instead of LK8 protein. The treatment was continued for 34 days, then, the size of a tumor was measured every 3 or 4 days. As a result, tumor growth was inhibited by the treatment of LK8 protein, which was 64% inhibition comparing to a control (FIG. 6a) . And, the weight of the tumor was decreased by the treatment of LK8 protein about 68.7%, which was measured on the final day of the experiment (FIG. 6b) .
- Example 5 Acute toxicity test of LK8 protein
- 5-week old SPF SD (Sprague Dawley) line rats were used in the test for acute toxicity. Rats were divided into 5 groups, and 5 rats per each group were administered once with LK8 protein by the dosage of 260 mg/kg, 364 mg/kg, 510 mg/kg, 714 mg /kg and 1000 -mg/kg, respectively, by intravenous injection (Table 2) .
- LK8 protein, administration, death, clinical symptoms and weight change in rats were observed.
- the hematological tests and biochemical tests of blood were performed, and any abnormal signs in the gastrointestinal organs of chest and abdomen were examined visually during autopsy.
- LK8 protein used in this experiment was evaluated to be safe substance since it did not cause any toxic change in rats up to the level of 1,000 mg/kg in rats and its estimated LD 50 values were much greater than 1,000 mg/kg in rats (Table 2).
- LK8 protein has an inhibiting effect on metastasis, in particular, on the growth of human prostatic cancer, lung cancer, colon cancer and rectal cancer as being systemically administered.
- an anticancer agent containing LK8 protein of the present invention can be effectively used as a treatment agent for a primary tumor or a metastasis inhibitor,
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002516172A CA2516172A1 (en) | 2003-02-20 | 2004-02-20 | Anticancer agent comprising lk8 protein as an active ingredient |
EP04713257A EP1608395A4 (en) | 2003-02-20 | 2004-02-20 | Anticancer agent comprising lk8 protein as an active ingredient |
JP2006500650A JP2006518342A (en) | 2003-02-20 | 2004-02-20 | Anticancer agent containing LK8 protein as active ingredient |
BRPI0407611-7A BRPI0407611A (en) | 2003-02-20 | 2004-02-20 | anti-cancer agent comprising protein lk8 as an active ingredient |
AU2004212856A AU2004212856B2 (en) | 2003-02-20 | 2004-02-20 | Anticancer agent comprising LK8 protein as an active ingredient |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020030010797A KR100595364B1 (en) | 2003-02-20 | 2003-02-20 | Anticancer agent comprising LK8 protein as an active ingredient |
KR10-2003-0010797 | 2003-02-20 |
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WO2004073730A1 true WO2004073730A1 (en) | 2004-09-02 |
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PCT/KR2004/000357 WO2004073730A1 (en) | 2003-02-20 | 2004-02-20 | Anticancer agent comprising lk8 protein as an active ingredient |
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EP (1) | EP1608395A4 (en) |
JP (1) | JP2006518342A (en) |
KR (1) | KR100595364B1 (en) |
CN (1) | CN100546646C (en) |
AU (1) | AU2004212856B2 (en) |
BR (1) | BRPI0407611A (en) |
CA (1) | CA2516172A1 (en) |
RU (1) | RU2306147C2 (en) |
WO (1) | WO2004073730A1 (en) |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005065720A1 (en) * | 2004-01-09 | 2005-07-21 | Mogam Biotechnology Research Institute | Therapeutic agent for treatment of cancer comprising human apolipoprotein (a) kringles lk68 or lk8 genes as effective ingredient, and method for treating cancer using the same |
US7285277B2 (en) | 2002-03-15 | 2007-10-23 | Mogam Biotechnology Research Institute | Anticancer agent |
WO2008075833A1 (en) | 2006-12-21 | 2008-06-26 | Mogam Biotechnology Research Institute | Fusion protein of immunoglobulin fc and human apolipoprotein(a) kringle fragment |
FR2919064A1 (en) * | 2007-07-19 | 2009-01-23 | Biomerieux Sa | METHOD OF ASSAYING APOLIPOPROTEIN ALL FOR IN VITRO DIAGNOSIS OF COLORECTAL CANCER |
US7960348B2 (en) | 2005-12-22 | 2011-06-14 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
WO2012067427A2 (en) * | 2010-11-16 | 2012-05-24 | 재단법인 목암생명공학연구소 | Pharmaceutical composition containing lk8 protein as an active ingredient for preventing or treating diabetic retinopathy or age-related macular degeneration |
US8361968B2 (en) | 2002-12-26 | 2013-01-29 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
US8361731B2 (en) | 2007-07-19 | 2013-01-29 | Biomerieux | Ezrin assay method for the in vitro diagnosis of colorectal cancer |
US8367806B2 (en) | 2008-07-10 | 2013-02-05 | Biomerieux | Protein disulfide isomerase assay method for the in vitro diagnosis of colorectal cancer |
US8367362B2 (en) | 2007-07-19 | 2013-02-05 | Biomerieux | Aminoacylase 1 assay method for the in vitro diagnosis of colorectal cancer |
US8404643B2 (en) | 2005-12-22 | 2013-03-26 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
US8445211B2 (en) | 2007-07-19 | 2013-05-21 | Biomerieux | I-Plastin assay method for the in vitro diagnosis of colorectal cancer |
US8765909B2 (en) | 2006-10-25 | 2014-07-01 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
US8778871B2 (en) | 2004-06-25 | 2014-07-15 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
US9726670B2 (en) | 2007-07-19 | 2017-08-08 | Biomerieux | Method for the assay of liver fatty acid binding protein, ACE and CA 19-9 for the in vitro diagnosis of colorectal cancer |
US9891223B2 (en) | 2007-07-19 | 2018-02-13 | Biomerieux | Method of assaying leukocyte elastase inhibitor for the in vitro diagnosis of colorectal cancer |
US10591482B2 (en) | 2007-07-19 | 2020-03-17 | Biomerieux | Method of assaying Apolipoprotein AI for the in vitro diagnosis of colorectal cancer |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001019868A1 (en) * | 1999-09-15 | 2001-03-22 | Mogam Biotechnology Research Institute | A novel angiogenesis inhibitor |
-
2003
- 2003-02-20 KR KR1020030010797A patent/KR100595364B1/en not_active IP Right Cessation
-
2004
- 2004-02-20 WO PCT/KR2004/000357 patent/WO2004073730A1/en active IP Right Grant
- 2004-02-20 JP JP2006500650A patent/JP2006518342A/en not_active Withdrawn
- 2004-02-20 EP EP04713257A patent/EP1608395A4/en not_active Withdrawn
- 2004-02-20 BR BRPI0407611-7A patent/BRPI0407611A/en not_active IP Right Cessation
- 2004-02-20 CN CNB2004800048895A patent/CN100546646C/en not_active Expired - Fee Related
- 2004-02-20 CA CA002516172A patent/CA2516172A1/en not_active Abandoned
- 2004-02-20 AU AU2004212856A patent/AU2004212856B2/en not_active Ceased
- 2004-02-20 RU RU2005129273/15A patent/RU2306147C2/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001019868A1 (en) * | 1999-09-15 | 2001-03-22 | Mogam Biotechnology Research Institute | A novel angiogenesis inhibitor |
Non-Patent Citations (5)
Title |
---|
GABEL ET AL.: "Sequences within apolipoprotein(a) kringle IV types 6-8 bind directly to low-density lipoprotein and mediate noncovalent association of apolipoprotein(a) with apolipoprotein B-100", BIOCHEMISTRY, vol. 37, no. 21, May 1998 (1998-05-01), pages 7892 - 7898, XP002909839 * |
LOGRASSO ET AL.: "Cloning, expression and characterization of human apolipoprotein (a) Kringle IV37", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 269, no. 34, August 1994 (1994-08-01), pages 21820 - 21827, XP002909804 * |
SCANU ET AL.: "A single point mutation (Trp72=>Arg) in human apo(a) kringle 4-37 associated with a lysine binding defect in Lp(a)", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1227, October 1994 (1994-10-01), pages 41 - 45, XP001059171 * |
SCANU ET AL.: "Apolipoprotein (a):structural and functional consequences of mutations in kringle type 10 (or kringle 4-37)", CLINICAL GENETICS, vol. 46, July 1994 (1994-07-01), pages 42 - 45, XP001077063 * |
See also references of EP1608395A4 * |
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US7285277B2 (en) | 2002-03-15 | 2007-10-23 | Mogam Biotechnology Research Institute | Anticancer agent |
US8361968B2 (en) | 2002-12-26 | 2013-01-29 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
WO2005065720A1 (en) * | 2004-01-09 | 2005-07-21 | Mogam Biotechnology Research Institute | Therapeutic agent for treatment of cancer comprising human apolipoprotein (a) kringles lk68 or lk8 genes as effective ingredient, and method for treating cancer using the same |
US8778871B2 (en) | 2004-06-25 | 2014-07-15 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
US8404643B2 (en) | 2005-12-22 | 2013-03-26 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
US7960348B2 (en) | 2005-12-22 | 2011-06-14 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
US8765909B2 (en) | 2006-10-25 | 2014-07-01 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
WO2008075833A1 (en) | 2006-12-21 | 2008-06-26 | Mogam Biotechnology Research Institute | Fusion protein of immunoglobulin fc and human apolipoprotein(a) kringle fragment |
US8361731B2 (en) | 2007-07-19 | 2013-01-29 | Biomerieux | Ezrin assay method for the in vitro diagnosis of colorectal cancer |
US8735078B2 (en) | 2007-07-19 | 2014-05-27 | Biomerieux | Apolipoprotein AII assay method for the in vitro diagnosis of colorectal cancer |
US10591482B2 (en) | 2007-07-19 | 2020-03-17 | Biomerieux | Method of assaying Apolipoprotein AI for the in vitro diagnosis of colorectal cancer |
US9891223B2 (en) | 2007-07-19 | 2018-02-13 | Biomerieux | Method of assaying leukocyte elastase inhibitor for the in vitro diagnosis of colorectal cancer |
US8367362B2 (en) | 2007-07-19 | 2013-02-05 | Biomerieux | Aminoacylase 1 assay method for the in vitro diagnosis of colorectal cancer |
WO2009019370A3 (en) * | 2007-07-19 | 2009-04-09 | Biomerieux Sa | Apolipoprotein aii assay method for the in vitro diagnosis of colorectal cancer |
US8445211B2 (en) | 2007-07-19 | 2013-05-21 | Biomerieux | I-Plastin assay method for the in vitro diagnosis of colorectal cancer |
US9890196B2 (en) | 2007-07-19 | 2018-02-13 | Biomerieux | Ezrin assay method for the in vitro diagnosis of colorectal cancer |
WO2009019370A2 (en) * | 2007-07-19 | 2009-02-12 | bioMérieux | Apolipoprotein aii assay method for the in vitro diagnosis of colorectal cancer |
FR2919064A1 (en) * | 2007-07-19 | 2009-01-23 | Biomerieux Sa | METHOD OF ASSAYING APOLIPOPROTEIN ALL FOR IN VITRO DIAGNOSIS OF COLORECTAL CANCER |
US9726670B2 (en) | 2007-07-19 | 2017-08-08 | Biomerieux | Method for the assay of liver fatty acid binding protein, ACE and CA 19-9 for the in vitro diagnosis of colorectal cancer |
US9388404B2 (en) | 2008-07-10 | 2016-07-12 | Biomerieux | Protein disulfide isomerase assay method for the in vitro diagnosis of colorectal cancer |
US8367806B2 (en) | 2008-07-10 | 2013-02-05 | Biomerieux | Protein disulfide isomerase assay method for the in vitro diagnosis of colorectal cancer |
WO2012067427A3 (en) * | 2010-11-16 | 2012-09-13 | 재단법인 목암생명공학연구소 | Pharmaceutical composition containing lk8 protein as an active ingredient for preventing or treating diabetic retinopathy or age-related macular degeneration |
WO2012067427A2 (en) * | 2010-11-16 | 2012-05-24 | 재단법인 목암생명공학연구소 | Pharmaceutical composition containing lk8 protein as an active ingredient for preventing or treating diabetic retinopathy or age-related macular degeneration |
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KR100595364B1 (en) | 2006-07-03 |
CA2516172A1 (en) | 2004-09-02 |
BRPI0407611A (en) | 2006-02-14 |
JP2006518342A (en) | 2006-08-10 |
RU2005129273A (en) | 2006-03-10 |
KR20040075270A (en) | 2004-08-27 |
CN1753685A (en) | 2006-03-29 |
AU2004212856B2 (en) | 2007-07-19 |
RU2306147C2 (en) | 2007-09-20 |
EP1608395A4 (en) | 2007-10-31 |
AU2004212856A1 (en) | 2004-09-02 |
CN100546646C (en) | 2009-10-07 |
EP1608395A1 (en) | 2005-12-28 |
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